Gastroparesis: time for a paradigm change

Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29. 3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy. Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g. , resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm. Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder. Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g. , fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis. Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g. , gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom. Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system. It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder. Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g. , fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis. Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g. , gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom. Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system. It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder. Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g. , fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis. Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g. , gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom. Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system. It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder. Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g. , fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis. Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g. , gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom. Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system. It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder. Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g., fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.Purpose of reviewGastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm.An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted.Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.Papers of particular interest, published within the annual period of review, have been highlighted as:Gastroparesis (GP) is currently defined by three key components: the absence of mechanical obstruction, symptoms suggestive of retained food in the stomach, and objective evidence of delayed gastric emptying [1]. Upon first inspection, this three-part definition seems simple and logical. For example, absence of mechanical obstruction can be confirmed by performing upper endoscopy; if endoscopy is not readily available, then a carefully executed upper gastrointestinal series with or without small bowel follow through is a reasonable alternative [2,3]. However, the other two components are inherently more complicated, resulting in controversy and confusion during the evaluation of patients with suspected GP. By definition patients should report symptoms suggestive of delayed stomach emptying. Nevertheless, the classic symptoms of GP (nausea, vomiting, early satiety, abdominal pain; see Table 1) are nonspecific and frequently reported by patients with motility disorders and other disorders of the upper gastrointestinal tract (e.g., functional dyspepsia, celiac artery compression syndrome, superior mesenteric artery syndrome, cannabis hyperemesis syndrome) [4-6,7,8]. Secondly, while an objective delay in gastric emptying is theoretically confirmed easily with current technology, evidence suggests that gastric emptying tests are frequently done incorrectly and contribute to misdiagnosis. These aforementioned challenges highlight a longstanding need to reconsider how the field thinks about the diagnosis and treatment of GP. This need is reinforced by the simple fact that no new class of medication has been approved for the treatment of GP in the US since the approval of metoclopramide in 1979. In the sections that follow, we hope to challenge clinicians and researchers to rethink the current diagnostic and treatment paradigm pertaining to GP by highlighting novel research findings. no caption availableSymptoms of gastroparesis and gastroparesis mimicsCHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; FD, functional dyspepsia; GP, gastroparesis; MALS, median arcuate ligament syndrome; SMAS, superior mesenteric artery syndrome.Vomiting may be present in patients with FD but is usually not the predominant symptom.Effective patient care is predicated on an evidence-based approach that utilizes data obtained from clinical trials. Multiple medications have been evaluated in randomized, controlled studies for the treatment of GP. Unfortunately, none have proved uniformly effective, and no new class of medication has been approved by the Food and Drug Administration (FDA) for the treatment of GP since 1979. To highlight major design flaws in GP clinical trials over the past four decades, we pose several questions. First, did study subjects truly have GP? Many studies performed in the 1980s and 1990s used imprecise inclusion criteria that resulted in enrollment of subjects with functional dyspepsia (FD) rather than GP [9]. Furthermore, gastric emptying scans were frequently performed incorrectly [10]. Second, were study populations too heterogenous? Many GP clinical trials included patients with postsurgical GP, a pathophysiologically different disorder than diabetic or idiopathic GP. This distinction warrants separate evaluation in clinical trials. Third, were sample sizes adequate? Many studies have been woefully underpowered and progress in the field will only be made when clinical trials enroll hundreds of patients, not tens of patients. Fourth, were study designs appropriate? Variation in study design, including criteria used to diagnose GP, presence of symptoms as criteria for inclusion, the use of a placebo run-in phase, amongst other issues, all challenge the final study endpoint regarding medication efficacy. Fifth, were study durations appropriate? While many clinical trials were performed for four weeks or less, evidence supports a minimum study duration of eight weeks [9]. Sixth, did the mechanism of action make sense? Over the past 40 years, the emphasis has been on accelerating gastric emptying to improve GP symptoms. However, when tested, multiple prokinetic agents have failed to improve global GP symptoms (e.g., mitemcinal, carmincial, relamorelin). Lastly, were primary endpoints correct? Despite using objective changes in gastric emptying as the standard primary endpoint for years, evidence from multiple studies demonstrates that accelerating gastric emptying may not improve global symptoms of GP. The FDA no longer recommends using changes in gastric emptying as an endpoint; rather, symptom improvement (e.g., nausea and vomiting) should be the focus of clinical trials.A growing collection of evidence supports the existence of a significant placebo response among participants in clinical trials for GP and other disorders of gut-brain interaction (DGBI) [11-13]. Especially important for evaluating new interventions, a comprehensive understanding of the placebo response enables accurate assessment of therapeutic gain and informs drug development processes. With downstream impacts on patient treatment and quality of life, it is imperative that placebo response be considered in randomized controlled trials (RCTs) involving GP patients and in subsequent deployment of therapeutic agents in clinical practice. Aggregating results from 23 RCTs involving 1011 patients with GP, a recent systematic review and meta-analysis revealed a pooled placebo response rate of 29.3% [95% confidence interval (CI), 23.7-35.2%] (Fig. 1) [9]. Several factors were associated with placebo response rates in GP trials, including GP etiology, use of validated questionnaires for symptom evaluation, duration of treatment, drug:placebo randomization ratio, dosing schedule, and use of confirmed GP diagnosis for trial inclusion (see Table 2). Treatment with placebo also resulted in reported adverse events (AEs) among a significant portion (33.8%) of trial participants (95% CI, 26.4-41.8%). Adverse effects were associated with diabetic GP etiology, lack of criteria confirming delayed gastric emptying prior to trial inclusion, RCT >= 9 weeks duration, once or twice daily dosing, and 1 : 1 active drug to placebo randomization. Despite substantial heterogeneity in results reported by GP RCTs to date, the existence of significant placebo response and AE rates should inspire recommendations for strict RCT criteria involving a trial duration greater or equal to eight weeks, separation of GP etiological subtypes, confirmed delay in gastric emptying using a standardized GES protocol, and the use of validated questionnaires to assess symptoms.Pooled placebo response rates among prior randomized controlled trials (RCTs) for GP. GP, gastroparesis.Analysis of placebo response and adverse events in gastroparesis studies based on etiology, type of gastric emptying test, use of validated questionnaires, year study was completed, length of study, dosing regimen and randomization ratiob.i.d., twice daily; GE, gastric emptying; GP, gastroparesis; o.d., once daily; q.i.d., four times daily; Sx, symptoms; t.i.d., three times daily.Gastric emptying scintigraphy (GES) is recognized as the "gold standard" diagnostic method for confirming delayed gastric emptying and establishing a diagnosis of GP [14]. In 2008, the American Neurogastroenterology and Motility Society published a joint report with the Society of Nuclear Medicine outlining consensus recommendations for the performance of GES [15]. According to these guidelines, correct performance of GES involves a specific protocol related to patient history-taking and preparation, meal preparation, and image acquisition. Several key quality indicators characterize a proper GES, including conducting a full 4-h scan, withholding pain medications (opiates) and other medications that influence gastric emptying rate (such as prokinetic and anticholinergic agents), and ensuring that blood glucose levels are controlled at the time of testing. Though historically debated in the literature, recent evidence further supports the use of a 4-h GES, as alternative endpoints (e.g., 90 min, 2 h, t1/2 time) may reduce the diagnostic accuracy of GP [16]. Despite the existence of published consensus guidelines for performing GES, evidence suggests that GES is frequently performed incorrectly, with medical institutions performing an average of only 64% of GES protocol measures according to guidelines [10]. Furthermore, less than 5% of institutions reported performing all four key quality indicators according to guidelines (Fig. 2). Although compliance with guidelines seems to be poor, performing GES correctly is integral to the accurate diagnosis and optimal treatment of GP patients, especially given the significant overlap in symptoms with other DGBI, such as FD.Percentage of medical institutions complying with recommended guidelines for key quality indicators of gastric emptying scintigraphy.Defined by an objective delay in gastric emptying, GP has fundamentally been considered a disorder of gastrointestinal motility. However, consideration of GP as solely a motility disorder would seem to limit the potential to better understand and treat this historically vexing disorder, particularly as our understanding of GP has evolved in recent years. For one, clinicians who have treated patients with GP understand the simple, unfortunate truth that not all patients experience improvement in symptoms with prokinetic treatment, such as metoclopramide. Indeed, studies have historically shown that accelerating gastric emptying does not lead to global improvement in GP symptoms [8]. Furthermore, prior studies have consistently noted that the degree of gastric emptying does not correlate with the severity of symptoms [17,18]. However, it should be noted that a more recent meta-analysis demonstrated that, when optimally measured, delayed gastric emptying correlates with symptoms of nausea, vomiting, abdominal pain, and early satiety [19]. Additionally, the same group demonstrated that prokinetic agents significantly reduced upper GI symptoms in patients with GP and functional dyspepsia (FD), as well as significantly improved gastric emptying, among patients with optimally measured gastric emptying [20]. Such data further emphasize the importance of accurately measuring gastric emptying in the assessment of GP (see above).While prokinetic therapies may improve nausea and vomiting in some patients with GP, there are practical limitations to many of the treatment options commonly considered, including metoclopramide (potential for neurologic adverse effects, namely tardive dyskinesia), domperidone (unavailable in the United States), erythromycin (tachyphylaxis), and prucalopride (currently only approved for treatment of chronic idiopathic constipation). Further, it should be emphasized that prokinetic therapies do not improve pain, a symptom present in 90% of patients with GP and a predominant symptom in 1 in 5 GP patients [21]. The truth is that GP is a heterogeneous disorder and the premise that all symptoms are the result of delayed stomach emptying is becoming increasingly outdated and misrepresents the complexity of the disorder.Experts in the field have long highlighted the significant overlap between FD and GP, as the symptoms of the two disorders can be indistinguishable and share some of the same pathophysiologic mechanisms (i.e., mildly delayed gastric emptying can be present in approximately 30% of patients with FD) [5,22,23]. Recently, a landmark study by the Gastroparesis Consortium involving 944 patients (720 of whom had GP) demonstrated that 42% of patients with GP were found to have normal gastric emptying at the conclusion of the 48-week study and 37% of patients with normal gastric emptying transitioned to a diagnosis of GP [7]. Given the significant percentage of patients with GP who transitioned to a diagnosis of FD, the authors suggested that GP and FD should be considered as part of the same spectrum of gastric sensorimotor dysfunction. Though this landmark study was not without limitations, the results suggest that advancement in our understanding of GP may very well be aided by recognizing the importance of the gut-brain interaction dynamic, akin to FD, in addition to delayed gastric emptying (see Fig. 3). Recent aforementioned evidence describing the significant placebo response rate in RCTs involving patients with GP, similar to other DGBI like FD, further supports this sentiment.Pathophysiology of gastroparesis. This slide illustrates the multiple pathophysiologic processes that can lead to symptoms of gastroparesis. Importantly, learned behaviors, changes in sensory function, and abnormalities in CNS processing likely play an important role in symptom generation. CNS, central nervous system.It is important to recognize that GP is a relatively uncommon disorder, particularly when compared to FD which has an estimated prevalence of approximately 12% in the United States [24]. A recent systemic review of 13 epidemiologic studies of patients with GP involving primarily U.S. databases or registries identified a prevalence ranging from 13.8-267.7 per 100 000 adults [25]. Thus, it is important for clinicians to consider a number of organic disorders (e.g., gastroesophageal reflux disease, peptic ulcer disease, median arcuate ligament syndrome, superior mesenteric artery syndrome, etc.) and disorders of gut-brain interaction (FD, chronic nausea with vomiting syndrome, cyclic vomiting syndrome, rumination syndrome), in addition to GP, when evaluating patients with upper gastrointestinal symptoms, such as nausea and vomiting.Our group recently conducted a retrospective study assessing the misdiagnosis of GP among patients referred to a single tertiary gastroenterology practice which yielded striking results. Among 339 patients referred for further evaluation due to symptoms thought to represent GP, we found that only 19.5% were ultimately confirmed to have GP, whereas 80.5% received alternative diagnoses - the most common being FD (44.5%) [26]. Notably, patients correctly diagnosed with GP were more often diabetic, had undergone abdominal surgery (e.g. , fundoplication, cholecystectomy, appendectomy) and had retained food contents on upper endoscopy, whereas patients with alternative diagnoses were significantly younger and had significantly lower median body mass indexes.It is important to emphasize that only 57.8% of the study cohort had definitively been evaluated with a GES prior to tertiary evaluation, despite being diagnosed with gastroparesis by their referring provider. Moreover, only 23 patients (6.8%) were known to have undergone a 4-h GES using a correct test meal of radiolabeled eggs. This finding supports data demonstrating poor compliance among U.S. medical centers with adherence to standardized GES protocols [10]. We propose that not performing a proper GES in the evaluation of GP frequently leads to misdiagnosis, specifically overdiagnosis of GP, in clinical practice today.The pylorus plays an essential role in the emptying of gastric contents. Antroduodenal dyscoordination and abnormalities of both pyloric tone and pressure (e.g., "pylorospasm") may impair gastric emptying in some patients, potentially leading to symptom generation [1,6,27,28]. Accurately measuring pyloric function (e.g., resting tone, phasic pressures, relaxation) is difficult and many pylorus-targeted therapies are thus performed empirically. For example, botulinum toxin injection of the pylorus was quickly adopted after early studies showed that the procedure was safe and improved GP symptoms in diabetic patients [29]. Unfortunately, while initial case reports and small uncontrolled studies appeared promising, larger placebo-controlled studies demonstrated that botulinum toxin of the pylorus benefited few patients [30]. The success of peroral endoscopic myotomy (POEM) to treat achalasia later led investigators to evaluate the role of endoscopic pyloromyotomy (G-POEM) for the treatment of GP, with two prospective studies worth mentioning. Gregor et al. performed G-POEM in 52 patients (88% female; diabetes, idiopathic, postsurgical) who had failed medical therapy for their GP symptoms [31]. Patients were surveyed using several validated questionnaires at baseline and 1, 3, 6, 12 and 24 months after G-POEM. Using a responder definition of a one-point improvement in the gastroparesis cardinal symptom index score, 58% and 48% of patients were classified as responders at the 6- and 12-month follow-up mark, respectively. Clinical response rates did not differ by etiology. Mean gastric emptying improved at 6 months (10% retention) compared to baseline (36% retention). A second study [32] involved a prospective, sham-controlled, cross-over design of 41 patients with diabetic, idiopathic, and postsurgical GP (median age = 46 years; 17 diabetic, 11 idiopathic). The authors reported that symptoms and gastric emptying improved at 6 months follow-up in the G-POEM group, and that those randomized to sham pyloromyotomy who had persistent symptoms reported improvement after being treated with G-POEM. The small sample size precluded subgroup analysis. These two studies present evidence that G-POEM may improve GP symptoms in some patients, although identifying the proper patient population, and performing larger sham-controlled trials is critical before recommending this therapy as standard of care.Our understanding of GP has evolved in the past 5 years, led in part by some of the studies highlighted in this review. Such advances are long overdue for a complex disorder with only one FDA-approved treatment (metoclopramide) and no new approved therapeutic interventions in over 40 years. A paradigm shift is needed and this review highlights work which will hopefully help to re-shape the way in which we view GP and ultimately inspire new treatments which are sorely needed.One of the most impactful viewpoints challenging the current GP paradigm suggests that GP is as much a disorder of gut-brain interaction as it is a disorder defined by delayed gastric emptying. The overlap between GP and FD has long been championed by some experts in the field, and now the landmark study conducted by the Gastroparesis Consortium adds convincing weight to this argument. Additionally, recent data describing the significant placebo effect in GP trials, similar to that seen in trials involving patients with DGBIs, further supports this view. Approaching GP as a DGBI has the potential to greatly expand the list of treatment options worthy of further investigation, including virtual reality and brain-gut behavioral therapies such as cognitive behavioral therapy and hypnotherapy, thereby shifting the current treatment paradigm.Furthermore, recent data suggests that GP is frequently misdiagnosed in the community, and one of the primary reasons for this is the general lack of adherence to standardized GES protocols. Therefore, we emphasize the importance of performing a proper, standardized GES in the evaluation of suspected GP, as well as the importance of recognizing alternative diagnoses, particularly FD, in the evaluation of bothersome upper GI symptoms. Finally, the use of G-POEM as an effective, durable, and safe treatment for select patients with GP is gaining support in clinical trials. However, important questions remain, particularly related to characterizing the ideal GP patient to be considered for G-POEM. There is hope that assessment of pyloric dynamics by endoluminal functional lumen imaging probe (EndoFLIP) may assist in identifying GP patients most suitable for G-POEM, and may be a part of future assessment, much like GES. Overall, recent advances highlighted in this review have expanded our understanding of GP and would seem to support a future of more personalized treatment approaches for GP, beyond prokinetic therapies, in which some patients are treated with gut-brain directed therapies and others are directed toward pyloric interventions.None.