The nuts and bolts of multimodal anaesthesia in the 21st century: a primer for clinicians

Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96). Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16]. MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39]. Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR). From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96). Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16]. MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39]. Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR).From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.Purpose of reviewThis review article explores the application of multimodal anaesthesia in general anaesthesia, particularly in conjunction with locoregional anaesthesia, specifically focusing on the importance of EEG monitoring. We provide an evidence-based guide for implementing multimodal anaesthesia, encompassing drug combinations, dosages, and EEG monitoring techniques, to ensure reliable intraoperative anaesthesia while minimizing adverse effects and improving patient outcomes.Opioid-free and multimodal general anaesthesia have significantly reduced opioid addiction and chronic postoperative pain. However, the evidence supporting the effectiveness of these approaches is limited. This review attempts to integrate research from broader neuroscientific fields to generate new clinical hypotheses. It discusses the correlation between high-dose intraoperative opioids and increased postoperative opioid consumption and their impact on pain indices and readmission rates. Additionally, it explores the relationship between multimodal anaesthesia and pain processing models and investigates the potential effects of nonpharmacological interventions on preoperative anxiety and postoperative pain.The integration of EEG monitoring is crucial for guiding adequate multimodal anaesthesia and preventing excessive anaesthesia dosing. Furthermore, the review investigates the impact of combining regional and opioid-sparing general anaesthesia on perioperative EEG readings and anaesthetic depth. The findings have significant implications for clinical practice in optimizing multimodal anaesthesia techniques (Supplementary Digital Content 1: Video Abstract, http://links.lww.com/COAN/A96).Papers of particular interest, published within the annual period of review, have been highlighted as:Anaesthesiologists are crucial in providing effective intraoperative anaesthesia and minimizing pain, delirium, and postoperative nausea and vomiting (PONV). With the opioid epidemic posing a significant threat, approaches like the opioid-free anaesthesia (OFA) [1] and multimodal general anaesthesia (MMA) [2] are gaining traction. These strategies aim to prevent opioid addiction and chronic postoperative pain, aligning with the goals of the Enhanced Recovery After Surgery (ERAS) protocols [3,4,5,6]. Thus, anaesthesiologists increasingly focus on preoperative, intraoperative, and postoperative analgesia to address factors contributing to chronic postoperative pain.High-dose intraoperative opioid administration has been reported to possibly lead to increased postoperative opioid requirements, a phenomenon known as 'opioids engender opioids' [7,8]. This review seeks to provide an evidence-based and practical guide to MMA. It will explore drug combinations and recommended dosages and illustrate the typical EEG changes associated with MMA. Additionally, the review will examine the relationship between MMA and current consciousness and pain processing models. Nonpharmacological interventions targeting preoperative anxiety and postoperative pain will be discussed. Deep states of general anaesthesia should be avoided to reduce overdose with possible hemodynamic and cognitive side effects such as postoperative delirium (POD), PONV, and delayed neurocognitive recovery (DNR). From a neurophysiological perspective, pain is no longer viewed solely as a bottom-up process. Emerging theories propose that consciousness actively generates hypotheses and predictions through predictive coding. These predictions interact with inputs related to maintaining internal balance, primarily controlled by the autonomic nervous system, brainstem, and subcortical affective circuits [9]. Disruptions to homeostasis trigger allostatic reactions to restore balance, leading to pain perception [10]. Preoperative anxiety and anticipation of pain can heighten postoperative pain levels and increase the need for opioids [11]. Recognizing the possibly predictive nature of consciousness underscores the importance of preemptive analgesia in MMA [12]. The interplay between the interoceptive system and nociceptive signals helps explain how inflammatory mediators and stress hormones influence the brain's interpretation of pain. Additionally, understanding the placebo effect and its modulation of pain expectations through empathetic communication aligns with the principles of MMA [13,14] (Supplemental Digital Content 2, http://links.lww.com/COAN/A97). no caption availableThe field of anaesthesia originates from using chemicals like ether and nitrous oxide to induce hypnosis, analgesia, and muscle relaxation [15]. Balanced anaesthesia, which combines hypnotic drugs and potent analgesics, was developed to optimize surgical outcomes. However, even classic balanced anaesthetic combinations, such as propofol + opioids or volatile anaesthetics + opioids, can sometimes lead to adverse effects such as PONV, worse pain control, impaired awakening, respiratory complications, and POD [15]. With the emergent opioid epidemic claiming numerous lives each year, there is a need for safer and more effective anaesthesia and analgesia approaches [16].MMA, defined as combining anaesthetics and analgesics with different mechanisms of action [17], aims to provide additive or synergistic pain relief while minimizing side effects associated with higher opioid doses [18]. Surgeons also support using MMA, combining general anaesthesia with regional or local anaesthesia techniques, to improve outcomes [19-21]. They actively contribute to postoperative MMA by employing techniques such as local infiltration or inserting surgical site catheters [2,22-24]. The concept of 'opioid stewardship' is promoted by the ERAS Society, advocating for a critical evaluation of the opioid administration [25,26].The prevalence of opioid-based anaesthesia, its synergies with inhaled or propofol anaesthesia [27], and the lack of patient follow-up can contribute to uncertainty and resistance towards MMA. However, it has been observed that high doses of intraoperative opioids can result in increased postoperative opioid requirements and vice versa [28,29,30,31]. In a meta-analysis conducted in 2019, the level of postoperative pain 2 h after major abdominal and gynaecological surgery was found to be similar between opioid-free and opioid-inclusive anaesthesia, but the incidence of PONV was significantly higher in patients treated with opioids [32]. Despite a medical history of PONV, practitioners tend to administer propofol anaesthesia without restricting intraoperative opioids [33]. Hyperalgesia induced by opioids, even in healthy individuals without surgery, is still not widely recognized as a problem [34]. Short-acting opioids, such as remifentanil, can cause an increased incidence of postoperative hyperalgesia, while long-acting opioids can lead to long-lasting pain reduction [35]. N-methyl-D-aspartate (NMDA) receptors play a significant role in suppressing hyperalgesia [36], which highlights the importance of using NMDA antagonists like methadone, along with magnesium and ketamine, in modern analgesia. Recent studies have shed light on the neuroinflammatory pathophysiology of opioid-induced mast cell-mediated microglia activation and 'immunosenescence' [37], contributing to the chronification of pain, particularly in older patients [38,39].Postoperatively, there is often a heavy reliance on opioid administration, which might exacerbate adverse events. For instance, the Prodigy study [39] revealed that opioid-induced respiratory depression is frequently underdiagnosed in hospital wards, leading to code-red calls. The association between opioids administered in oncologic surgery and poorer outcomes remains controversial and requires further clarification [40,41,42]. Figure 1 demonstrates how the abovementioned predisposing factors and intraoperative strategies might influence negative postoperative outcomes.The interplay of preoperative risk factors and postoperative pain. A simplified chart illustrating the connection between postoperative pain, preoperative anxiety, and other risk factors like sleep disorders or smoking. Risk factors influence and intensify each other, are potentiated by certain intraoperative actions, influencing pain and its chronification, sleep patterns, and cognitive recovery, in a vicious cycle.Intraoperative opioids can offer advantages beyond analgesia, particularly in brain and eye surgeries, effectively reducing brainstem reflexes such as coughing, gagging, and pressing. In cases where large wounds or bone trauma are not adequately covered by regional anaesthesia, administering opioids, along with ketamine, becomes imperative. Knowledge of the specific noxious surgical steps involved in a procedure enables the titration of analgesic boluses and the overall reduction of opioid infusion.Opioids can induce changes in the perioperative EEG [43,44], often having a synergistic effect to increase or stabilize hypnotic effect. These changes can include the loss or retention [44,45] of alpha waves (8-12 Hz) or an increase in delta power (0.5-4 Hz). These alterations can be observed in the raw EEG [46]. The spectrogram can sometimes show an increase in theta power. When analgesia is provided by a combination of ketamine and magnesium with propofol, opioid partial NMDA receptor agonists such as remifentanil and methadone can increase beta power in the EEG [47], and commercial indices can falsely indicate a lighter level of hypnotic depth.