A Strategy for Conversion From Subcutaneous to Oral Ketamine in Cancer Pain Patients: Effect of a 1:1 Ratio

Methods Patients with opioid poorly responsive cancer pain, who responded to 0.4, 0.6, or 0.8 mg s.c. ketamine bolus, were treated with 0.1, 0.15, or 0.2 mg/kg/h ketamine infusion, respectively. Switching to the oral route, by applying a 1:1 dose ratio, was carried out in patients who experienced adequate pain relief and continued to need ketamine as a coanalgesic. Pain, somnolence, feelings of insobriety, confusion, and cardiovascular parameters were assessed throughout the process. Results Twenty-nine patients were enrolled in the study. Ketamine infusion decreased pain intensity from severe to no pain or slight pain in 23 of 29 and six of 29 patients, respectively. The median of s.c. ketamine doses was 0.2 mg/kg/h (range 0.1–0.5). After oral switching, 27 of 29 patients remained as successfully controlled as when receiving s.c. ketamine. The other two patients needed a slight dose ratio readjustment, to 1:1.3 and 1:1.5, to maintain pain control. The median of oral ketamine doses was 300 mg/day (interquartile range 240–382.5). Seven of 29 patients receiving s.c. ketamine developed moderate and transitory side effects, such as feelings of insobriety and somnolence. No side effects were present while receiving oral ketamine. No significant changes were observed in cardiovascular parameters. Conclusion A 1:1 dose ratio for conversion from s.c. to oral ketamine is safe and effective in cancer pain patients. Key Words Subcutaneous ketamine oral ketamine dose ratio cancer pain Introduction Most cancer pain patients obtain suitable analgesia from opioids during most of the course of their disease. However, sometimes, certain factors, such as opioid tolerance and dose-limiting adverse effects and the occurrence of new pain mechanisms because of progression of the disease, can contribute to inadequate pain control. At this stage, the use of alternative analgesic strategies, such as opioid rotation or the use of adjuvant analgesics, have proved to be of great value. 1,2 In palliative care practice, ketamine has been administered as a coanalgesic in addition to opioids and coadjuvant drugs. Ketamine is now considered to be an essential adjuvant analgesic for refractory cancer pain, and it is on the World Health Organization’s Essential Drugs List for patients who no longer respond to high doses of opioids or have predictable breakthrough pains. 3 Although it has been administered predominantly by subcutaneous (s.c.) infusion, ketamine taken orally has obvious advantages: it is not necessary to carry a pump around, which needs frequent refilling, and it avoids s.c. inflammation at the site of injection. As yet, there is no clear picture about the more appropriate dose ratio for the parenteral to oral transition of ketamine. Certain clinical guidelines suggest that the s.c. to oral ketamine dose ratio is uncertain although probably equianalgesic. 4,5 Based on a retrospective comparison of four cases, we suggested that the s.c./oral ketamine equianalgesic ratio is, in terms of daily dose, roughly 1:1. 6 The aim of this study was to confirm and extend, in a series of 29 cancer patients, our previous observation that a 1:1 dose ratio is safe and effective to switch ketamine from parenteral to oral administration. Methods We evaluated the effect of using a 1:1 s.c./oral ketamine dose ratio in a cohort of cancer patients enrolled in a protocol of ketamine for treatment of uncontrolled pain (intensity ≥ 7/10) with neuropathic characteristics. The criterion for using ketamine was the inefficacy of a quick escalation in opioid doses, with one or two associated coanalgesics, in the presence of no contraindications for using it. A quick escalation was defined as an increase of three or more doses, for one or two weeks, reaching oral morphine equivalent doses of more than 400 or 800 mg/day or, in the specific case of methadone, 150 and 250 mg/day, respectively. For the purpose of this study, we have only used data from patients who fulfilled the following criteria for switching ketamine to the oral route: 1) pain under control with s.c. stable doses of ketamine for 48 hours, 2) patients who wanted to be discharged while continuing to need ketamine as a coanalgesic, 3) life expectancy longer than two weeks, and 4) availability of an enteral route (oral or tube feeding). Pain was considered to be successfully controlled when patients reported a pain level ≤3/10 for at least two consecutive days and the use of no or one opioid rescue dose per 24 hours. Patients receiving anticancer treatment (radiotherapy, chemotherapy, or both) for at least two weeks before switching, and those with a Karnofsky performance index <40%, were excluded from the study because of difficulties in evaluating the response to ketamine by different routes. Ketamine Treatment Protocol Testing Ketamine Responsiveness and Choosing a Continuous S.C. Ketamine Dosage First, we administer one s.c. dose of 0.4 mg/kg ketamine with s.c. midazolam 2.5 mg to avoid side effects. We assess the analgesic effect, 30–45 minutes later, using a 0–10 numerical rating scale (0 = no pain; 10 = the worst), and then we proceed as follows: 1. If pain decreases, at least, up to ≤3/10, we start an s.c. infusion of 0.1 mg/kg/h ketamine; 2. If pain decreases to 4–6/10, we inject a new s.c. ketamine dose of 0.2 mg/kg (0.6 mg/kg in total). We reassess patient response as above and 2.1. if pain declines below 4/10, we start an s.c. ketamine infusion at 0.15 mg/kg/h and 2.2. if the pain level does not change, we start a ketamine perfusion at 0.2 mg/kg/h. 3. If pain improvement does not exist, we repeat the administration of 0.4 mg/kg ketamine (0.8 mg/kg in total). Afterward, if the pain level is rated as ≤3/10 or 4–6/10, we start ketamine perfusion at 0.2 mg/kg/h or 0.3 mg/kg/h, respectively. In the case of no pain relief after the second ketamine testing dose, in exceptional cases we consider using higher ketamine doses (i.e., 0.4–0.5 mg/kg/h) or other analgesic approaches. A ketamine test is not performed in patients suffering from discontinuous pain (i.e., lancinating pain), and s.c. ketamine infusion is started at 0.1 mg/kg/h. Daily Titration of Continuous S.C. Ketamine Infusion To get the best possible pain control, the daily s.c. ketamine dose is titrated upward or downward every 24 hours, by 0.05–0.1 mg/kg/h, depending on clinical criteria and patient satisfaction with pain improvement and side effects. The protocol we follow in this step is to change daily opioid doses in the event of the presence of severe somnolence or other opioid side effects. Patients receive 5 mg oral diazepam daily to avoid ketamine side effects. Adjuvant drugs normally used for symptom control (e.g., corticosteroids, laxatives, and so on) are continued at the same dose. Coanalgesics (i.e., gabapentin, antidepressants, etc.) are progressively withdrawn. Switching to Oral Ketamine Patients fulfilling the above-mentioned criteria are switched to the oral route. A 1:1 s.c./oral dose ratio is applied to every patient. Daily s.c. ketamine dose is divided in thirds and administered orally every eight hours, using Ketolar ® (Pfizer Ireland Pharmaceuticals, Dublin, Ireland) mixed with fruit juice. The first oral ketamine dose is given four to eight hours after s.c. treatment is stopped (Day 0). Afterward, oral ketamine is titrated daily from Day 2 in an amount equivalent to 0.05–0.1 mg/kg/h, depending on clinical criteria and patient satisfaction with pain relief and side effects. Diazepam is discontinued after switching to the oral route. Patients undergo clinical assessment, including monitoring of blood pressure, heart rate, and respiratory rate every six to eight hours, by one or more of the full-time Palliative Care Unit physicians and attending palliative nurses throughout the ketamine treatment. Written informed consent for using ketamine is obtained from all the patients. We also ask permission of the Ministry of Health for unlicensed use of oral ketamine for every patient. Data Collection and Statistical Analysis The following data were collected for each patient: age, gender, primary tumor site, Karnofsky index, type of pain and its intensity, opioid and ketamine doses, ketamine side effects, and time of exposure to s.c. ketamine. Type of pain was determined on the basis of clinical evaluation and categorized as neuropathic, mixed (nociceptive plus neuropathic), or ischemic, using the Edmonton Staging System. Opioid doses were expressed as daily equivalent oral morphine doses. Pain, somnolence, and insobriety scores, obtained before and after switching to oral ketamine, were recorded using a 0–10 numerical rating scale (0 = absent symptom; 10 = the worst). For clinical decision-making purposes, the scores were considered as being of slight (1–3 of 10), moderate (4–6 of 10), and severe (≥7 of 10) intensity. Confusion was assessed by the Mini-Mental State Examination and codified using a categorical scale (yes/no) by applying a cutoff of 24/30 points. After switching to the oral route, patients were evaluated for a minimum of five days. This period was considered sufficient for evaluating the efficacy of route switching. Afterward, patients were attended to according to the physician’s usual clinical practice. The Friedman test, followed by a Dunn multiple comparison test, was used to compare pain intensity before and after ketamine treatment. Results We enrolled 29 patients who were receiving s.c. ketamine and fulfilled the criteria for switching to the oral route. Table 1 summarizes the most relevant characteristics of these patients. As shown in Fig. 1 , pain intensity decreased, after s.c. ketamine treatment, from severe to no pain or to slight pain in 23 of 29 and six of 29 patients, respectively. Table 2 summarizes the different s.c. ketamine doses that were useful to control pain. The median s.c. ketamine dose was 0.2 mg/kg/h (range 0.1–0.5) or, in other terms, 300 mg/day (range 120–750). The median length of s.c. ketamine treatment was five days (interquartile range [IQR] 3 to 9.5 days). After switching, using a 1:1 s.c./oral dose ratio, 27 of 29 patients remained as successfully controlled at Day 2 as when receiving s.c. ketamine ( Fig. 1 ). The oral ketamine dose needed to be increased to a dose ratio higher than 1:1 (specifically to 1:1.3 and 1:1.5) to improve pain control in only 7% (two of 29) of the patients ( Fig. 1 and Table 3 ). Both patients were on methadone and on s.c. ketamine for seven and 12 days before switching. Fig. 2 shows the distribution of oral ketamine doses at Day 5 after switching. The median of oral ketamine doses was 300 mg/day (IQR 240–382.5 mg/day). Table 4 summarizes the side effects observed throughout the use of s.c. and oral ketamine. Seven of 29 patients receiving s.c. ketamine developed moderate side effects: two, feelings of insobriety; three, insobriety plus somnolence; one, somnolence; and one, hallucinations. These effects were present in most of the patients receiving ketamine doses ≥0.25 mg/kg/h (or ≥400 mg/day). All the above side effects were adequately tolerated by patients and were transitory, making it unnecessary to stop the ketamine treatment. Indeed, it is worth pointing out that they were absent during oral ketamine administration ( Table 4 ). No significant changes were observed in cardiovascular parameters. The median oral equivalent morphine dose for the whole sample before starting s.c. ketamine was 750 mg/day (range 430–3250 mg/day). Opioid doses were not changed while ketamine was being used. Discussion The effect of a strategy for converting s.c. ketamine to oral ketamine in 29 patients suffering from opioid poorly responsive cancer pain was analyzed in the present study. All our patients were selected from those who responded to s.c. ketamine and met the criteria for switching to the oral route. Our data show that a 1:1 s.c./oral ketamine conversion ratio was both safe and effective in 93% (27/29) of the patients. Although increasingly used for pain management, there is no agreement on a single best ketamine protocol or dose for treating refractory cancer pain. Some practitioners use a parenteral approach, by the intravenous or the s.c. route, 7–12 whereas others prefer oral delivery. 13,14 Some authors start directly with a continuous intravenous infusion, with others following a loading dose or titration schedule. 7,10,11,15 As yet, no specific guidelines have been published for converting parenteral to oral ketamine. Because of the pharmacokinetic and pharmacodynamic peculiarities of oral ketamine, it is a difficult task to propose a dose ratio for the successful conversion from s.c. to oral ketamine. Thus, the bioavailability of oral ketamine has been reported to be between 15% and 23%. 16,17 Oral ketamine is rapidly metabolized to norketamine, 18 which has been suggested as contributing to the analgesic effect of oral ketamine. 19–22 The analgesic effect of ketamine and norketamine has been attributed to the blockade of the N -methyl- d -aspartate (NMDA) receptor, but animal studies have shown that norketamine has a twofold to fourfold lesser affinity for the NMDA receptor than ketamine. 19 Finally, it has been suggested that NMDA receptor-independent mechanisms play a role in ketamine analgesic effects, especially in chronic pain. 23 Taken together, the above data do not provide a clear picture about the most suitable conversion ratio when switching from s.c. to oral ketamine. In our protocol, we started by testing pain response to s.c. ketamine boluses of 0.4–0.8 mg/kg. After achieving prespecified levels of pain relief, and depending on the total ketamine testing dose at which this outcome was obtained, we started an infusion at doses of between 0.1 and 0.3 mg/kg/h. Afterward, the infusion dose was finely adjusted, when needed, to get closer to the best pain control. Both the ketamine boluses and infusion rates are in the range that is most commonly used. 11,23,24 We consider the above parenteral titration an essential approach for pain control before using oral ketamine. Therefore, we agree with the conclusion of Hocking and Cousins 23 in their systematic review that a good therapeutic response to parenteral administration of ketamine suggests a greater likelihood of benefit from oral dosing. Regarding s.c./oral ketamine switching, the only available data, proceeding from a few patients, show a wide variability of dose ratios, which have ranged from 1:0.3 to 1:8.5. 25 Our data do not agree with these figures, and, in fact, we obtained a remarkable effectiveness in 27 of 29 patients when we substituted s.c. with oral ketamine using the 1:1 dose ratio. The other two patients, who had a slight worsening of their pain by Day 2, were controlled by a slight dose readjustment. We think that there is not a unique and simple explanation of our data. First, it can be argued that the s.c. ketamine had caused an initial “wind down” of hyperalgesia and, consequently, pain relief that continued well beyond the treatment period in most of the patients. This effect may be related to ketamine desensitization of central NMDA receptors and, perhaps, also to a resetting of glutamatergic brain circuits involved in pain transmission. 26 Reminiscent of that phenomenon is the persistent analgesic effect reported in 60%–70% of the patients when using a short “burst” of ketamine as the treatment for refractory pain. 12,27 Nevertheless, it is difficult to assume that a sustained antihyperalgesic effect of the s.c. treatment was present in all of our patients, with different ketamine doses, without signs of opioid overdosing, and with exactly the same efficacy for justifying a 1:1 ratio in 27 of 29 patients. In this regard, our protocol proceeds from the observations made in four patients who, after achieving pain control with around 250 mg/day of continuous s.c. ketamine, were initially switched to a low 75–150 mg/day of oral ketamine. 6 In every patient, worsening pain obliged us to titrate up oral ketamine to a 1:1 dose ratio to resume pain control. Second, we cannot dismiss the possibility that our 1:1 s.c./oral ratio was effective because the initial “wind down” of hyperalgesia was subsequently maintained by the low ketamine plasma levels, scarcely a few tens of nanograms per milliliter, 18 obtained after oral administration. Supporting this explanation, it has been reported that ketamine at a C 50 concentration of 10.5 ng/mL is effective for pain relief in Complex Regional Pain Syndrome Type 1. 27 Third, because oral ketamine maintained pain control when substituted for s.c. ketamine, we might presume that norketamine contributes to the analgesic effects of oral ketamine. It could be hypothesized that an s.c./oral 1:1 dose ratio represents the amount of oral ketamine needed to reach norketamine plasma levels to maintain pain control. This would suggest that norketamine should have sufficient antihyperalgesic effect for extending the effect of the previous s.c. ketamine. In this regard, experimental data provide evidence that norketamine is effective in preventing central sensitization and in reversing an established hyperalgesia. 22 However, norketamine, whose analgesic potency in humans is unknown, has been suggested to have only a small contribution to ketamine effect in chronic pain. 27 We clearly need more pharmacokinetic and pharmacodynamic data about ketamine and norketamine in connection with different administration regimens and clinical situations characterized by different pain mechanisms before a definitive explanation for the present data can be made. A matter of concern when using ketamine is the appearance of side effects. It has been reported that dosage rates below 2.5 μg/kg/min (0.15 mg/kg/h) or around 200–350 mg/day are unlikely to be associated with severe adverse effects. 28 In our cases, the median ketamine doses used (0.2 mg/kg/h and 300 mg/day by the s.c. or oral route, respectively) are in the range reported by others as being effective to control refractory cancer pain. 7,8,12,23,29,30 We only detected transitory side effects during s.c. ketamine titration in 25% of our patients at the low subanesthetic doses used. After switching ketamine to the oral route, we did not detect relevant side effects, despite stopping previous treatment with diazepam. In this regard, some reports suggest that oral ketamine produces fewer and less severe adverse effects, especially those of a psychomimetic nature, than parenterally administered ketamine. 13,14,24,31–33 To the contrary, there are a number of articles reporting a high rate of adverse effects associated with oral ketamine. 30,34,35 These contradictory reports might be explained by differences in the schedules of ketamine administration, polypharmacy, patient characteristics, and the complex nature of chronic pain. In addition, patients with severe and incapacitating pain, especially that secondary to terminal cancer, may accept and minimize reporting of nonsevere side effects from a treatment if pain relief is effective and their quality of life is improved. In spite of the fact that we did not detect it, a cautionary note must be made about the possibility of a serious bladder dysfunction when using oral ketamine. This side effect has been recently reported mainly in relation with recreational drug users 36,37 and also in the palliative care setting 38 when using oral ketamine as an analgesic at high doses (700–800 mg/day) for the long term (usually for several months). Notwithstanding the limitations of this observational study, especially those related to the small size of our sample and their nonrandomized and unblinded characteristics, we recommend a 1:1 dose ratio when switching to oral ketamine in patients who respond to parenteral ketamine. The suitability of the above dose ratio rests on the fact that most patients remained pain free and that oral ketamine doses were not titrated downward as a result of side effects. Further prospective studies will be needed to ascertain the adequacy of our ketamine protocol and the proposed conversion ratio in a larger patient sample. References 1 S. 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