Intravenous Methadone in the Management of Chronic Cancer Pain

CancerVolume 92, Issue 7 p. 1919-1925 Original ArticleFree Access Intravenous methadone in the management of chronic cancer pain Safe and effective starting doses when substituting methadone for fentanyl Juan Santiago-Palma M.D., Juan Santiago-Palma M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorNatalia Khojainova M.D., Natalia Khojainova M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorCraig Kornick M.D., Craig Kornick M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorDaniel J. Fischberg M.D., Ph.D., Daniel J. Fischberg M.D., Ph.D. Mount Sinai School of Medicine, Hertzberg Palliative Care Institute, Department of Geriatrics and Adult Development, New York, New YorkSearch for more papers by this authorLouis H. Primavera Ph.D., Louis H. Primavera Ph.D. Adelphi University, Derner Institute of Advanced Psychological Studies, Garden City, New YorkSearch for more papers by this authorRichard Payne M.D., Richard Payne M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorPaolo Manfredi M.D., Corresponding Author Paolo Manfredi M.D. Manfredp@mskcc.org Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New York Fax: (212) 717-3081Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer Center, Department of Neurology, 1275 York Ave, New York, NY 10021===Search for more papers by this author Juan Santiago-Palma M.D., Juan Santiago-Palma M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorNatalia Khojainova M.D., Natalia Khojainova M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorCraig Kornick M.D., Craig Kornick M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorDaniel J. Fischberg M.D., Ph.D., Daniel J. Fischberg M.D., Ph.D. Mount Sinai School of Medicine, Hertzberg Palliative Care Institute, Department of Geriatrics and Adult Development, New York, New YorkSearch for more papers by this authorLouis H. Primavera Ph.D., Louis H. Primavera Ph.D. Adelphi University, Derner Institute of Advanced Psychological Studies, Garden City, New YorkSearch for more papers by this authorRichard Payne M.D., Richard Payne M.D. Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New YorkSearch for more papers by this authorPaolo Manfredi M.D., Corresponding Author Paolo Manfredi M.D. Manfredp@mskcc.org Memorial Sloan-Kettering Cancer Center, Pain and Palliative Care Service, New York, New York Fax: (212) 717-3081Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer Center, Department of Neurology, 1275 York Ave, New York, NY 10021===Search for more papers by this author First published: 09 October 2001 https://doi.org/10.1002/1097-0142(20011001)92:7<1919::AID-CNCR1710>3.0.CO;2-GCitations: 55 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract BACKGROUND Patients often are rotated from other opioids to methadone when side effects occur before satisfactory analgesia is achieved. Various strategies have been proposed to estimate safe and effective starting doses of methadone when rotating from morphine and hydromorphone; however, there are no guidelines for estimating safe and effective starting doses of methadone when rotating from fentanyl. METHODS The authors prospectively observed 18 consecutive patients experiencing chronic pain from cancer who underwent opioid rotation from intravenous patient-controlled analgesia (PCA) with fentanyl to intravenous PCA with methadone. Patients were switched from fentanyl to methadone because of uncontrolled pain associated with sedation or confusion. A conversion ratio of 25 μg/hour of fentanyl to 0.1 mg/hour of methadone was used to calculate the initial dose of methadone in all patients. RESULTS Mean pain scores decreased from 8.1 to 4.8 on Day 1 after the switch and to 3.22 on Day 4 after the switch. Mean sedation scores were 1.5 before the switch and 0.44 and 0.16 on Days 1 and 4, respectively. Among the 6 patients who experienced confusion while on fentanyl before the switch, 5 improved within 2 days of the switch. None of the patients experienced toxicity from methadone. CONCLUSIONS On the basis of this preliminary study, the authors suggest that when switching from intravenous fentanyl to methadone a conversion ratio of 25 μg/hour of fentanyl to 0.1 mg/hour of methadone may be safe and effective. Cancer 2001;92:1919–25. © 2001 American Cancer Society. Patients with cancer pain treated with opioids may develop adverse effects before achieving adequate analgesia.1 Sequential trials with various opioids often are used to find the opioid with the most favorable balance between analgesia and toxicity. The substitution of another opioid for a previous one has been termed "opioid rotation."2-5 In recent years, numerous investigators have described the successful rotation from other opioid analgesics to methadone.6 Several reports have underscored the efficacy of methadone in the treatment of cancer pain, especially for pain refractory to high doses of other opioids.4, 7-10 The main concern when using methadone for the treatment of pain is its long and unpredictable half-life and associated risk of delayed overdose,11, 12 unless careful and individualized dose titration is undertaken. Methadone is a synthetic opioid that differs from other opioids because of its long half-life, N-methyl-D-aspartate (NMDA) receptor antagonist activity, and lack of known active metabolites.11 Fentanyl is a synthetic opioid compound related to the phenylpiperidines. The drug functions primarily as a mu agonist and is estimated to be 40 times more potent than morphine as an analgesic.13 As with other opioids, patients also can develop intolerable side effects from fentanyl and require rotation to another opioid such as methadone. Various strategies have been used to estimate safe and effective starting doses for methadone when rotating from morphine and hydromorphone.9, 14 However, to our knowledge, the rotation from fentanyl to methadone has not been described previously, and there are no data to estimate a safe and effective starting methadone dose. We describe the effects of the rotation from intravenous patient-controlled analgesia (PCA) fentanyl to intravenous PCA methadone by using novel conversion parameters. MATERIALS AND METHODS We prospectively collected data on patients with cancer-related pain referred to the Pain and Palliative Care Service of a U.S. cancer center from October 1999 to June 2000. We enrolled all consecutive patients requiring opioid rotation from intravenous PCA fentanyl to intravenous PCA methadone because of inadequate pain control associated with sedation or confusion. Inadequate pain control was defined as pain intensity of 5 or more on a 0–10 verbal numeric scale. Sedation was defined as a subjective feeling of sleepiness rated by the patient using a 0–3 point verbal numeric scale. On this scale, 0 means no sedation, 1 mild sedation, 2 moderate, and 3 severe sedation. This numeric sedation scale is part of our routine assessment of all patients receiving intravenous PCA opioids. Confusion was defined as a deficit in orientation, attention, recall, and ability to perform simple calculations. As part of our assessments of patients receiving opioids by PCA, all patients were asked daily if they felt confused. Patients who reported confusion were assessed daily for orientation, attention, recall, and ability to perform simple calculations. The initial hourly infusion rate of methadone was calculated based on the previous hourly infusion rate of fentanyl and not on the total hourly dose, which is the sum of the hourly basal rate and the hourly demand use. A conversion of 25 μg/hour of fentanyl to 0.1 mg/hour of methadone was used to select the initial infusion basal rate of methadone (0.25 ratio between fentanyl and methadone). The selection of the conversion ratio and the decision to base the initial hourly basal rate of methadone on the previous hourly basal rate of fentanyl, rather than on the total hourly dose of fentanyl, were based on our clinical experience with opioid rotation while using intravenous PCA. Self-administered bolus doses of intravenous methadone equal to 50–100% of the hourly infusion rate were allowed every 20 minutes in all patients via the PCA. Patient also could receive additional boluses of 100–200% of the hourly infusion rate every 60 minutes; the nursing staff administered these additional boluses. Patients were followed for a minimum of 4 consecutive days. The following data were collected for each patient: age, gender, primary tumor site, site of pain, and the reason for the opioid switch. The type of pain was determined on the basis of a clinical evaluation and was categorized as somatic, visceral, neuropathic, or mixed. The dose of intravenous PCA fentanyl used in the 24 hours before the switch and the daily dose of intravenous PCA methadone used in each of the days after the switch were recorded. Pain and sedation scores were obtained before the switch and after the switch. Pain scores were recorded using the 0–10, 11-point verbal numeric scale. Sedation was recorded using a 0–3, 4-point verbal numeric scale. Confusion was assessed by testing orientation to place, space, and time, ability to do simple calculations, and short-term memory. Patients were also asked if their "mind was clear" and if they "felt confused." Overall satisfaction with analgesic treatment was assessed using a categoric scale ("yes" or "no"). The Wilcoxon signed rank-sum test was used to compare the total quantity of methadone used on Day 1 to that used on Day 4 and to compare pain and sedation scores before and after the opioid rotation. Scatterplots were used to show the relation between previous fentanyl and final methadone dose. This relation was evaluated using the Pearson correlation coefficient. RESULTS All patients had been on opioid therapy for a minimum of 2 weeks and had received fentanyl via intravenous PCA for a minimum of 3 days before the switch. All patients required a switch to methadone because of uncontrolled pain and opioid induced sedation or confusion. Table 1 lists the age, gender, primary tumor sites, pain sites, pain type, and reason for opioid rotation in the 18 patients. The mean age was 57.6 years (range, 23–79 years); 7 patients had somatic pain, 4 neuropathic pain, 3 visceral pain, and 4 mixed neuropathic and somatic pain. Table 1. Patient Characteristics Characteristic No. of patients (n = 18) Gender Female 9 Male 9 Age (yrs) Mean 57.6 Range 23–79 Carcinoma diagnosis Multiple myeloma 3 Prostate 3 Breast 2 Lymphoma 2 Appendix 1 Esophagus 1 Larynx 1 Lung 1 Osteosarcoma 1 Uterine 1 Unknown 2 Type of pain Somatic 7 Visceral 3 Neuropathic 4 Mixed 4 Site of pain Back 6 Abdomen 3 Multifocal 3 Limb 4 Chest 2 Reason for opioid switch Sedation 12 Confusion 6 All patients were observed for at least 4 consecutive days. The median hourly infusion dose of fentanyl before the switch was 375 μg/hour (range, 50–2500 μg/hour), and the median hourly total dose (hourly infusion rate plus demand PCA dose) was 483.29 μg/hour (range, 91.6–2706 μg/hour). The starting median hourly infusion dose and total hourly dose of methadone 24 hours after the switch were 1.5 mg/hour (range, 0.2–10 mg/hour) and 2.68 mg/hour (range, 0.3–28.3 mg/hour), respectively. The median hourly infusion dose and total hourly dose of methadone on Day 2 was 2 mg/hour (range, 0.2–10 mg/hour) and 2.5 mg/hour (range, 0.3–16.25 mg/hour). The median hourly infusion dose and total hourly dose of methadone on Day 4 was 2 mg/hour (range, 0.3–10 mg/hour) and 2.25 mg/hour (range, 0.4–15.4 mg/hour), respectively (see Fig. 1). There was a 10% increase in the median hourly infusion dose of methadone from Day 1 to Day 2; after Day 2, the median hourly infusion dose of methadone remained the same. The median total methadone 24-hour dose decreased from 64.45 mg (range, 7.6–680 mg) on Day 1 to 54 mg (range, 9.9–370 mg) on Day 4. Figure 1Open in figure viewerPowerPoint Median hourly use of methadone on Days 1 through 4. Shaded areas show median hourly constant infusion rate of methadone. Unshaded areas show median hourly dose of methadone used as demand. The calculated final mean dose ratio between fentanyl and methadone was 0.22 (range, 0.06–0.49) across the 17 patients who achieved pain control. Figure 2 suggests a linear positive relation of this dose ratio (r = 0.8). Figure 3 suggests that there is no significant correlation between the total dose of fentanyl before the switch and the ratio between the total daily dose of fentanyl before the switch and the total daily dose of methadone on Day 4 (r = −0.01). Figure 2Open in figure viewerPowerPoint Total hourly dose of methadone in the 17 patients who achieved satisfactory pain control pain on Day 4 versus the total hourly dose of fentanyl administered before the switch. There is a linear positive relation between the total hourly doses of methadone and fentanyl (r = 0.8). mcg, micrograms. Figure 3Open in figure viewerPowerPoint Dose ratio between fentanyl and methadone versus the previous total fentanyl dose in the 17 patients who achieved pain control. (r = −0.01). mcg, micrograms. To determine whether the dose decreased more in patients who received a higher dose than in patients who received a lower dose, we divided the patients into 2 groups by splitting the total group of 18 patients at the median dosage of methadone administered on Day 1 (median, 64.5). Patients who were at or above the median were classified as being on a higher dosage of methadone on Day 1, and patients who were below the median were classified as being on a lower dosage of methadone on Day 1. The two groups were compared using a Mann–Whitney Wilcoxon test, and the dose changes from Day 1 to Day 4 were not found be to significantly different (P = 0.297). Satisfactory pain control without significant side effects was achieved in 16 (88.8%) patients. The mean pain score for all patients before the switch was 8.1 (range, 5–10). The mean pain score decreased to 4.8 (range, 1–10) on Day 1 after the switch and to 3.22 (range, 1–6) on Day 4 after the switch (see Fig. 3). There is a statistical difference between pain scores before the switch and pain scores 1 day after the switch (P < 0.001). None of the patients rated analgesic treatment as satisfactory before the switch. Fourteen patients rated analgesic treatment satisfactory 24 hours after the switch. An additional two patients achieved pain control on Day 2 and one patient on the third day. Only one patient continued to rate pain as unsatisfactory 4 days after the rotation. This patient then was treated with epidural opioids. The side effect limiting the use of a higher fentanyl dose was sedation in 12 of the patients and confusion in 6 of the patients. Mean sedation scores for these patients were 1.5 before the switch and 0.44, 0.22, 0.16, and 0.16 on Days 1 through 4 after the switch, respectively. There is statistical difference in the sedation scores before and 4 days after the switch (P = 0.001). All 6 patients who developed confusion while on fentanyl improved subjectively ("feeling clear minded" and "not feeling confused") and objectively (testing of orientation, simple calculations, and short-term memory) 2 days after the switch except for 1 patient. For this patient, whereas the pain was controlled, the confusion worsened until he died a week after the switch of bacterial sepsis. DISCUSSION Clinical practice guidelines recommend morphine as the first-line opioid for the treatment of chronic cancer pain. Fentanyl and hydromorphone are viewed as second-line opioids. Methadone generally is used for patients who have not obtained an adequate balance between analgesia and side effects with hydromorphone or fentanyl. Despite recent reports showing its efficacy and safety in cancer pain, methadone has remained a third-line opioid mostly because of lack of data on safe and effective conversion parameters and lack of guidelines for its use, especially when administered by intravenous PCA. A successful conversion from one opioid to another requires an understanding of the pharmacokinetic parameters of both opioids and knowledge of the available data on relative analgesic potency. The information about the relative analgesic potency of two opioids can be obtained from published equianalgesic tables.1 Equianalgesic dose tables were intended to provide information about oral and parenteral dose ratios and to serve as a general guideline for choosing a starting dose when switching from one drug to another. These equianalgesic tables are based on single dose studies and have a limited role for calculating safe starting doses of constant infusions of methadone. The inadequacy of these opioid conversion tables for calculating starting doses of continuos opioid infusions is even more apparent when comparing opioids with very different half-lives such as fentanyl and methadone. Some authors have recommended that, when converting a short half-life analgesic to methadone, for patients who are taking opioids chronically, 10–25% of the calculated equianalgesic dose based on the available opioid potency tables should be used as the starting dose, with titration on an as needed basis.15, 16 Alternatively, other authors have suggested titrating the analgesic therapy with an initial loading dose of methadone followed by progressive dose reduction during the first week of treatment.12, 17 Methadone plasma level declines in a biexponential manner with a half-life of 2–3 hours during the initial phase and 15–60 hours during the terminal phase. This biexponential decline with a long terminal half-life may account for the relatively short analgesic action of single doses and the tendency for drug accumulation with repeated dosing.17 Equianalgesic tables indicate that 10 mg of parenteral morphine are equianalgesic to 10 mg of parenteral methadone and 100 μg of fentanyl. If these tables would have been utilized to calculate the initial hourly infusion rate of methadone, a conversion ratio of 25 μg of fentanyl to 2.5 mg of methadone would have been used. This conversion ratio is 25 times larger than the one used for our patients and most likely would have resulted in an overdose of methadone. The median total methadone dose (hourly infusion rate plus demand PCA use) decreased from 2.68 to 2.25 mg/hour from Day 1 to Day 4 as a result of decreased PCA demand use. The median hourly infusion rate increased from 1.5 to 2 mg/hour. This suggests that a slightly higher starting methadone infusion rate may be used in some patients. If the final mean hourly infusion dose of methadone were used to calculate the initial hourly infusion rate, a conversion of 25 μg/hour of fentanyl for 0.125 mg/hour of methadone would result. In the cancer population, pain ratings in the range of 1–4 on a visual analog scale are classified as mild pain, rating in the range of 5–7 are classified as moderate pain, and ratings in the range of 8–10 are classified as severe pain. Ratings greater or equal to 5 have been shown to significantly impact on patients' quality of life by interfering with activity, mood, sleep, enjoyment, and relations.1, 18 The mean intensity score for our patients before the rotation was 8.01, and it decreased to 4.8 1 day after the switch and to 3.22 on Day 4 after the switch. The reduction in pain scores observed in our patients is likely to have resulted in a marked improvement in the patients' quality of life, although direct measurements of quality of life were beyond the scope of this study. Methadone's NMDA receptor antagonistic activity17 in addition to the well known clinical phenomenon of incomplete cross-tolerance to the effects of various opioids may explain this marked improvement also observed by other authors when rotating to methadone from opioids other than fentanyl.4, 10, 11 Our study confirms that methadone when used via intravenous PCA after appropriate conversion parameters is safe and can be drastically effective for the relief of pain refractory to fentanyl. The calculated mean dose ratio between fentanyl and methadone doses on Day 4 was 0.22. There was an eightfold variation in this ratio. The dose ratio ranged from 0.06 to 0.49. These results are consistent with the results of retrospective and prospective studies showing a wide interindividual variability in dose ratios when switching from other opioids to methadone. In this small sample of patients, there is a linear positive relation of the fentanyl/methadone dose ratio. The dose ratio was not affected by higher doses of fentanyl in contrast with the findings of other studies looking at the morphine/methadone and hydromorphone/methadone dose ratio. In these larger studies, intravenous PCA was not used; patients were switched to define equianalgesic dose ratios14 or because the development of side effects irrespective of the level of analgesia and pain scores did not change significantly before and after the switch.2, 19 In our patients, a switch to methadone was performed only when uncontrolled pain was present, and the pain scores decreased significantly after the switch. The use of intravenous PCA, the various reasons for the switch, the significantly lower pain scores obtained after the rotation, and the use of fentanyl may help explain why we did not observe the change in dose ratio with higher opioid doses described in other opioid rotation studies. This small study can be considered descriptive only. Patients were not prospectively assigned, and investigators and patients were not blinded to the effects of methadone. Future studies could compare this conversion ratio with other conversion ratios in a double-blind randomized fashion. CONCLUSIONS Opioid rotation to methadone is an effective therapeutic tool for the treatment of cancer pain. When performing opioid rotation, the application of conversion parameters for calculating safe and effective starting doses of the new opioid is essential. On the basis of this preliminary study, we suggest that when switching from fentanyl via intravenous PCA to methadone via intravenous PCA, a conversion ratio of 25 μg/hour of fentanyl to 0.1 mg/hour of methadone is a safe and effective method for calculating the starting hourly infusion rate of methadone. Although the conversion ratio of 25 μg/hour of fentanyl to 0.125 mg/hour of methadone was not studied, on the basis of our data this conversion ratio might be preferable. 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