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Methadone as a First-Line Opioid in Cancer Pain Management: A Systematic Review

Open ArchivePublished:October 31, 2017DOI:https://doi.org/10.1016/j.jpainsymman.2017.10.017

      Abstract

      Aim

      The objective of this review was to assess the existent evidence for the use of methadone as a first-line therapy in cancer pain management.

      Methods

      A systematic literature search on MEDLINE and Embase databases was carried out from each database, setting up the date to August 30, 2017. Studies were included if methadone was a first-line drug as a Step 3 of World Health Organization analgesic ladder, or at low doses (Step 2), if they were conducted in adult patients with cancer pain, and if they contained outcomes on pain- and opioid-related adverse effects.

      Results

      The initial search yielded 219 records. Ten articles were considered after the initial screening according to inclusion and exclusion criteria. They included three longitudinal open-label studies. In two studies methadone was initiated at low doses (≤10 mg/day). These studies suggested that methadone was effective in providing analgesia and well tolerated as first opioid at different starting doses and in different conditions and settings. Five additional studies were randomized controlled studies with morphine in patients who had received opioids for moderate pain. Methadone, compared with oral morphine, or transdermal fentanyl, either at low (Step 2 level) or relatively higher doses (Step 3 level), provided similar analgesia with similar adverse effects profile with limited dose escalation in time.

      Conclusion

      Available data are not sufficient to draw net conclusion. However, open-label and controlled studies have shown that methadone may be effective as first-line drug in the management of cancer pain, providing analgesia and adverse effect profiles similar to those produced by other opioids. The finding that methadone doses tend to remain stable suggests that metabolic characteristics and extraopioid analgesic effects, as its well antihyperalgesic properties may be interesting potential advantages. Further studies should provide information regarding the long-term use of methadone or the need to switch from methadone to other opioids when a loss of analgesic response occurs.

      Key Words

      Introduction

      Pain is a common problem in cancer patients. Various nationwide studies have revealed that 30%–40% of patients receiving active therapy experience pain and the number of patients with cancer pain increases to 70%–90% in the advanced stage of disease.
      • van den Beuken-van Everdingen M.H.
      • Hochstenbach L.M.
      • Joosten E.A.
      • Tjan-Heijnen V.C.
      • Janssen D.J.
      Update on prevalence of pain in patients with cancer: systematic review and Meta-analysis.
      Pain may have a significant impact on function. Pain that is uncontrolled impairs daily life and social interaction and is associated with anxiety and depression.
      • Portenoy R.K.
      Treatment of cancer pain.
      Opioids are indicated for moderate to severe cancer pain. Opioid drugs commonly prescribed for cancer pain management of moderate-severe intensity include fentanyl, hydromorphone, methadone, morphine, and oxycodone. The evidence around the use of opioids for the management of cancer pain is disappointingly low, despite it has been reported that most patients with moderate or severe pain who are prescribed opioids will tolerate them and will achieve a reduction in pain intensity within two weeks.
      • Wiffen P.J.
      • Wee B.
      • Derry S.
      • Bell R.F.
      • Moore R.A.
      Opioids for cancer pain–an overview of Cochrane reviews.
      Methadone is commonly considered an alternative choice to other opioids, when they loss their efficacy. The drawbacks of methadone include high potential for accumulation that may lead to the development of delayed toxicity, highly variable pharmacokinetics between individuals, possible drug interactions, concerns over dose titration and conversion from other opioids,
      • Mercadante S.
      Opioid metabolism and clinical aspects.
      • Weschules D.J.
      • Bain K.T.
      • Richeimer S.
      Actual and potential drug interactions associated with methadone.
      and the potential for prolongation of the QT interval and consequent potential serious arrhythmias.
      • Cruciani R.A.
      Methadone: to ECG or not to ECG. That is still the question.
      Thus, the proven therapeutic efficacy of methadone in the management of cancer pain is hindered by several concerns regarding its complex pharmacokinetic-pharmacodynamic profile. Moreover, methadone is looked upon as a second choice drug and used prevalently for switching from another opioid to improve the balance between analgesia and adverse effects, that is, the opioid response, in difficult pain control scenarios.
      • Mercadante S.
      • Bruera E.
      Opioid switching in cancer pain: from the beginning to nowadays.
      Due to limited research in this area, methadone dosing remains a challenge, with vigilant dose initiation, adjustment, and monitoring required. In some countries the use of methadone is limited to some well-experienced centers only.
      • Mercadante S.
      • Valle A.
      • Agnellotti C.
      • Caruselli A.
      The poor use of methadone in Italian hospices.
      Even the long-term prescription of methadone encounters barriers among general practitioners.
      • Hawley P.
      • Liebscher R.
      • Wilford J.
      Continuing methadone for pain in palliative care.
      • Mercadante S.
      • Ferrera P.
      • Casuccio A.
      Outcome of opioid switching 4 weeks after discharge from a palliative care unit.
      Methadone is a potent agonist at the μ-opioid and delta-opioid receptors. Methadone has also been demonstrated to have an antagonist activity at the N-methyl-d-aspartate (NMDA) receptor, resulting in interest in many clinical conditions, including neuropathic pain syndromes and hyperalgesic states.
      • Salpeter S.R.
      • Buckley J.S.
      • Bruera E.
      The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia.
      • Mercadante S.
      Methadone in cancer pain.
      A combination of opioid agonism and NMDA receptor may potentially provide valuable analgesic effects with fewer side effects than other analgesics.
      • Gorman A.L.
      • Elliott K.J.
      • Inturrisi C.E.
      The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord.
      On the other hand, the characteristics of methadone, including high oral bioavailability, rapid onset of analgesic effect, long half-life (resulting in less frequent dosing schedules), lack of active metabolites, and the low rate of induction of tolerance, may make its use convenient in the management of pain in cancer patients. Finally, methadone is cheap and potentially an ideal therapeutic option to start opioid therapy, particularly in developing countries, where drug costs are of concern and may represent a barrier to provide a good analgesia ubiquitously.
      • Fainsinger R.
      • Schoeller T.
      • Bruera E.
      Methadone in the management of cancer pain: a review.
      • Good P.
      • Afsharimani B.
      • Movva R.
      • Haywood A.
      • Khan S.
      • Hardy J.
      Therapeutic challenges in cancer pain management: a systematic review of methadone.
      The main problems that happen when methadone is used in rotation such as variable and unpredictably dose ratio, and variable effects on hyperalgesia, are much less important at the moment of opioid initiation, and therefore, methadone might be much easier to use as an initial opioid. The objective of this review was to assess the existent evidence for the use of methadone as a first-line therapy in cancer pain management.

      Methods

      A systematic literature search on MEDLINE and Embase databases was carried out from each database, setting up the date to August 30, 2017; text words and MeSH/EMTREE terms were “methadone” AND “cancer pain.” Hand search of the references list of identified articles was also performed independently by the authors. Congress proceedings with complete text were also taken into consideration.
      Studies were included if methadone was a first-line drug as a Step 3 of World Health Organization analgesic ladder, or at low doses (Step 2), if they were conducted in adult patients with cancer pain, if they contained outcomes on pain- and opioid-related adverse effects, and if they were written in English language. Given the expected paucity of comparative studies, noncomparative observational studies and retrospective data with a minimum set of 10 patients were also considered. We did not include short abstracts (usually meeting reports), letters, and case reports. Abstracts that matched the inclusion criteria and those with no clear information to be considered for exclusion were selected for full reading by the two authors after achieving an agreement. Titles and abstracts of retrieved citations were reviewed and potentially relevant articles read in full text.

      Results

      The initial search yielded 219 records. Twelve abstracts were found to be of interest, and full text was examined. Three additional records
      • Mercadante S.
      • Sapio M.
      • Serretta R.
      • Caligara M.
      Patient-controlled analgesia with oral methadone in cancer pain: preliminary report.
      • Mercadante S.
      • Porzio G.
      • Ferrera P.
      • et al.
      Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management.
      • Bruera E.
      • Rico M.A.
      • Bertolino M.
      • et al.
      A prospective, open study of oral methadone in the treatment of cancer pain.
      were retrieved by hand search or cross-references. Four retrospective studies, despite reporting the use of low doses of methadone, were assessing the outcome of a switching from strong opioids to methadone.
      • Salpeter S.R.
      • Buckley J.S.
      • Bruera E.
      The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia.
      • Bruera E.
      • Rico M.A.
      • Bertolino M.
      • et al.
      A prospective, open study of oral methadone in the treatment of cancer pain.
      • Hawley P.
      • Chow L.
      • Fyles G.
      • Shokoohi A.
      • O'Leary M.J.
      • Mittelstadt M.
      Clinical outcomes of start-low, Go-slow methadone initiation for cancer-related pain: What's the Hurry?.
      • Salpeter S.R.
      • Buckley J.S.
      • Bruera E.
      The use of very-low-dose methadone and haloperidol for pain control in the hospital setting: a preliminary report.
      Similarly, one study of patient-controlled analgesia with methadone was performed in patients who were receiving high doses of opioids.
      • Sawe J.
      • Hansen J.
      • Ginman C.
      • et al.
      Patient-controlled dose regimen of methadone for chronic cancer pain.
      Only 10 papers were considered after the initial screening according to inclusion and exclusion criteria (Fig. 1). Three longitudinal open-label studies were performed in cancer patients requiring Step 3 opioids or in opioid-naive patients. Five additional studies were randomized controlled studies with morphine in patients who had received opioids for moderate pain. Finally, in two studies, methadone was initiated at low doses (≤10 mg/day). The characteristics of these studies are presented in Table 1.
      Table 1Characteristics of Studies Selected for the Review
      AuthorDesignNInitial Methadone Dose (Mean mg/day)Maximum Dose of Methadone (Mean mg/day)Analgesic ResponseFollow-upSevere Adverse Effects
      De Conno, 1996Retrospective196Nine (opioid naive)

      15 (from Step 2)
      23Significant pain reduction (>35%)90 daysNot reported
      Mercadante, 1996Prospective open label1916 (opioid naive except for five patients)15.5Pain reduction to ≤4/10, unless one patientEight weeksConfusion (1 patient)
      Mercadante 1999Prospective open label4514 (from Step 2)27Pain reduction to <4/10Three weeksNot reported
      Parsons, 2010Retrospective8910 (median)10 (median)35% partial successAbout two weeks96% of patients continued to receive methadone
      Peraino, 2016Retrospective5 (median) (opioid naive)7.5 (median)Marked decrease in patients with moderate-severe pain11 days15% required switching
      Ventafridda, 1986Randomized controlled with oral morphine5418 (from Step 1 to 2)18Similar decrease in pain intensityTwo weeksMore headache and less dry mouth
      Mercadante, 1998Randomized controlled with oral morphine4013 (from Step 2)25Similar decrease in pain intensityAbout six weeksSimilar adverse effect profile
      Bruera, 2004Double blind Randomized controlled with oral morphine10315 (median) (from Step 1 to 2)20Similar decrease in pain intensityFour weeksMore withdrawal because of adverse effects
      Mercadante, 2008Randomized controlled with transdermal fentanyl and oral morphine10815 (from Step 2)17.7Similar decrease in pain intensityFour weeksSimilar dropout

      Similar need to switch for adverse effects
      Haumann, 2016Randomized controlled with transdermal fentanyl52Four to 10 (from Step 2)Five to 12Similar decrease in pain intensity (faster with methadone)Five weeksNo differences

      Noncomparitive Studies

      Five studies reported data regarding methadone at different initial doses and in different clinical circumstances. In an open-label study, 23% and 53% of 196 advanced cancer patients who started methadone were opioid naive or were treated with opioids for moderate pain, respectively. Initial doses of nine and 15 mg/day were given to these groups of patients. Doses were increased during a time of evaluation of 90 days up to a mean of 23 mg/day. The pain score decreased from a median of 40 (corresponding to “a lot”) at baseline to values ranging 14–19 (corresponding to mild or no pain) recorded in the subsequent three months. Acceptable analgesia was achieved in most patients. Patients discontinued the treatment for inability to swallow (10%), analgesic inefficacy (11%), or methadone-related adverse effects (6%).
      • De Conno F.
      • Groff L.
      • brunelli C.
      • Zecca E.
      • Ventafridda V.
      • Ripamonti C.
      Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients.
      Nineteen of 24 strong opioid-naive patients with cancer pain were prescribed a patient-controlled analgesia with oral methadone. They were started with three to five mg three times a day, and then after stabilization, the same dose was used as needed, with a fixed dose at night. A mean maximum dose of 30 mg/day was reached in about four weeks. Pain intensity was maintained in a range of 2.5–4.5, on a numerical scale 0–10. The dose escalation index was low, and acceptable analgesia was maintained until death for most patients reporting no relevant adverse effects.
      • Mercadante S.
      • Sapio M.
      • Serretta R.
      • Caligara M.
      Patient-controlled analgesia with oral methadone in cancer pain: preliminary report.
      A prospective study was carried out in 45 very advanced cancer patients followed at home who had never received strong opioids for their pain. The mean starting doses of methadone was 14 mg/day. Doses were increased up to a mean of 27 mg/day during a period of about 8 weeks providing adequate pain control in most cases (mean pain intensity = 3.4), without relevant adverse effects. Methadone was never discontinued, unless when swallowing was no longer possible, mainly during the last days of life.
      • Mercadante S.
      • Casuccio A.
      • Agnello A.
      • Barresi L.
      Methadone response in advanced cancer patients with pain followed at home.
      Two studies provided data of methadone initiation at low doses. Eighty-nine of 189 patients, initiated methadone at a median dose of 10 mg/day (range: five–15 mg). The dose did not change significantly at the first and second follow-up visits, that occurred about two weeks (six–21 days), and three weeks after baseline consultation, respectively. Successful initiation was defined as improvement ≥30% or ≥2 points in pain intensity. There was a 35% partial success among initiation patients, due to pain, nonadherence, and adverse effects, although data were not completely available at the second follow-up visit.
      • Parsons H.A.
      • de la Cruz M.
      • El Osta B.
      • et al.
      Methadone initiation and rotation in the outpatient setting for patients with cancer pain.
      This study suggested that initiation of methadone can be performed successfully in an outpatient clinic, although it does not allow timely intervention due to the intrinsic limitation of the setting (intervals of seven–15 days). Interestingly, continuation of methadone treatment was more frequently reported among opioid-naive patients than in patients undergoing opioid switching.
      More recently, a retrospective review of patients who were started methadone as a first-line treatment for cancer pain in a developing country was reported. Patients were opioid naive or were receiving opioids for moderate pain. Methadone was the most prescribed opioid (70% of 56 patients available for the analysis), mostly in outpatients. A significant decrease of patients reporting moderate-severe pain and increase of patients reporting mild or no pain were observed between initial consultation and follow-up visit. The mean follow-up time was 11 days. The doses of methadone were increased from a mean initial dose of five mg/day up to 7.5 mg/day, with an opioid escalation index of 0.2 mg/day. Only a minority of patients had to stop methadone therapy. Of interest, patients on methadone underwent less percentage of opioid switching and had a longer time to switching than patients receiving other opioids. However, there was a lack of information about adverse effects, and documentation was often incomplete.
      • Peraino G.P.
      • Mammana G.P.
      • Bertolino M.S.
      • et al.
      Methadone as first-line opioid treatment for cancer pain in a developing country palliative care unit.
      Globally, noncomparitive studies, either prospectively or retrospectively, suggest that methadone is effective in providing analgesia and well tolerated as a first opioid at different starting doses and in different conditions and settings.

      Controlled Studies

      Oral methadone was compared to other analgesic regimens in five controlled studies. In a pioneer study, 54 advanced cancer patients followed at home, who had been treated with Step one–two drugs of the analgesic ladder unsuccessfully, were randomized to receive morphine or methadone, orally. Initial doses of morphine and methadone were chosen according to the pain intensity (24–144 mg/day and eight to 28 mg/day, respectively). Although doses of methadone remained constant (mean = 18 mg/day) along the 14-day period of study, a 63% increase of morphine doses was reported (from a mean of 72 mg/day up to 119 mg/day). Pain intensity significantly decreased in both groups. Adverse effects were similar with dry mouth and headache prevailing in morphine and methadone groups, respectively.
      • Ventafridda Ventafridda V.
      • Ripamonti C.
      • Bianchi M.
      • Sbanotto A.
      • De Conno F.
      A randomized study on oral administration of morphine and methadone in the treatment of cancer pain.
      A randomized controlled study was performed in a sample of 40 advanced cancer patients requiring Step 3 analgesic drugs. Pain control and adverse effects were similar in the two groups, but patients receiving methadone had a slower escalation index in comparison with patients receiving oral morphine. Methadone was also more effective in providing less gaps in equianalgesic score, an integrated score including pain intensity and analgesic consumption.
      • Mercadante S.
      • Casuccio A.
      • Agnello A.
      • Serretta R.
      • Calderone L.
      • Barresi L.
      Morphine versus methadone in the pain treatment of advanced cancer patients followed up at home.
      In a randomized, double-blind, multicenter study, 103 patients requiring initiation of a strong opioid were randomized to receive methadone or morphine at initial doses of 30 and 60 mg/day, respectively, and were followed up for four weeks. Reduction of pain intensity was observed after a week in both group, but patients who were assigned to methadone group had more dropouts due to opioid-related adverse effects. The dose escalation index was similar in the two groups of patients. Methadone offered similar analgesia to that of morphine. The finding of higher methadone-induced toxicity could be explained by the lower dose ratio used in this study (1:2).
      • Bruera E.
      • Palmer J.L.
      • Bosnjak S.
      • et al.
      Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.
      One hundred eight cancer patients no longer responsive to opioids for moderate pain were randomized to receive oral morphine, transdermal fentanyl, or oral methadone at initial doses of 60 mg/day, 25 μg/hour (0.6 mg/day), or 15 mg/day, respectively.
      • Mercadante S.
      • Porzio G.
      • Ferrera P.
      • et al.
      Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management.
      No differences in pain and symptoms were reported along the four weeks of study among the three groups. Opioid escalation index was lower with methadone, although more dose changes were necessary, suggesting that dose titration of methadone requires major expertise. The costs of symptomatic drugs used to manage opioid-related adverse effects were similar in the three groups, but methadone therapy resulted to be less expensive.
      A randomized trial was performed in strong opioid-naive patients with neuropathic pain due to head and neck cancer. Fifty-two patients were randomized to receive methadone or transdermal fentanyl (Step 3). Methadone four–10 mg/day or transdermal fentanyl 12–25 μg/hour (approximately 0.3 mg–0.6 mg/day) was given. Significant decrease in pain intensity was observed in both groups. Clinical success, considered to be a decrease of 50% in pain intensity, was significantly achieved faster with methadone than with fentanyl after a week, but the initial difference diminished over the subsequent weeks. No difference in the occurrence and intensity of adverse effects was reported. Slight but not significant differences were observed in opioid increase ratio during the five weeks of study. Many patients were lost during the five-week period of study. This was attributed to treatment success, suggesting that an expected improvement of disease with anticancer treatment strongly influenced the outcome, including secondary improvement of the pain condition. Moreover, the sample size calculated was not achieved, due to the large number of dropouts.
      • Haumann J.
      • Geurts J.W.
      • van Kuijk S.M.J.
      • Kremer B.
      • Joosten E.A.
      • van der Beuken-van Everidngen M.H.J.
      Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer.
      Taken together, comparitive studies have shown that methadone, compared with oral morphine or transdermal fentanyl, either at low (Step 2 level) or relatively higher doses (Step 3 level), provided similar analgesia with similar adverse effects profile. At least in two studies, doses of methadone tended to be more constant in time compared to fentanyl or morphine.

      Discussion

      Open-label and controlled studies have shown that methadone may be effective as a first-line drug in the management of cancer pain, providing similar analgesia and adverse effect profiles to those produced by other opioids. In particular, methadone doses seem to remain more stable in time with slow escalation indexes. Methadone has been used at doses approximately equivalent to oral morphine equivalents of 60 mg/day, as it commonly occurs in patients who start Step 3 of the analgesic ladder.
      • Caraceni A.
      • Hanks G.
      • Kaasa S.
      • et al.
      European Palliative Care Research Collaborative (EPCRC)European Association for Palliative Care (EAPC)
      Use of opioid analgesics in the treatment of cancer pain: evidence-based 14. Recommendations from the EAPC.
      Methadone has been also initiated successfully as a first line drug in patients who were opioid naive that is candidate to receive opioids for moderate pain.
      Although available data are not sufficient to draw net conclusion, observational and controlled studies with other strong opioids have shown that methadone is a valuable drug even as a first-choice opioid, either at Step 3 and Step 2 level of the analgesic ladder. Most studies have also demonstrated a limited tendency to increase the dose, although the periods of observation did not exceed one month. Metabolic characteristics and extraopioid analgesic effects, as its well antihyperalgesic properties have been often reported to explain these potential advantages.
      • Salpeter S.R.
      • Buckley J.S.
      • Bruera E.
      The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia.
      • Mercadante S.
      Methadone in cancer pain.
      Moreover, methadone is a convenient drug, due to its limited cost, which is an enormous advantage in developing countries. Despite its pharmacokinetics is recognized as an increased risk of accumulation and delayed toxicity, other than the potential for drug-drug interaction,
      • Weschules D.J.
      • Bain K.T.
      • Richeimer S.
      Actual and potential drug interactions associated with methadone.
      the appropriate and experienced use of methadone may be of paramount importance, as it occurs for opioid switching. Of interest, physicians should be confident with this drug, that is seldom used in clinical practice because the unique characteristics of this opioid.
      • Mercadante S.
      • Valle A.
      • Agnellotti C.
      • Caruselli A.
      The poor use of methadone in Italian hospices.
      Although opioid switching from other opioids to methadone may be problematic, particularly when using high doses, because the unpredictable conversion ratios dependent on many individual and clinical variables,
      • Mercadante S.
      • Bruera E.
      Opioid switching in cancer pain: from the beginning to nowadays.
      paradoxically, initiating methadone first could be easier, as dose can be titrated against the effect with less unexpected clinical responses.
      This review has intrinsic limitations, due to the limited number of studies and their quality. Moreover, information about the modalities of dose titration is lacking. Of concern, the use of methadone in pediatric population could be an interesting indication, worthwhile of future research. More studies with an appropriate design should provide information regarding the long-term use of methadone along the progression of disease in the prevention of opioid-induced hyperalgesia or opioid dose escalation, titration methods, as well the need to switch from methadone to other opioids in case of loss of analgesic response in time.

      Disclosures and Acknowledgments

      This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.

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