• A B Nicholson.
• West Midlands Deanery, Compton Hospice, Compton Road West, Wolverhampton, UK, WV3 9DH.
• Cochrane Db Syst Rev. 2004 Jan 1(2):CD003971.

BackgroundMethadone is an opioid used in the management of cancer pain both in opioid naïve patients and in rotation from other opioids. A particular role in neuropathic pain has been suggested. The quest for evidence based palliative care prompted a formal appraisal of methadone in comparison with other analgesics.ObjectivesTo determine the effectiveness and safety of methadone analgesia in cancer pain patients.Search StrategyMEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), CancerLit (1993 to August 2002), CINAHL (1982 to August 2002) and Cochrane databases were searched using a strategy developed with the Cochrane Pain, Palliative and Supportive Care Group. Assiduous efforts were made to identify unpublished or current trial work.Selection CriteriaRandomised controlled trials of methadone against active or placebo comparator in patients with cancer pain were included. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. There were no language restrictions. Absence of patient reported data was an exclusion criterion.Data Collection And AnalysisEligible studies were selected with independent collaboration from a colleague in Bristol (AND). Full text was retrieved if any uncertainty about eligibility remained. Non-English texts were screened by Cochrane contacts aware of the eligibility criteria. Quality assessment and data extraction were conducted using standardised data forms. Drug and placebo dose, titration, route and formulation were compared and detail of all outcome measures (if available) recorded.Main ResultsEight randomised controlled trials (five double blinded, two crossover) with 356 recruits and 326 completing patients were included. All involved active placebo (five morphine, one dextromoramide or pethidine, one diamorphine with cocaine mixture). All employed different starting doses, titration regimens and pain scoring scales. Few presented complete pain data sets and no meta-analysis has been possible. No differentiation by cancer pain syndrome was made. Complete adverse events data were recorded in every study, and were similar in incidence and severity to those experienced with morphine.Reviewers' ConclusionsThere is evidence to suggest that methadone is an analgesic with similar efficacy to morphine and a comparable side effect profile. However, the majority of studies involved single dose comparisons or short term use. This methodology fails to reproduce clinical practice. Therefore there is a very significant danger that the effects of methadone accumulation leading to delayed onset of adverse effects which occurs with chronic administration has not been represented. Fixed interval dosing schedules conducted over several days are associated with a high risk of serious morbidity and mortality. There is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin. Conclusions have been limited by the variations in trial design, dosing regimens and limited presentation of primary outcome data. The complex and highly individual pharmacokinetics of methadone require that experienced clinicians take responsibility for initiating, titrating and monitoring this drug.

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