Nicholson, A.B. (2006). Methadone for cancer pain [Cochrane review]. In The Cochrane Library, Volume 4, 2006. Oxford, UK: Update Software.

To determine the effectiveness and safety of methadone analgesia in patients with cancer pain; to assess the adverse effects associated with methadone analgesia for the treatment of cancer pain

Databases searched were Cochrane Pain, Palliative & Supportive Care Group Trials Register; The Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CancerLIT; CINAHL; National Research Register; CenterWatch clinical trials listing service; Current Controlled Trials; National Institutes of Health Clinical Trials Databases; BioMed; Glaxo Wellcome Clinical Trials Register; National electronic Library for Health (NeLH); System for Information on Grey Literature in Europe (SIGLE); Dissertation Abstracts OnDisc; Index to Theses (ASLIB Index); Proquest Digital Dissertations; Cochrane Database of Systematic Reviews (CDSR); and Database of Abstracts of Reviews of Effects (DARE).

• Studies were included if they
  • Involved patients of any age and gender with cancer pain that was chronic and of any intensity and any pain with a malignant etiology. (Etiology could be primary or secondary malignancy, solid or hematologic).
  • Involved patients in a home, outpatient, or inpatient setting.
• Studies were excluded if they involved patients who took methadone for the suppression of cough or patients taking or who had taken methadone for rehabilitation from opioid dependence.
• Of studies retrieved, author analyzed only randomized, controlled trials that assessed symptom control of cancer pain. The control group could be a placebo or an active control. Active controls included any opioid other than methadone, another analgesic, or an adjuvant analgesic. Author accepted published and unpublished trials and, in determining eligibility, established no size restriction.
• Six of the analyzed studies used only the oral route.
  • Three studies compared methadone to morphine.
  • One study compared methadone to a methadone-ibuprofen combination.
  • One study compared methadone to dextromoramide or pethidine.
  • One study compared methadone to diamorphine with cocaine.
• Two of the analyzed studies compared oral and parenteral routes of administration.
  • One study compared IM morphine with IM methadone with oral methadone
  • One study compared methadone with morphine administered intravenously and orally.
• The final study the author analyzed compared methadone with morphine analgesia delivered by a patient-controlled IV infusion system.
• Starting doses, titration schedules, and pain scoring varied widely among analyzed studies.

• The sample included patients, of any age and gender, with cancer pain that was chronic and with a malignant etiology. (Etiology could be a primary or secondary malignancy, solid or hematologic). The pain could be of any intensity. Patients could have been at home or in an outpatient or inpatient setting.
• Patients were excluded from the study if they were taking methadone for suppression of cough or if they were taking or had taken methadone for rehabilitation from opioid dependence.
• Of the trials retrieved, the author analyzed nine randomized controlled trials (six double-blinded trials and two crossovers).
• The sample was composed of 459 recruits, of whom 392 completed the trials.
• All studies involved an active placebo (five morphine, one dextromoramide or pethidine, one diamorphine-cocaine mixture). In each study the starting dose was different, as was each titration regimen and each pain scale.
• Six trials were inpatient studies. Two were outpatient studies. Author added one outpatient study after the last review, to make a total of three outpatient studies analyzed.

Evidence suggests that methadone is an analgesic with an efficacy similar to that of morphine and with side effects that are similar to those of morphine. Although methadone is similar to morphine, the pharmacokinetics and pharmacodynamics of methadone make dose titration difficult. Methadone presents the risk of drug accumulation to toxic levels. There is a significant danger that the effect of methadone accumulation leading to delayed onset of adverse effects has not been represented. The majority of studies involved were single-dose comparisons or pertained to short-term use. Such comparisons fail to reproduce clinical practice; such studies do not reveal delayed adverse effects. One study, which compared methadone to morphine over 28 days, reported an increased rate of withdrawal from the methadone group. Withdrawal was due to side effects. Author drew no conclusion regarding the relative merits, in the management of various pain syndromes, of methadone compared to those of other opioids. The additional study found methadone to be as effective as morphine in the treatment of neuropathic pain, but not superior to morphine.

Few studies presented complete data sets regarding pain. No meta-analysis was possible.