Is oral methadone better than placebo or other oral/transdermal opioids in the management of pain?

Aim: To address the question: is oral methadone better than placebo, or other oral/transdermal opioids in the management of cancer pain? Method: A literature search was performed to identify relevant studies. Search strategies included: (1) methadone (title) AND placebo (title or abstract) AND pain (title or abstract); (2) methadone (title) AND randomized (title or abstract) AND pain (title or abstract) AND cancer (title or abstract). Papers were reviewed for relevance to first-line opioid therapy. Results: No studies were identified comparing methadone to placebo for cancer pain. A single study compared methadone to placebo for neuropathic pain and demonstrated evidence of analgesic effect at a dose of 20 mg/day but not at a dose of 10 mg/day. Four studies compared oral methadone to either oral morphine, or oral morphine and transdermal fentanyl in a first-line setting: Gourlay 1986 (N = 18), Ventafridda 1986 (N = 54), Bruera 2004 (N = 106) and Mercadante 2008 (N = 108). All studies demonstrated comparable, but not superior, analgesia with, overall, a comparable adverse effect profile. The duration of the study period for the three largest studies was 28 days. Two of these studies, Ventafridda 1986 and Mercadante 2008, indicated that, over time, the opioid escalation index was lower for methadone than for morphine. One study that used a 2:1 dose ratio between morphine and methadone was associated with a high attrition rate in the first week because of excessive sedation. This effect was not seen in the study that used a 4:1 morphine to methadone dose ratio with dose titration. Conclusion: This limited data suggests that (1) methadone may be an equally effective candidate for first-line opioid therapy, (2) that it is possibly less expensive, (3) that there may be a propensity to sedation and dose accumulation unless there is close monitoring and conservative dose selection and (4) that it should be initiated with a calculated dose based on a morphine to methadone dose ratio of not less than 4:1.