Methadone for Pain Management

Over the past 20 years there has been renewed interest in using methadone as an analgesic—raising concerns about its safety. This educational review discusses the efficacy and safety of methadone when used in chronic pain management.
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Methadone is a synthetic opioid agent that was initially introduced in the United States as an analgesic in the 1940s.1-3 In the 1960s, methadone became widely used as a maintenance drug for the treatment of opioid addiction.3,4 It is a Schedule II controlled substance that, when used for the treatment of addiction, may only be prescribed by providers registered with the Drug Enforcement Agency for this purpose. When used for the treatment of pain, methadone may be prescribed by any provider registered to prescribe Schedule II controlled substances.5 Over the past 20 years there has been renewed interest in using methadone as an analgesic. In fact, from 1999 to 2002 sales of methadone in the United States increased 70.7%.6 This increase was largely a result of methadone’s use outside of narcotic treatment programs. Although methadone has become increasingly popular for the treatment of pain, concerns regarding its safety also are on the rise. In fact, although methadone accounts for less than 5% of prescription opioids, it has been linked to one-third of opioid-related deaths.7 This educational review discusses the efficacy and safety of methadone when used for chronic pain management.

Pharmacology and Pharmacokinetics
Methadone possesses a number of properties that are unique among the opioid class of drugs. Methadone is a racemic mixture; the L isomer has approximately 50 times higher affinity for the opioid receptors than the S isomer.1,3 In addition to its affinity for the opioid receptors, methadone is an antagonist at the N-methyl-d-aspartate receptor as well as a serotonin norepinephrine reuptake inhibitor.1,2,8 Binding at these receptors may account for decreased tolerance and improved efficacy in neuropathic pain states compared with other opioids, although evidence for this is lacking.4,8,9

Methadone exhibits large interindividual variation in both bioavailability and elimination half-life.2,10 Following oral administration, bioavailability has been reported to be between 36% and 100%, while the half-life ranges from 8 to 59 hours (up to 120 hours has been reported).2,8 There is a disconnect between the 6- to 12-hour duration of analgesia and the prolonged time to elimination from the body; thus, accumulation of methadone resulting in respiratory suppression is a concern.8 Methadone is metabolized by a number of cytochrome P450 (CYP) enzymes including CYP3A4, CYP2B6, and CYP2C19.2 The enzymes CYP2C9 and CYP2D6 are involved to a lesser extent. Physicians need to be cautious when prescribing methadone to avoid unwanted drug interactions.

Two advantageous pharmacokinetic properties of methadone when compared with morphine are its lack of active metabolites and minimal accumulation in patients with renal disease.2,8 Although patients with liver disease may accumulate methadone, this has not been well studied.

Place in Therapy
The analgesic efficacy of methadone primarily has been studied in patients with cancer pain. The National Comprehensive Cancer Network (NCCN) has developed guidelines for the treatment of these patients.11 The guidelines recommend morphine as the typical first-choice opioid. However, methadone is not a preferred initial treatment because of its long half-life, which makes it difficult to titrate. Other problems noted with methadone are its high potency and interindividual pharmacokinetic variability. When methadone is chosen for pain management in cancer patients, careful initiation or conversion from another opioid must take place. Generally, methadone is administered three to four times daily and is not recommended for breakthrough pain.

A 2008 Cochrane systematic review identified nine randomized controlled trials that compared methadone to morphine or other opioids for the treatment of cancer pain.12 No meta-analysis was performed due to the high variability among the studies; however, the authors concluded that methadone was similar to morphine in its analgesic efficacy. The authors did express concern over the fact that only one study was long-term (28 days); thus, there is limited literature evaluating methadone use that mimics clinical practice. Although comparative trials have described decreased need for escalating doses of methadone in cancer patients compared with morphine, this was refuted in a 2004 publication that demonstrated similar opioid dose-escalation indices for methadone and morphine.13-15

Guidelines from the American Pain Society (APS) and American Academy of Pain Medicine (AAPM) describe a role for methadone in the management of chronic pain that is unrelated to cancer.16 They suggest that it be used cautiously due to safety concerns and poor quality evidence surrounding its efficacy.9,16 In fact, only one small, randomized crossover trial for the treatment of noncancer pain has been published.17 Morley and colleagues compared methadone 10 mg per day (Phase I) or 20 mg per day (Phase II) to placebo in 19 patients with treatment-resistant neuropathic pain. Patients received active methadone therapy or placebo on odd days and no medication on even days during each 20-day treatment period. The results of 18 patients were reported for Phase I. No significant differences were found between methadone and placebo for maximum intensity or average intensity pain scores on a 100-mm visual analog scale (VAS); however, the scores were numerically better with methadone. There were significant differences in VAS scores between groups in the 11 patients who completed Phase II of the study. The mean maximum intensity score was an average of 9.25 points lower with methadone 20 mg per day and the mean average intensity score was an average of 6.56 points lower (P<0.02) compared with placebo. The external validity of this study is questionable based on the fact that patients received methadone every other day, which is not done in clinical practice.

Methadone has been evaluated for a variety of pain types in uncontrolled studies including back pain, neuropathic pain, chronic headache, and complex regional pain syndrome.18 In a review of 20 uncontrolled studies in patients with chronic noncancer pain (CNCP), 59% had meaningful pain relief with methadone (meaningful was defined as statistically significant changes in any of the quantitatively measured outcomes, satisfactory or acceptable pain relief in categorical outcomes, or worthwhile relief determined by consensus of the reviewers).18 Initial methadone doses ranged from 2.5 to 80 mg per day and the maximum doses varied from 20 to 930 mg per day.

First published on: March 1, 2012