Besides being one of the least expensive opioid analgesics, methadone has characteristics that differentiate it from other opioids and suggest that it may have a different efficacy and safety profile. Researchers in Denmark conducted a Cochrane Systematic Review to assess the analgesic efficacy and safety of methadone in the treatment of chronic noncancer pain, but they found little relevant supportive evidence.
Researchers at the Danish Pain Research Center in Aarhus, Denmark, conducted an extensive literature review to identify both randomized controlled trials (RCTs) and non-randomized studies of methadone use in chronic noncancer pain (CNCP) in adults [Haroutiunian et al. 2012]. Their search covered the Cochrane Central Register of Controlled Trials, MEDLINE (from 1950 to November 2011), and EMBASE (1980 to November 2011), together with reference lists in retrieved papers and reviews.
The researchers included RCTs with pain assessment as either the primary or secondary outcome. Lower-quality evidence from quasi-randomized studies, cohort trials, and case-control trials also was considered for inclusion since the investigators suspected that benefits and risks of methadone in CNCP were not adequately addressed in RCTs.
The literature searches yielded 49 potentially relevant studies, of which only 3 were adequate to meet inclusion criteria: 2 RCTs and 1 non-randomized study, involving a total of 181 participants. Both RCTs were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes and the other involving 76 participants with postherpetic neuralgia — study duration was 20 days and approximately 8 weeks, respectively. The non-randomized study retrospectively evaluated 86 outpatients during an average of roughly 9 months. Here are specific outcomes…
- One RCT examined average pain intensity and pain relief, and found statistically significant improvements with methadone versus placebo for both outcomes, with 10 mg and 20 mg daily doses of methadone.
- The second RCT investigated differences in pain reduction between methadone and morphine, with morphine being statistically superior.
- The non-randomized study found that methadone was effective in proportionately fewer participants than in those prescribed other long-acting opioids: ie, 28% versus 42%, 33%, and 50% for morphine, oxycodone, and transdermal fentanyl, respectively.
- Incidences of adverse events were assessed in 1 RCT, but a significant difference between methadone and placebo was found for only one event, dizziness (P = 0.04).
The researchers conclude that the 3 studies of reasonable quality provide very limited evidence of methadone’s efficacy for CNCP. Furthermore, there were too few data for a pooled meta-analysis of efficacy or harm, or to have confidence in the results of the individual studies. Therefore, they concede that on the basis of available evidence no conclusions can be affirmed regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.
COMMENTARY: Systematic reviews and meta-analyses were discussed in a previous UPDATE [here], and approaches endorsed by the Cochrane Collaboration are among the most rigorous and thorough. Therefore, a strikingly unexpected finding of this study by Haroutiunian et al. was there are so few studies of reasonable quality examining methadone for chronic noncancer pain.
Methadone has been available since the 1940s and was originally used as an analgesic; however, early applications in children and adults revealed how difficult methadone can be to safely prescribe and its widespread use for analgesia was disparaged until roughly 1999. However, there have been problems associated with the resurgence of methadone prescribed for pain.
As we noted in an UPDATE last July [here], the U.S. Centers for Disease Control and Prevention (CDC) reported that methadone accounted for 4.4 million (1.7%) of the 257 million opioid analgesic prescriptions in 2009; however, about 5,000 persons died of methadone-related overdose, which accounted for approximately 30% of all deaths associated with prescription opioids. Methadone-related deaths reportedly increased 6-fold from 1999 to 2009 [see Figure].
Methadone appears to carry greater risks than other opioids because it tends to build up in the body and can incur respiratory depression or, allegedly, cardiac rhythm disturbances. CDC researchers stress, however, that methadone has been used safely and effectively for decades in treating opioid addiction, and that modality does not appear to be part of the current problems.
In an excellent commentary article, Reisfield and Friedman  recently observed, “The paradox is that, whereas methadone maintenance therapy has reduced the mortality associated with opioid addiction, methadone analgesic therapy for chronic pain has been an outsized source of opioid-related deaths.” They further note that patients with substance use disorders and comorbid pain are at particularly high risk of adverse events with methadone analgesic therapy.
As an opioid analgesic, methadone is a relatively inexpensive generic product, so there may have been little incentive (or funding) through the years to conduct high quality studies of its efficacy or safety for CNCP, as Haroutiunian and colleagues found in their literature search. And, apparently, there may have been negligible motivation on the parts of methadone manufacturers to invest extensively in practitioner education on safe prescribing. In the CDC data [Figure above] there appears to be a decline in methadone prescribing for pain during recent years, with an associated waning of death rates; but, it is unknown whether this trend was a data artifact or will continue.
> Haroutiunian S, McNicol ED, Lipman AG. Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012(Nov);11:CD008025 [abstract here].
> Reisfield GM, Friedman CK. Methadone in the Chronic Pain Patient With a Substance Use Disorder. J Pain Palliative Care Pharmacother. 2012;26:368-370 [abstract here].
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