Tried-and-true methadone shows superiority over buprenorphine

Newer treatments often supplant older ones. In terms of medication assisted treatment for opioid disorders, methadone, which predates buprenorphine by almost three decades, may be more effective and have higher rates of patient retention than buprenorphine.

The superiority of methadone is robustly demonstrated in two domains, and otherwise these are both very effective interventions for opioid use disorder, as aptly shown in this comprehensive meta-analysis.

WHAT PROBLEM DOES THIS STUDY ADDRESS?

Medications have become an integral component for the treatment of opioid use disorders. Methadone treatment has been in use in the United States since 1947, whereas buprenorphine (often prescribed in tandem with naloxone as the brand name Suboxone) was approved in 1981.

The head-to-head studies conducted to evaluate the relative effectiveness of these two treatments have shown mixed results. By combining the data from all of the high quality trials conducted (comparing methadone and Suboxone to each other or testing each separately as compared with placebo), more robust conclusions about their relative effectiveness for the treatment of opioid use disorders can be drawn.

HOW WAS THIS STUDY CONDUCTED?

This Cochrane Review spanned 31 studies that evaluated the relative effectiveness of methadone and buprenorphine.

READ MORE ON STUDY METHODS

DESIGN: Primary outcomes measured included retention in treatment, use of other opioid or other substances of misuse as detected by urinalysis, criminal activity per self-report and mortality. Secondary outcomes measured include physical health, psychological health and adverse medication effects. These outcomes were pre-determined and independent of the main outcomes for the studies included. For each outcome measure included in a study, a standardized mean difference (for continuous variables) or a risk ratio (for dichotomous outcomes) was determined

SELECTION CRITERIA: Randomized controlled trials of buprenorphine maintenance treatment versus placebo or methadone in management of opioid use disorder in publication as of January 2013. Of the 6495 studies identified, a total of 31 trials (with 5430 participants) were deemed to be sufficiently unbiased and included in this analysis (high quality data suggests that further research is unlikely to change findings). Of the 31 trials analyzed, 20 included comparisons of methadone and buprenorphine, with interventions ranging from two weeks to 52 weeks in duration.

PARTICIPANTS: The 31 studies included 5430 participants. The majority of participants were male, predominantly with heroin-dependence based on third and fourth versions of the diagnostic and statistical manual of mental disorders, or DSM, averaging 30 years of age with various treatment histories and use of other drugs.

WHAT DID THIS STUDY FIND?

Buprenorphine was superior to placebo in retention of participants at all doses examined. The superiority was shown at doses as low as 2-6mg with increasing retention at increasing dosing up to and above 16mg (high quality evidence).

Only high doses of buprenorphine (>16mg) suppressed illicit opioid use as compared with placebo when measured by urinalysis. This is based on three studies (729 participants) and the evidence is of moderate quality. Low-dose (2-6mg) and medium dose (7-15mg) buprenorphine did not decrease illicit opioid use as compared with placebo.

Methadone and buprenorphine are equally effective (statistically there is no difference) in the suppression of opioid use in those subjects retained in treatment (1027 participants, moderate quality of evidence). This was primarily heroin use as measured by both self-report and urinalysis results.

Methadone was superior to flexible dose buprenorphine in retaining participants (788 participants, high quality of data) in aggregate. However, this superiority is primarily due to low dose methadone (≤ 40mg) being superior to low dose buprenorphine (2-6mg) at retaining participants, with no differences in retention seen for medium or high dose buprenorphine as compared with medium (40-85mg) or high dose (≥ 85mg) methadone.

A possible explanation for the lower retention rates seen with buprenorphine as compared with methadone is that these studies often included a very slow induction process for buprenorphine (where the dose is gradually increased over time), which has changed clinically since these studies were performed.

There is limited data comparing side effects. Only two studies examined side effects in detail and found no difference between methadone and buprenorphine other than a single finding of more sedation among those receiving methadone (56% of participants for methadone versus 26% for buprenorphine).

These results were all similar to the results found in a more recent follow-up study of longer terms outcomes comparing Suboxone (buprenorphine/naloxone) to methadone.

WHAT ARE THE IMPLICATIONS OF THE STUDY FINDINGS?

Despite the more rapid expansion of buprenorphine treatment as compared with methadone treatment for opioid use disorder, this study suggests that methadone treatment is superior to buprenorphine when comparing lower doses of each. Flexible dosing of methadone also seems to be more effective at participant retention than flexible dosing of buprenorphine. Both treatments suppress heroin use, albeit the higher doses of buprenorphine (versus low and medium doses) are needed to produce this effect.

Having two treatment options that work through different mechanisms and are generally equally effective does enhance patient care by increasing patient choice. Buprenorphine is available in outpatient settings, including primary care, and is generally more accessible but methadone continues to be an effective treatment with high retention rates over time.

LIMITATIONS

The authors refer to opioid use as measured by urinalysis although the text suggests that it is primarily heroin use that is measured (and the subjects enrolled were predominantly users of heroin). Given the expanding opioid preferences currently (e.g. oxycontin), these results may not translate exactly for other opioid drugs of choice including prescription opioids. The largest trial of prescription opioid dependence treatment focused on buprenorphine treatment.
The authors were limited by there being no studies comparing high dose methadone and high dose buprenorphine with respect to opioid use as detected by urinalysis.
There was insufficient data to analyze the effects on the secondary outcomes (legal involvement and death) although there was limited date to suggest no differences in these outcomes for methadone versus buprenorphine.

BOTTOM LINE

For individuals & families seeking recovery: Methadone is a highly effective treatment for opioid use disorder. Although buprenorphine is increasingly more available, this data suggests that retention rates for methadone are higher, and flexible dosing (which is more in tune with clinical use) is more effective for methadone as opposed to buprenorphine. However, the studies included in this review all used slow induction rates for buprenorphine (slowly increasing the dose over days rather than starting at a higher more effective dose). This gradual ramp-up for buprenorphine is expected to lower retention as it would initially be perceived as less effective. Currently, buprenorphine is administered at higher doses from the start so future studies may show more similarities between buprenorphine and methadone in terms of retention and success of flexible dosing.
For scientists: Investigating the possible mechanisms underlying the lower retention rate for buprenorphine (versus methadone) would increase the effectiveness of buprenorphine. Possible mechanisms are the rate of induction; the withdrawal induced by buprenorphine and by the preparation for induction; the fact that it is easier to discontinue buprenorphine versus the significant withdrawal induced by methadone, or other possible explanations. This Cochrane review does suggest that there is no need for further randomized controlled trials comparing the relative efficacy of methadone and buprenorphine. Given the adequate number of trials comparing both to placebo, at this point it may be unethical to include a placebo arm given that would involve providing substandard treatment for opioid use disorder.
For policy makers: Although there are public relations issues around the expansion of methadone clinics, this review suggests that this modality of treatment remains superior to buprenorphine in some respects and should not be supplanted by more easily accessible office-based buprenorphine.
For treatment professionals and treatment systems: Although buprenorphine treatment is becoming more widely available, patients are demonstrably more adherent to methadone treatment, an important determinant for recovering from opioid use disorder. Referrals to methadone clinics should be considered a first-line intervention.

CITATIONS

Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD002207. DOI: 10.1002/14651858.CD002207.pub4