Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds

Mode of action of opioid drugs

Opiate drugs, such as heroin (diamorphine), are natural derivates from opium, whereas opioids, such as methadone and buprenorphine, are synthetic derivates of opiates. There are a number of opioid receptor subtypes in the central nervous system and the effect of their activation is shown in Table 1. For both buprenorphine and methadone mμ and delta receptor subtypes mediate adenyl cyclase activity and activation of inwardly rectifying potassium channels leading to a release of endogenous opioids, such as endorphins and enkephalins, thus both are effective at bringing about analgesia and euphoria, but to differing degrees.

Table 1 Activity of opioid receptor subtypes

Mode of action of buprenorphine

Due to its unique pharmacologic profile, buprenorphine has, in principle, a number of advantages over methadone for use as an opioid replacement therapy. For example, it has low intrinsic activity at mμ receptors. This means that buprenorphine is not as potent as a full mμ agonist, like methadone, and causes less analgesia and euphoria but nonetheless ameliorates withdrawal symptoms [Table 2]. Anecdotal clinical experience is in keeping with these findings and recipients of buprenorphine often complain about missing the “high” of methadone.

Table 2 Comparison of buprenorphine and methadone in the treatment of opioid dependence

As a partial agonist, buprenorphine has a “ceiling effect,” that is, after a certain point taking more will not increase any of the effects of the drug. In addition, buprenorphine has a high affinity for the mμ receptor, which means that it reduces the effects of additional opioid use. As a potent kappa antagonist, buprenorphine has less dysphoriant effects than methadone and, therefore, may be better tolerated according to an open-label study.[10]

Efficacy of opioid replacement therapies

Cost-effectiveness

A number of studies have addressed the issue of the cost-effectiveness of buprenorphine and methadone. A comparison of these studies is problematic because they use different parameters to evaluate cost-effectiveness.[15] Where comparison is possible, flexible dose methadone maintenance (UK£14,000; US$23,100; Indian Rupees 1,030,400) performs somewhat better in terms of quality-adjusted life years than buprenorphine (UK£27,000; US$44,550; Indian Rupees 1,987,200) when both are compared to no drug therapy for heroin users. Table 2 compares buprenorphine to methadone in terms of pharmacology, preparation, effects, and costs.

Safety of opioid replacement therapies

The safety features of pharmacotherapies for heroin dependence must be weighed up against the benefits of continued illicit drug use. All opioid replacement therapies considered here can potentially cause death but continued heroin use is associated with high morbidity. For example, Caplehorn and Drummer found that methadone maintenance saved two lives for every one lost in a year.[8] There are a number of safety domains that could be considered here but these will be limited to the most significant, being:

• Overdose potential;

• Abuse potential; and

• Serious side effects, for example, cardiovascular problems.

Overdose liability

Buprenorphine causes less respiratory depression than methadone due to its ceiling effect and, thus, has lower overdose potential.[16] In a recent pooled analysis of RCTs of opioid maintenance therapy buprenorphine showed no significant differences in serious adverse events compared with methadone.[15] However, when the authors conducted an indirect comparison from population cross-sectional studies there was less mortality associated with buprenorphine than methadone use. Two caveats need to be added here. Firstly, when used in combination with other respiratory depressants, such as alcohol or benzodiazepines, buprenorphine use can result in sedation, coma, and death.[17] Secondly, patients who have not been educated about the pharmacology of buprenorphine and use additional opioids seeking a “high” are at risk of overdose when the effects of buprenorphine wear off.

Abuse potential

Like all opioid drugs, buprenorphine has the potential for misuse. For instance, in opioid users in Glasgow in Scotland in the 1980s and 1990s, buprenorphine prescribed for pain management was obtained and used illicitly.[18] In countries where buprenorphine has been used widely for the treatment of opioid dependence, such as France, diversion has been a problem in 20% of recipients.[19] Furthermore, there is evidence suggesting that buprenorphine diversion is an increasing problem.[20] Although, where toxicological measures are recorded nationally diversion seems to be less of a problem—the average quarterly ratio of abuse cases per 1000 Subutex (the trade name for buprenorphine when used to treat opioid dependence) prescriptions dispensed in the USA was only 0.08.[21]

Nonetheless, buprenorphine diversion is a particular problem when it leads to use by the intravenous route, since as a preparation buprenorphine is formulated as a tablet and is associated with a number of complications, such as phlebitis. The higher prevalence of buprenorphine diversion—10 times more so than methadone, according to a recent Australian study[22] —may be due to its sublingual tablet formulation and difficulty associated with supervising its consumption compared to that of an oral liquid, such as methadone linctus or mixture. The recent adoption of a combined buprenorphine–naloxone tablet (Suboxone) may go some way to countering the effects of diversion—when taken sublingually buprenorphine avoids first pass metabolism (unlike naloxone, an opioid antagonist), but if Suboxone is injected naloxone blocks the effect of buprenorphine thus negating any “high.” However, once established at mμ receptor sites, there is some evidence that buprenorphine has been difficult to antagonize with naloxone.[23]

Serious side effects

Although buprenorphine has been used as an analgesic for over three decades it is a relatively new compound in terms of the treatment of opioid dependence, certainly in comparison with methadone. As with all new treatments, unknown medical complications may become apparent as clinical experience and usage of buprenorphine develops. Reports already exist of buprenorphine-induced hepatitis, in particular when used intravenously, and national guidelines now recommend regular monitoring of liver function, especially when commencing treatment.[24] However, alternative treatments are not without serious side effects; it has only recently been established that methadone, probably when prescribed in high doses, can cause cardiac problems, such as Torsades de Pointes.[25]

Indian perspective

India has a substantial opiate dependence problem with reports of up to 2 million addicts in the Sub-continent (although this must be considered in the light of a huge population pushing 1 billion people).[26] Although men are overwhelmingly more likely to use opiates in India compared to Europe and North America, and the urban-rural differential rates of use are not as marked. Official guidelines are very similar to those used in the UK and other developed nations, and the same treatments—both psychosocial and pharmacological—are available, but the health care system that delivers these interventions is different.[7] Both methadone and buprenorphine are available and used for opiate detoxification and maintenance purposes, but the enthusiasm for the latter agent in not shared quite to the same degree as in the West. Furthermore, there are differences in the licensing of the two compounds between India and Europe/North America.

Choosing between buprenorphine and methadone