Article: Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: Implications for clinical use and policy

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Greenwald MK, Comer SD, Fiellin DA (2014) “Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: Implications for clinical use and policy.” Drug Alcohol Depend S0376-8716 (14)01025.

Despite the increasing clinical use of buprenorphine (BUP) and buprenorphine/naloxone (BUP/NX), there are still questions about how the binding of these medications to the mu-opiate receptor in the brain relates to their treatment effects. One important clinical question is whether there is any benefit to prescribing higher doses than those needed to prevent opioid withdrawal.

It has been found that higher doses of buprenorphine result in greater saturation of the opiate brain receptors; that is, fewer receptors are available for opiates to bind. When higher doses of BUP are prescribed, the risk of BUP being diverted (e.g. sold or misused) must be weighed against possible greater clinical benefits.  Higher maintenance doses of BUP offer more complete opioid blockade – which is more important than withdrawal suppression at preventing opioid use.  Thus, patients early in recovery who continue to use opioids despite the absence of withdrawal will likely need higher BUP doses to maximize the blockade of opioid receptors, in addition to minimizing their opioid withdrawal symptoms.

Re-analyzing data from a number of earlier studies has shown that there is a lot of inter-patient variability in BUP plasma levels; therefore, doses need to be individualized – rather than assuming that there is a dose level effective for the majority of patients. In order to fully block heroin self-administration, nearly all the mu opioid receptors in the brain need to be occupied, and this may require doses higher than 16 mg per day (achieving plasma levels of 3 ng/ml BUP).  By contrast, opioid withdrawal can be suppressed with doses as low as 4 mg daily (approximately a 50% receptor blockade, with plasma levels of 1 ng/ml BUP).  This article shows that there are limits to the scientific evidence available for determining appropriate doses of buprenorphine.  Research data should not be interpreted to suggest that 16 mg is necessarily a sufficient daily dose of buprenorphine.  In addition, the conclusions regarding plasma BUP levels are drawn from a small number of subjects; larger trials may make it possible to use plasma BUP levels to inform dosing decisions. The clinical goal should be to provide sufficient blockade of the opiate receptors that the patient stops using opioids, and in some cases this goal will necessitate higher BUP doses.