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Is Buprenorphine a ‘Partial Agonist’? Preclinical and Clinical Evidence

Buprenorphine has a unique pharmacological profile, and while much remains to be learned, it is clear that it is an important treatment option for the management of moderate to severe cancer and non-cancer pain syndromes
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Abuse Potential

Another important aspect of opioid action is the potential for abuse. Buprenorphine is a psychoactive medication classified as a Schedule III substance under the Controlled Substance Act. It can elevate feelings of euphoria, well-being, and pleasure in certain individuals; as such, it has the potential for abuse. Unlike some other MOR agonists, the subjective and physiological effects plateau,21,22 and this ceiling effect may limit greater abuse. While buprenorphine certainly can be abused, it is usually not a "gateway" drug. That is, it is typically abused by drug-experienced rather than drug-naïve persons and usually is taken opportunistically rather than preferentially.23,24 In a study of known opioid abusers in treatment, fewer than 1% stated that buprenorphine was their drug of preference.25

The drug ‘liking’ scores of buprenorphine may seem paradoxical. On the one hand, injected buprenorphine was not well ‘liked’ in a study of morphine-maintained abusers.26 Buprenorphine increases positive subjective feelings compared to placebo, particularly when taken intravenously.27 Interestingly, the physiologic and subjective responses to buprenorphine do not exhibit a consistent relationship to dose, which may be due to a multimechanistic pharmacology.28 This may limit its "likability." Long-term buprenorphine use is known to reduce the dopamine response in the nucleus accumbens; in a preclinical study, the chronic use of buprenorphine reduced response to reward-related cues.29

Similar to methadone, buprenorphine can serve as a maintenance treatment for opioid addiction.30, 31 Indeed, its use in this setting is increasing. Methadone treatment has been associated with improved social function and reduced criminal activity.32 It is thought that certain opioid agents also may help treat concomitant mental disorders.33 Outpatients seeking drug treatment for opioid addiction evidence a preference for buprenorphine over methadone,34 but drop-out rates for buprenorphine treatment can be higher than for methadone treatment.35 Buprenorphine might have a better safety profile compared to methadone for routine outpatient use under medical supervision.24

Increasingly, clinicians are faced with the dilemma of managing legitimate chronic pain syndromes in known substance abusers. The challenge is whether or not to prescribe opioid agents in patients who may be actively or have recently abused them. Combination products of buprenorphine-naloxone may be an important therapeutic option in such cases.36,37 It is beyond the scope of this article to discuss the role of such combination products in clinical practice, but clinicians should be aware that they are available for treating this growing patient population.


New formulations have rekindled an interest in buprenorphine as an analgesic. Because the terminology used to characterize drugs in preclinical studies can lead to erroneous predictions or perceptions of a compound’s clinical utility, it is inappropriate to label an analgesic as either a "full agonist" or a "partial agonist" based on these alone. As an example, a ceiling effect in a preclinical test cannot be assumed to translate to a ceiling effect in clinical settings. The same drug can be either/both a full agonist and partial agonist, depending on the specific application. This is a particularly relevant principle for buprenorphine, which can act as a full agonist in analgesic effect and yet act as a partial agonist at the endpoints of respiratory depression or euphoria, clearly demonstrating the endpoint-dependent nature of these terms. As with all analgesics, proper patient selection is critical when deciding whether or not to initiate opioid therapy with agents such as buprenorphine, and appropriate opioid risk management strategies need to be used if therapy is started.

Last updated on: September 25, 2013