Buprenorphine is an opioid analgesic with unique pharmacologic properties that can serve as a powerful tool for pain management in the primary care setting. It appears to possess antihyperalgesic qualities, and rotating therapy to buprenorphine from other high-dose opioids has been demonstrated to result in improved pain control.^1,2 Constipation also appears to be less of an issue.³ Buprenorphine has a ceiling effect for respiratory depression,⁴ making it potentially safer—though not risk free^5,6,7—for individuals with respiratory comorbidities. Buprenorphine is available for administration via sublingual, buccal, and transdermal routes, which makes it an attractive option for those who have difficulty swallowing, unreliable intestinal absorption, or malignant bowel obstruction. There is still abuse potential,⁸ and therefore similarly to other medications, only the minimum effective dose that provides a functional benefit should be used after careful analysis of the risks and benefits.

The possibility of reduced immunosuppression has been raised based on animal models⁹ as well as the finding in human trials involving heroin abusers that both buprenorphine and methadone maintenance improves immune function relative to active heroin abuse¹⁰ and matches functional markers found in healthy controls.¹¹

Buprenorphine has been purported to have less of an effect on testosterone levels and sexual function based on a single study comparing it to methadone.¹² We consider this to be an unresolved clinical question as the expected potency of the mean buprenorphine dose was significantly lower than the mean methadone dose used in the comparison. However, it is worth noting that the testosterone levels of the buprenorphine-treated subjects were within the reported reference range despite being on a dose we would consider quite high in most chronic noncancer pain contexts.

Buprenorphine is an interesting molecule because of its distinctive receptor binding profile: in regard to its opioid receptor binding behavior, it acts as a partial agonist at the mu receptor and as an antagonist at the kappa receptor¹³. It appears to have further agonist activity at the nociceptin receptor,¹⁴ the clinical impact of which remains unclear but may have a role in terms of both analgesia and reducing reward pathway activation.

When binding to the mu receptor, buprenorphine produces a number of effects including analgesia, respiratory depression, and euphoria—just like any other opioid. Where its clinical effects depart from other opioids is the presence of an apparent ceiling dose for some effects. After a certain dose is reached, there is no further increase in the observed effect on the patient. This phenomenon is most well-described for respiratory depression⁴ but appears to hold true for euphoria as well.¹⁵ Studies demonstrating a ceiling effect were largely limited to opioid addiction settings, which may have led to extrapolation of the observed plateau in the drug’s effect to analgesia. It is important to note that while buprenorphine clearly behaves as a partial mu agonist at the receptor level, the observed clinical effect varies between that of a partial agonist and full agonist depending on the affected organ system and efficacy endpoint.^13,16 In terms of analgesia, convincing evidence of a ceiling effect for analgesia in humans has not been demonstrated.^17,18,19

The antagonist activity at the kappa receptor is a possible explanation for the antihyperalgesic qualities of buprenorphine, at least in part. Opioid administration stimulates expression of dynorphin, a kappa receptor agonist that has been implicated in the development of pain sensitization²⁰. That said, this is certainly an oversimplification of a complex process that is not fully understood. It is also important to note that neither the kappa receptor antagonist nor the partial mu receptor agonist properties prevent the successful use of other opioids for breakthrough pain, as multiple human trials have demonstrated.^18,21 If a patient on buprenorphine requires acute pain management (e.g., in the event of trauma or surgery), they can expect to respond to therapy in a manner similar to other patients on prior opioid therapy.