An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Receptor Modulator Buprenorphine

Abstract

Buprenorphine, an analogue of thebaine, is a Schedule III opioid in the United States used for opioid-use disorder and as an analgesic. Research has shown drugs like buprenorphine have a complicated pharmacology with characteristics that challenge traditional definitions of terms like agonist, antagonist, and efficacy. Buprenorphine has a high affinity for the mu (MOR), delta (DOR), kappa (KOR), and intermediate for the nociceptin opioid receptors (NOR). Buprenorphine is generally described as a partial MOR agonist with limited activity and decreased response at the mu-receptor relative to full agonists. In opioid naïve patients, the drug’s analgesic efficacy is equivalent to a full MOR agonist, despite decreased receptor occupancy and the “ceiling effect” produced from larger doses. Some argue buprenorphine’s effects depend on the endpoint measured, as it functions as a partial agonist for respiratory depression, but a full-agonist for pain. Buprenorphine’s active metabolite, norbuprenorphine, attenuates buprenorphine's analgesic effects due to NOR binding and respiratory depressant effects. The method of administration impacts efficacy and tolerance when administered for analgesia. There have been eleven-thousand reports involving buprenorphine and minors (age < 19) to US poison control centers, the preponderance (89.2%) with children. The consequences of prenatal buprenorphine exposure in experimental animals and humans should continue to be carefully evaluated. In conclusion, buprenorphine’s characterization as only a partial mu-agonist is an oversimplification. Contemporary research shows the traditional explanation of the pharmacology of buprenorphine does not take into account changes to receptor theory, pharmacological terminology, route of administration, and biologically active major metabolites.

Pronounced State-Level Disparities in Medicaid Prescribing of Buprenorphine for Opioid Use Disorder (2019–2020)

“…Buprenorphine is active at all four of the opioid receptors, mu, kappa, delta, and nociception. 12,13 Agonism of mu1 and mu2 receptors in the central nervous system causes euphoria, analgesia, nausea and vomiting, and respiratory depression. 8 Antagonism of the kappa receptor causes dysphoria.…”

“…Buprenorphine is metabolized in the liver by CYP450 3A4 to its active metabolite norbuprenorphine. 12,13 This metabolite has a greater affinity for the nociceptin receptor and is partially responsible for the respiratory depression that may occur after buprenorphine administration. 12,13 Respiratory depression is particularly a concern when buprenorphine is combined with benzodiazepines.…”

Dynamic changes in methadone utilisation for opioid use disorder treatment: a retrospective observational study during the COVID-19 pandemic

“…In regions where available, methadone is frequently used for severe OUD cases due to its full mu receptor agonist properties and its doses can be titrated up as needed. Buprenorphine is a partial mu receptor agonist with less higher-end dosing flexibility 13. Methadone necessitates expert handling, especially in the early stages of treatment because of its full agonism properties combined with high lipophilicity, long serum half-life and active metabolites 14…”

Pronounced State Level Disparities in Medicaid Prescribing of Buprenorphine for Opioid Use Disorder (2019-2020)

“…Buprenorphine is active at all four of the opioid receptors, mu, kappa, delta, and nociception. 12, 13 Agonism of mu 1 and mu 2 receptors in the central nervous system causes euphoria, analgesia, nausea and vomiting, and respiratory depression. 8 Antagonism of the kappa receptor causes dysphoria.…”

“…It additionally has moderate affinity for the nociceptin receptor.Buprenorphine is metabolized in the liver by CYP450 3A4 to its active metabolite norbuprenorphine. 12, 13 This metabolite has a greater affinity for the nociceptin receptor and is partially responsible for the respiratory depression that may occur after buprenorphine administration. 12, 13 Respiratory depression is particularly a concern when buprenorphine is combined with benzodiazepines.…”