A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain

Abstract

Buprenorphine is a Schedule III opioid analgesic with unique pharmacodynamic and pharmacokinetic properties that may be preferable to those of Schedule II full μ-opioid receptor agonists. The structure of buprenorphine allows for multimechanistic interactions with opioid receptors μ, δ, κ, and opioid receptor-like 1. Buprenorphine is considered a partial agonist with very high binding affinity for the μ-opioid receptor, an antagonist with high binding affinity for the δ- and κ-opioid receptors, and an agonist with low binding affinity for the opioid receptor-like 1 receptor. Partial agonism at the μ-opioid receptor does not provide partial analgesia, but rather analgesia equivalent to that of full μ-opioid receptor agonists. In addition, unlike full μ-opioid receptor agonists, buprenorphine may have a unique role in mediating analgesic signaling at spinal opioid receptors while having less of an effect on brain receptors, potentially limiting classic opioid-related adverse events such as euphoria, addiction, or respiratory depression. The pharmacokinetic properties of buprenorphine are also advantageous in a clinical setting, where metabolic and excretory pathways allow for use in patients requiring concomitant medications, the elderly, and those with renal or hepatic impairment. The unique pharmacodynamic and pharmacokinetic properties of buprenorphine translate to an effective analgesic with a potentially favorable safety profile compared with that of full μ-opioid receptor agonists for the treatment of chronic pain.

Keywords: Buprenorphine; Chronic pain; Opioid receptor; Pharmacodynamics; Pharmacokinetics; Pharmacology.

Fig. 1

Buprenorphine exhibits a higher binding affinity at the µ-opioid receptor than full μ-opioid receptor agonists. A low K_i value corresponds to greater binding affinity but does not necessarily translate to greater receptor activity [18]

Fig. 2

Buprenorphine promotes analgesia and limits side effects through unique downstream signaling events at the μ-opioid receptor. Activation of the μ-opioid receptor by full agonists (e.g., fentanyl) or a partial agonist such as buprenorphine results in G-protein signaling, which promotes the dissociation of the G_α and G_βγ subunits [12, 27]. The G_βγ subunit inhibits the opening of voltage-gated calcium channels and activates G-protein–gated potassium channels, whereas the G_α subunit suppresses cAMP levels [12, 27]. These signaling events lead to reduced neurotransmitter release and membrane hyperpolarization, thereby resulting in analgesia [12, 27]. Full agonist opioids cause substantial phosphorylation on multiple amino acid residues on the receptor’s carboxyl-terminal cytoplasmic domain, leading to β-arrestin recruitment and the endocytosis-mediated downregulation of analgesic signaling [28, 36, 37]. In addition, β-arrestin signaling has been correlated with adverse events [12, 33]. Buprenorphine-mediated activation of the μ-opioid receptor is unique in that it limits phosphorylation of the receptor and β-arrestin recruitment [12, 17, 33]. Ca²⁺ calcium ion, cAMP cyclic adenosine monophosphate, K⁺ potassium ion, OR opioid receptor, P phosphorylation

Fig. 3

Buprenorphine activity at spinal µ-opioid receptors provides analgesia while limiting euphoria and respiratory depression. Activation of the µ-opioid receptor results in varying effects depending on the extent of the activation. Full µ-opioid receptor agonists (e.g., fentanyl) promote analgesia but have a high probability of adverse events. As a partial µ-opioid receptor agonist, buprenorphine has receptor activity that sufficiently reaches the analgesic threshold but may demonstrate a ceiling effect on otherwise common opioid-related adverse events. Buprenorphine’s partial agonist effects at the µ-opioid receptor and preferential lower CNS activity provide several clinically desirable pharmacological properties compared with full agonists, including less potential for euphoria and respiratory depression in addition to providing equal or superior analgesia [, , –61]. CNS central nervous system

Fig. 4

The unique pharmacodynamics of buprenorphine promote analgesia while potentially reducing adverse effects. The multimechanistic regulation of opioid receptors by buprenorphine results in enhanced analgesia and decreased side effects [72]. Partial agonism at the μ-opioid receptor may result in moderate signaling activity but potent analgesia [6, 23, 41]; a ceiling effect on respiratory depression and euphoria [, , –44]; limited impact on GI motility [69, 73]; limited physical dependence, abuse potential, and withdrawal symptoms [14, 45, 62]; reduced immunosuppression and impact on the HPA axis [42, 69]; reduction in suicidal thoughts, anxiety, and depression [62]; and limited dysphoria [62]. Antagonism at the δ-opioid receptor may result in anti-opioid action [67, 69]; myocardial protection [63]; a limited impact on GI motility* [67]; and limited respiratory depression* [67]. Antagonism or inverse agonism [20] at the κ-opioid receptor may result in reduced depression [5, 66], dysphoria [65, 67], suicidal tendencies [62], anxiety [62], and hostility [62]; a limited potential for addiction* and tolerance [5, 20]; and reduced immunosuppression [6]. Full agonism at ORL1 may result in reduced supraspinal analgesia [64, 74]; enhanced spinal analgesia [74]; diminished opioid-rewarding effects [5, 68, 75]; and a limited potential for tolerance [9]. *Predicted effect on the basis of known receptor function. COOH carboxylic acid, GI gastrointestinal, HPA hypothalamic pituitary adrenal, OR opioid receptor, ORL1 opioid receptor-like 1