Buprenorphine is a thebaine derivative originally developed in the 1970s as an analgesic.¹⁵,¹⁶ Due to its unique pharmacologic profile, it was later discovered to have the potential for treatment in OUD.¹⁶ Buprenorphine is a partial agonist at the µ-opioid receptor and a full antagonist at the κ-opioid receptor.¹⁶ It also binds the delta and opioid-receptor-like 1 (ORL-1) receptors.¹⁶ As an ORL-1 receptor agonist, buprenorphine has a distinct interaction with pain processing.¹⁷ Activating the ORL-1 receptor in the dorsal horn is analgesic, but as illustrated in animal models, cerebral activation of ORL-1 blunts antinociception.¹⁷ Antagonism at the κ-opioid receptor reduces opioid misuse and has been implicated in the treatment of depressive symptoms.¹⁶,¹⁸,¹⁹ Many of buprenorphine’s clinical attributes come from its partial agonism at the µ-opioid receptor. Buprenorphine is a lipophilic compound that dissociates very slowly from the µ-opioid receptor; this along with its long half-life is both thought to play a role in its extended duration of action.¹⁸,²⁰ In addition to its dissociative properties, buprenorphine has a high affinity for the µ-opioid receptor and will not be readily displaced by either µ-opioid receptor full agonists or antagonists, such as naloxone.¹⁸,²¹ Conversely, because of its heightened affinity, buprenorphine will compete for binding at the receptor site and displace receptor-bound opioid agonists precipitating withdrawal when taken by individuals physically dependent on opioids.¹⁶

Once absorbed, buprenorphine is metabolized primarily by the CYP3A4 enzymes in the liver into the metabolite norbuprenorphine.¹⁵ At therapeutic doses, buprenorphine and its metabolites do not inhibit cytochromes resulting in few drug-drug interactions.²⁰ The clearance of buprenorphine is largely via the gastrointestinal tract, and its elimination is not impacted by renal function making it safe to use in those with renal failure or on hemodialysis.¹⁷ Buprenorphine has been shown to provide effective analgesia at low to moderate doses and on average is 30 times more potent than morphine.¹⁸,²¹ Unlike other opioids, buprenorphine has a dose-ceiling effect on respiratory depression but not on analgesia.¹⁷ The respiratory depression associated with buprenorphine is found to be related to its metabolite and not the parent compound itself.¹⁷

Buprenorphine comes in sublingual, transdermal, subcutaneous, and intravenous formulations. Sublingual buprenorphine is typically taken once daily, but some patients may split their dosing into twice (BID) or three (TID) times a day dosing to maintain its therapeutic effect throughout the day and night. For the treatment of OUD, the combination product of buprenorphine with naloxone as a sublingual film is most commonly used. Naloxone, an opioid antagonist, is active parenterally; however, it has limited oral and sublingual bioavailability. Therefore, the naloxone component is solely a diversion and misuse deterrent.²² Specifically, if the combination product of buprenorphine with naloxone is injected, the naloxone component becomes active within 20 minutes, which would initiate withdrawal with opiates
present²² and would attenuate any “rush” that could occur, decreasing the risk of misuse.²² Most patients on buprenorphine for OUD are on doses between 8 and 24 mg. Based on clinical studies with small sample sizes, the percentage of µ-opioid receptors occupied by buprenorphine is <50% at a dose of 2 mg/day and >80% at a higher dose of 16 mg/day.²¹,²³ From empirical data, the higher dose of buprenorphine has been shown to decrease withdrawal symptoms and displace or block full opioid agonists such as hydromorphone.²⁴ However, clinically, there is extensive individual variation in the daily dosages required to achieve stability for patients. For example, some patients only require 8 mg daily to not have any withdrawal or craving symptoms throughout a 24-hour period, while other patients may require 24 mg daily to achieve the same clinical effect.

The implementation of the Drug Addiction Treatment Act (DATA) in 2000 has allowed more providers to prescribe MOUD, resulting in more adults who are prescribed buprenorphine present for surgery and procedural interventions. Controversy has ensued as there are limited guidelines on the management of acute pain in patients on buprenorphine; therefore, achieving effective analgesia during this period can be difficult due to its pharmacological predominance as a partial µ-receptor agonist. Based on early case reports and expert opinion, initial management was to stop buprenorphine 72 hours prior to an anticipated procedure or intervention that results in acute pain.²⁵ The thought behind this recommendation was based on the potential interference of buprenorphine with full µ-opioid receptor agonists. Because buprenorphine has a high affinity to its receptors, maintaining a patient on buprenorphine preprocedure would require higher and more frequent dosing of opioid agonists to manage pain. However, Kornfeld and Manfredi reported potential complications, including acute withdrawal, which can worsen pain from abruptly discontinuing buprenorphine prior to surgery.²⁶ Moreover, a recent retrospective cohort and other observational studies have concluded that continuing buprenorphine perioperatively and adding opioid analgesics along with multimodal adjuncts (Table 32.1) for breakthrough pain after surgery is an effective management strategy.⁹,¹⁴ Further, splitting a patient’s buprenorphine total daily dose into split dosing, such as three- or four-times daily dosing, is a useful strategy to continue a patient on their dose of buprenorphine that ensures OUD and recovery stability (no withdrawal, craving) with additional analgesic benefits from the buprenorphine itself. At our institution, this is a common method we use for patients in the perioperative period.

Another strategy (but not preferred) for acute pain control involves converting buprenorphine to a methadone regimen with the thought that better analgesia can be achieved using a full opioid agonist over a partial agonist²⁷; the data on this specific regimen, however, are limited. Additionally, this method lends to complex postprocedure management for restarting patients on buprenorphine given methadone’s long half-life; this delayed restart of a patient’s
medication for OUD can place the patient at risk of instability and substance use recurrence. Lastly, some experts suggest that the κ-antagonist effect of buprenorphine may help reduce opioid-induced hyperalgesia, which is commonly seen in patients receiving MOUD.²⁵ Thus, continuation of buprenorphine through the perioperative period with the use of an individualized multimodal pain management plan may be the optimal strategy for many patients. Discontinuation of buprenorphine in stabilized OUD or chronic pain patients without appropriate periprocedural pain management presents medical risks and burdens patients, prescribers, and the health system as a whole.