Buprenorphine

Buprenorphine is a partial mu-opioid agonist and kappa antagonist with very high receptor affinity and slow dissociation. It provides strong analgesia with a ceiling for respiratory depression, is used for chronic pain and opioid use disorder, and can be continued through surgery. Its high affinity makes it hard to reverse and able to precipitate withdrawal in patients on full agonists.

Class. Partial mu-opioid agonist; semisynthetic opioid.

Mechanism. Partial mu agonism with high affinity and slow dissociation, giving a ceiling on respiratory depression and euphoria but not on analgesia at usual doses. Kappa antagonism and nociceptin receptor activity contribute.

Pharmacokinetics. Poor oral bioavailability (under 15%) because of first-pass metabolism; sublingual bioavailability about 30 to 55%, onset 15 to 30 minutes, duration 6 to 8 hours. Intravenous or intramuscular duration 6 to 8 hours. Transdermal patches deliver for 3 to 7 days. Half-life 24 to 42 hours (long terminal phase). Hepatic metabolism by CYP3A4 to norbuprenorphine (active), biliary excretion.

Indications are moderate to severe pain (including chronic and cancer pain), opioid use disorder treatment, and perioperative analgesia in patients already on it.

Analgesia, adults

• Sublingual: 200 to 400 micrograms every 6 to 8 hours.
• Intramuscular or slow intravenous: 300 to 600 micrograms every 6 to 8 hours.
• Transdermal, 7-day patch: 5, 10, 15 or 20 micrograms/hour. Start 5 micrograms/hour in opioid-naive patients (7-day patch). Do not increase before 72 hours. Replace every 7 days.
• Transdermal, 3 to 4 day patch: 35, 52.5 or 70 micrograms/hour. Replace every 3 to 4 days.
• Approximate equivalence: 5 micrograms/hour is about 12 mg oral morphine daily; 10 micrograms/hour about 24 mg; 20 micrograms/hour about 48 mg.
• No loading dose for analgesia. Maximum for transdermal is two patches at once (not above 40 micrograms/hour in total).

Opioid use disorder (specialist)

• Begin induction when in mild to moderate withdrawal (typically at least 12 hours after short-acting opioid, 24 to 72 hours after methadone).
• Day 1: sublingual 2 to 4 mg, repeated after 2 to 4 hours to a maximum of 8 mg (up to 12 mg).
• Target 8 to 16 mg daily, adjusted to withdrawal and craving. Maximum 24 mg daily in most practice.
• Combination with naloxone is used to deter injection.

Children. Intravenous or intramuscular 3 to 6 micrograms/kg every 6 to 8 hours in specialist use.

Perioperative. Continue buprenorphine; split the dose if needed; add multimodal analgesia; use high-affinity-adjusted doses of full agonists with monitoring.

Contraindications. Respiratory depression without ventilatory support; acute alcohol intoxication; severe hepatic impairment (opioid use disorder products); hypersensitivity; transdermal use in opioid-naive patients for acute pain; monoamine oxidase inhibitor within 14 days.

Boxed-warning-level risks. Addiction, abuse and misuse; life-threatening respiratory depression; accidental exposure; neonatal opioid withdrawal syndrome; concurrent benzodiazepines and other central nervous system depressants; hepatitis and liver injury with long-term use; QT prolongation with transdermal doses over 20 micrograms/hour.

Adverse effects. Common: nausea, vomiting, constipation, headache, dizziness, drowsiness, sweating, application-site reactions. Serious: respiratory depression (especially with benzodiazepines), precipitated withdrawal, hepatitis, hypotension, QT prolongation and adrenal insufficiency.

Interactions. Benzodiazepines, alcohol and other depressants add sedation and respiratory depression. CYP3A4 inhibitors (ritonavir, ketoconazole, clarithromycin) raise levels; CYP3A4 inducers (rifampicin, carbamazepine) lower them. Full opioid agonists given too soon after buprenorphine may be blocked, and buprenorphine given to a patient on full agonists can precipitate withdrawal. Naloxone reversal needs larger doses.

Common prescribing errors. Starting induction too early (precipitated withdrawal); stopping buprenorphine before surgery; combining with benzodiazepines; applying external heat to a patch; increasing a patch before steady state.

Special groups

• Pregnancy: used in opioid use disorder treatment, with foetal and neonatal monitoring; neonatal withdrawal expected.
• Breastfeeding: compatible at usual doses.
• Older adults: start at the lowest dose.
• Kidney impairment: no adjustment required; preferred when other opioids accumulate.
• Liver impairment: reduce the dose in moderate disease; avoid in severe disease; monitor liver enzymes.
• Regional: opioid use disorder services and supervised dispensing vary; use local arrangements.

Formulations. Sublingual tablets (0.2, 0.4, 2, 8 mg), combination sublingual tablets with naloxone, injection 300 micrograms/mL, transdermal patches (5 to 70 micrograms/hour), buccal films in some markets.

Administration. Place sublingual tablets under the tongue until dissolved, without swallowing or chewing. Apply patches to clean, hairless skin on the upper torso or arm and rotate sites. Keep external heat away from the patch.

Baseline. Respiratory rate, sedation, liver enzymes, hepatitis B and C status in opioid use disorder, current opioid doses and last use, QT interval if cardiac risk.

Monitoring. Pain, withdrawal scores (during induction), respiratory rate, sedation, liver enzymes at baseline and periodically in opioid use disorder, and QT interval at higher patch doses. Review after patch changes at 72 hours.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Reduce or remove the patch for excessive sedation or respiratory depression (effect persists 24 hours or more after removal). Stop for hepatitis or marked enzyme rise.

Referral and escalation. Respiratory depression needs airway support and naloxone in larger or repeated doses (initial 2 mg, then infusion). Opioid use disorder needs addiction service involvement. Perioperative planning should involve anaesthetic and pain teams.