Partial Opioid Agonists

Partial opioid agonists bind mu receptors with high affinity but lower intrinsic activity than full agonists. They provide analgesia and treatment of opioid use disorder with a ceiling on respiratory depression, but not on analgesia at usual doses. Buprenorphine is the principal member; mixed agonist-antagonists such as nalbuphine and pentazocine are related.

Mechanism. Buprenorphine is a partial mu agonist, a kappa antagonist and a nociceptin receptor agonist. Its slow dissociation from the mu receptor gives long duration and blocks full agonists. Nalbuphine and pentazocine are kappa agonists and partial or antagonist at the mu receptor.

Pharmacokinetics. Buprenorphine: sublingual bioavailability about 30 to 50%, onset 30 to 60 minutes, duration 6 to 8 hours; half-life 24 to 42 hours; hepatic CYP3A4; mostly biliary excretion, so safer in renal failure. Nalbuphine half-life 5 hours.

Buprenorphine for pain.

• Sublingual: 200 to 400 micrograms every 6 to 8 hours.
• Intravenous or intramuscular: 300 to 600 micrograms every 6 to 8 hours.
• Transdermal 7-day patch: 5, 10 or 20 micrograms/hour; titrate no sooner than 3 days; steady state takes 72 hours.
• Transdermal 96-hour patch: 35, 52.5 or 70 micrograms/hour.

Buprenorphine for opioid use disorder.

• Induction: first dose 2 to 4 mg sublingually once withdrawal is established (usually 12 to 24 hours after short-acting opioids; 48 to 72 hours after methadone), repeated up to 8 mg on day 1.
• Maintenance: 8 to 16 mg daily, maximum 24 mg daily.
• Combination with naloxone reduces injection misuse.

Nalbuphine. 10 to 20 mg (0.1 to 0.3 mg/kg) intravenously, intramuscularly or subcutaneously every 3 to 6 hours; maximum single dose 20 mg and 160 mg daily. Respiratory depression reaches a ceiling at about 30 mg.

Pentazocine and butorphanol. Mixed agonist-antagonists with psychotomimetic effects and withdrawal in opioid-dependent patients; use is limited and dosing varies by region.

• First-line. Opioid use disorder maintenance; chronic pain in renal failure or older adults using transdermal buprenorphine.
• Alternative. Moderate to severe pain where renal impairment limits morphine; postoperative pain, with nalbuphine where a ceiling on respiratory depression is wanted.
• Specialist. Buprenorphine in patients on methadone; high-dose induction and low-dose overlap induction regimens run by addiction specialists.
• Emergency. Nalbuphine for pruritus caused by neuraxial opioids (low doses) and for reversal of mu effects while keeping analgesia.

Perioperative practice. Continue buprenorphine at the usual dose in most patients and add multimodal analgesia; stopping risks relapse. For severe pain add a high-affinity full agonist, such as fentanyl or hydromorphone, in titrated doses, with monitoring.

Switching. Moving from full agonist to buprenorphine without waiting for mild-to-moderate withdrawal can precipitate withdrawal.

Contraindications. Acute respiratory depression; severe hepatic impairment (high-dose buprenorphine); paralytic ileus; hypersensitivity. Nalbuphine and pentazocine in opioid-dependent patients because they precipitate withdrawal.

Serious adverse effects. Respiratory depression (reduced but present, with benzodiazepines and alcohol); precipitated withdrawal; hepatotoxicity; QT prolongation (with the 20 micrograms/hour patch); constipation; sedation; local skin reaction; dental decay with long-term sublingual use.

Major interactions. Benzodiazepines and alcohol; CYP3A4 inhibitors (ritonavir, clarithromycin) raise levels; rifampicin and carbamazepine lower them; full opioid agonists compete for receptors and reduce their effect; naloxone only partially reverses buprenorphine.

Common prescribing errors.

• Starting induction too early.
• Stopping buprenorphine before surgery.
• Heat applied to patches.
• Substituting patch strengths by mg.
• Giving naloxone at too low a dose to reverse buprenorphine.

Special groups.

• Pregnancy: buprenorphine is used in opioid use disorder; neonatal abstinence syndrome occurs but is usually milder than with methadone.
• Breastfeeding: compatible.
• Children: limited licensed use.
• Older adults: transdermal patches are well tolerated.
• Kidney: preferred opioid in renal failure.
• Liver: reduce dose and monitor.
• East Africa: availability of buprenorphine and addiction services varies and may be limited.

Monitoring. Respiratory rate and sedation after dose changes; liver enzymes at baseline and at 3 to 6 months; ECG in QT risk; withdrawal scores during induction.

Referral and escalation. Addiction specialist referral for induction and for patients with complex co-morbidity; anaesthetic or pain referral before surgery.

Comparison with alternative classes. Compared with full agonists, buprenorphine has a respiratory ceiling and safer use in renal failure but is harder to reverse and displaces full agonists. Nalbuphine has less abuse potential but more dysphoria.