Buprenorphine Naloxone

Buprenorphine naloxone is a sublingual combination used for maintenance treatment of opioid use disorder. Buprenorphine is a partial opioid agonist with high receptor affinity, which gives a ceiling on respiratory depression and a lower overdose risk than full agonists. Naloxone is poorly absorbed under the tongue but blocks the effect if the product is injected, which discourages misuse. Starting too early in opioid withdrawal can precipitate severe withdrawal.

Classification. Opioid partial agonist with an opioid antagonist (fixed combination).

Mechanism. Buprenorphine is a partial agonist at mu opioid receptors with slow dissociation, and an antagonist at kappa receptors, which relieves withdrawal and craving and blocks other opioids. Naloxone is an opioid antagonist with low sublingual bioavailability.

Pharmacokinetics. Poor oral bioavailability, so it is given sublingually (bioavailability about 30%), peak in 1 to 4 hours. Metabolised by CYP3A4 to norbuprenorphine (active). Half-life 24 to 42 hours, giving once-daily dosing. Naloxone is mostly inactive by the sublingual route.

All regimens are sublingual with no loading dose.

Opioid use disorder, induction.

• Start when the patient shows clear signs of mild to moderate withdrawal: at least 6 to 12 hours after the last short-acting opioid, and at least 24 to 72 hours after a long-acting opioid. For a patient on methadone, reduce methadone to 30 mg daily or lower first.
• Day 1: 2 to 4 mg sublingual; repeat every 1 to 2 hours based on withdrawal, to a day 1 total of 8 to 12 mg.
• Day 2: up to 16 mg once daily.

Maintenance. 8 to 24 mg once daily; usual 12 to 16 mg. Maximum 24 mg daily (32 mg in some regions).

Dose limits. Liver impairment: use the combination product cautiously in moderate impairment; avoid in severe impairment (use buprenorphine alone under specialist care). Older adults: start low. Kidney impairment: no adjustment.

Contraindications. Severe respiratory insufficiency, severe liver impairment, acute alcoholism or delirium tremens, hypersensitivity. Avoid starting while opioid agonists are still active. Major warning of respiratory depression, particularly with benzodiazepines and other sedatives; neonatal opioid withdrawal syndrome; and precipitated withdrawal.

Serious adverse effects. Precipitated opioid withdrawal, respiratory depression (especially with benzodiazepines, alcohol or injection misuse), liver injury, adrenal insufficiency, hypersensitivity, orthostatic hypotension, QT prolongation (at high doses), dependence and withdrawal.

Common adverse effects. Headache, nausea, constipation, insomnia, sweating, oral numbness, mouth redness, tooth decay and dental problems, dizziness, drowsiness.

Interactions. Benzodiazepines, alcohol, gabapentinoids and other sedatives add respiratory depression. Strong CYP3A4 inhibitors (ketoconazole, ritonavir, atazanavir, clarithromycin) raise levels. Rifampicin, carbamazepine, phenytoin and St John’s wort lower levels. Opioid agonists and naltrexone are blocked by buprenorphine, and naltrexone causes precipitated withdrawal. Monoamine oxidase inhibitors need caution.

Common prescribing errors. Starting before withdrawal has begun; starting within 24 hours of methadone; underdosing in the first days; swallowing instead of dissolving the tablet; combining with benzodiazepines; not warning about dental care; failing to offer naloxone.

Special groups.

• Pregnancy: buprenorphine is an option; the single-ingredient product is often used, and the combination is acceptable in many services; neonatal withdrawal needs monitoring.
• Breastfeeding: low transfer to the infant; compatible; monitor for sedation.
• Children: accidental ingestion is dangerous; store safely; adolescents only under specialist care.
• Older adults: start low.
• Kidney impairment: no adjustment.
• Liver impairment: avoid in severe impairment.

Formulations. Sublingual tablets 2 mg/0.5 mg and 8 mg/2 mg; sublingual film in some regions; combination strengths vary. Place under the tongue and let the tablet dissolve fully (5 to 10 minutes); do not swallow, chew or speak while it dissolves. Sip water afterwards to rinse the mouth, wait 1 hour before brushing teeth, and arrange a dental review.

Baseline. Opioid use history and time since last use, withdrawal score, urine drug screen, liver function, HIV, hepatitis B and C status, pregnancy status, mental health, alcohol and benzodiazepine use, medicines list.

Monitoring. Review withdrawal and craving daily during induction, then weekly at first and monthly once stable. Repeat liver function after 1 month and then every 3 to 6 months. Repeat urine drug screens. Provide naloxone and teach the patient and family how to use it.

Stopping. Reduce gradually, for example by 2 mg every 1 to 2 weeks, with the pace set by withdrawal symptoms. Warn that opioid tolerance falls after stopping.

Referral and escalation. Refer to an opioid treatment service for induction and supervised maintenance. Precipitated withdrawal that is severe needs urgent care. Slow breathing or drowsiness needs emergency care with naloxone, which may need repeated or high doses because buprenorphine has high receptor affinity.