Drugs for Opioid Use Disorder

Drugs for opioid use disorder include opioid agonist treatment (methadone and buprenorphine), antagonist treatment (naltrexone), withdrawal medicines (lofexidine, clonidine) and the overdose reversal agent naloxone. Agonist treatment reduces mortality by about half and lowers infection risk, and is the first-line approach.

Mechanism. Methadone is a full mu-opioid agonist and NMDA antagonist. Buprenorphine is a high-affinity partial mu agonist with a ceiling on respiratory depression. Naltrexone and naloxone are competitive antagonists. Lofexidine and clonidine are alpha-2 agonists that reduce noradrenergic withdrawal symptoms.

Pharmacokinetics. Methadone half-life 24 to 36 hours, steady state in about 5 days, metabolised by CYP3A4 and CYP2B6. Buprenorphine half-life 24 to 42 hours, with sublingual bioavailability about 30%. Naloxone acts for 30 to 90 minutes, shorter than most opioids.

Differences. Methadone retains more patients in treatment but has QT and overdose risks. Buprenorphine is safer in overdose and easier to initiate, but induces withdrawal if started too early.

• Opioid agonist treatment: methadone or buprenorphine as maintenance, for as long as needed, with psychosocial support.
• Buprenorphine start: wait for clear withdrawal (a score of at least 8 to 12 on a clinical scale), 12 to 24 hours after short-acting opioids and 48 to 72 hours after methadone.
• Methadone start: start low, supervise doses for the first weeks, and avoid rapid increases. Overdose risk is highest in the first 2 weeks.
• Missed methadone doses: reassess after 3 days and reduce the dose; restart titration after 5 consecutive missed days.
• Antagonist treatment: for motivated, fully detoxified patients.
• Naloxone: supply to patients, family and peers; give after any opioid overdose, with a repeat dose or infusion at two thirds of the effective bolus each hour if respiratory depression returns.
• Withdrawal: lofexidine or clonidine with symptomatic drugs for those not on agonist therapy.

Special groups. Pregnancy: continue methadone or buprenorphine; neonatal abstinence syndrome is monitored and treated. Breastfeeding: compatible. Children: specialist use only. Older adults: lower doses. Kidney impairment: buprenorphine and methadone are acceptable. Liver impairment: reduce doses. Regional: opioid agonist treatment programmes exist in some East African countries but access remains limited, and HIV, hepatitis C and tuberculosis are frequent in people who inject drugs, so co-management is important.

Adverse effects. Sedation, constipation, sweating, nausea, hypogonadism and sexual dysfunction, QT prolongation (methadone), respiratory depression, and neonatal withdrawal. Buprenorphine: headache, injection-site reaction with depot forms.

Contraindications. Methadone with prolonged QT interval, and naltrexone with current opioid use. Buprenorphine with severe liver disease.

Interactions. Rifampicin, efavirenz, nevirapine and carbamazepine lower methadone levels and can trigger withdrawal. Fluconazole, ciprofloxacin and clarithromycin raise levels. QT-prolonging drugs (macrolides, quinine, antipsychotics, ondansetron) add risk. Benzodiazepines and alcohol add respiratory depression.

Monitoring. ECG at baseline and at doses over 100 mg methadone daily or with risk factors (reduce the dose if QTc is over 500 ms), urine drug screens, sedation in the first weeks, liver enzymes, and blood-borne virus screening.

Referral and escalation. QTc over 500 ms, repeated overdose, severe withdrawal, pregnancy, or need for inpatient stabilisation.