Methadone

Methadone is a long-acting full opioid agonist used for maintenance treatment of opioid use disorder, for opioid detoxification, and, in specialist hands, for severe chronic pain. Its long and variable half-life means it accumulates over the first days to weeks, so most deaths occur in the first two weeks of treatment. It prolongs the QT interval and has many interactions, including with rifampicin and antiretroviral medicines. It is prescribed and dispensed only through a supervised treatment programme in most settings.

Classification. Opioid analgesic, full mu-receptor agonist, long-acting; also an NMDA receptor antagonist.

Mechanism. Agonist at mu opioid receptors, which relieves withdrawal and craving and blocks the euphoric effect of other opioids through cross-tolerance.

Pharmacokinetics. Well absorbed orally (bioavailability about 80%), peak in 2 to 4 hours. Metabolised by CYP3A4, CYP2B6 and, to a lesser extent, CYP2D6 to inactive metabolites. Half-life 24 to 36 hours, with wide variation between patients (13 to 58 hours). Steady state takes 5 to 7 days or longer.

All regimens are oral with no loading dose.

Opioid use disorder, adults (initiation).

• Start 10 to 30 mg once daily, using the lower end (10 to 20 mg) for low or uncertain tolerance, older adults, or use of benzodiazepines, alcohol or other sedatives.
• If withdrawal persists after 3 to 4 hours, a further 5 to 10 mg may be given; total on day 1 should not exceed 40 mg.
• Titration: increase by 5 to 10 mg every 3 to 5 days (slower in the first week; weekly in higher-risk patients) based on withdrawal, craving and sedation. Do not increase by more than 30 mg in the first week.
• Maintenance: usual 60 to 120 mg once daily; some patients need more. Give under supervision at first.

Opioid detoxification (inpatient or specialist). Stabilise on a dose, then reduce by 5 to 10 mg daily or every few days, adjusted to withdrawal.

Chronic pain (specialist use only). 2.5 to 10 mg every 8 to 12 hours; titrate no faster than every 5 to 7 days.

Missed doses. After 3 or more missed days, reassess tolerance and consider restarting at a lower dose; after 5 or more missed days, restart with the initiation doses.

Dose limits. Older adults and frail patients: start at the low end and titrate slowly. Liver impairment: reduce doses; avoid in severe impairment. Kidney impairment: use cautiously. Reduce the dose if the QTc is prolonged or sedation develops.

Contraindications. Significant respiratory depression, acute asthma, paralytic ileus, concurrent or recent monoamine oxidase inhibitor, severe liver impairment, raised intracranial pressure, acute alcohol intoxication, hypersensitivity. Major warning of life-threatening respiratory depression, QT prolongation and serious arrhythmias, neonatal opioid withdrawal syndrome, accidental ingestion by children, and profound sedation with benzodiazepines and other central nervous system depressants.

Serious adverse effects. Respiratory depression and death (especially in the first 2 weeks and with sedatives), QT prolongation and torsades de pointes, hypotension, hypoglycaemia, adrenal insufficiency, serotonin syndrome with serotonergic medicines, misuse and diversion, tolerance, dependence and withdrawal.

Common adverse effects. Constipation, sedation, nausea, sweating, reduced libido and sexual dysfunction, dry mouth, weight gain, dizziness, itching.

Interactions. Benzodiazepines, alcohol, gabapentinoids and other sedatives add respiratory depression.

Rifampicin lowers levels sharply, so withdrawal can emerge within days and doses often need to rise by 50% or more; reduce again when rifampicin stops.

Ritonavir-boosted protease inhibitors, efavirenz, nevirapine, carbamazepine, phenytoin and St John’s wort lower levels. Fluconazole, ketoconazole, clarithromycin, ciprofloxacin and fluvoxamine raise levels.

QT-prolonging medicines (macrolides, fluoroquinolones, antipsychotics, ondansetron, azole antifungals) add risk. Zidovudine levels rise.

Common prescribing errors. Starting too high or increasing too quickly; assuming tolerance from a patient’s reported use; no ECG when QT risk factors exist; missing the interaction with rifampicin or antiretroviral medicines; co-prescribing benzodiazepines; giving take-home doses early; not offering naloxone.

Special groups.

• Pregnancy: preferred over illicit use or unsupervised withdrawal; dose may need to rise in the third trimester and fall after delivery; neonatal opioid withdrawal syndrome needs monitoring.
• Breastfeeding: compatible at stable doses; monitor the infant for sedation.
• Children: accidental ingestion can be fatal; store out of reach and use child-resistant containers.
• Older adults: start low; higher risk of sedation and falls.
• Kidney impairment: use cautiously.
• Liver impairment: reduce doses; avoid in severe disease.

Formulations. Oral solution 1 mg/mL (and stronger concentrates); tablets 5 mg and 10 mg; dispersible tablets 10 mg to 40 mg; injection 10 mg/mL in some regions. Supervised daily consumption at the start. Dispense in a labelled child-resistant container for take-home doses.

Baseline. Opioid use history and tolerance, urine drug screen, ECG when there is cardiac disease, syncope, a family history of sudden death, or QT-prolonging medicines, liver function, HIV, hepatitis B and C and tuberculosis status, pregnancy status, mental health and suicide risk, sedative and alcohol use, medicines list.

Monitoring. Review sedation, withdrawal and craving daily in the first week and then at each titration step. Repeat an ECG after dose rises over 100 mg or if new QT-prolonging medicines start. If the QTc is over 500 ms, reduce the dose or change treatment. Caution if the baseline QTc is over 450 ms in men or 470 ms in women. Repeat liver function and urine drug screens periodically. Provide naloxone and teach the patient and family how to use it.

Stopping. Reduce slowly, by 5 to 10% of the dose every 1 to 2 weeks, with the pace set by withdrawal symptoms. Warn that tolerance falls after stopping, so a return to previous opioid doses can be fatal.

Referral and escalation. Refer to a licensed opioid treatment service for initiation and supervision. Sedation, slow breathing, pinpoint pupils or oxygen saturation under 92% needs emergency care with naloxone and prolonged observation because the effect outlasts naloxone. Syncope or palpitations needs an urgent ECG.