Section 19 · Monograph
Methadone
Reviewed Nov 2026FDA label
Dolophine / MethadoseOpioid agonist + NMDA antagonist (CII)
- Forms
- Tab: 5, 10mg | Soln: 5, 10mg/5mL, 10mg/mL
- Dose
- Neuropathic or refractory pain (specialist-guided): start 2.5mg every 8-12h; nonlinear opioid conversion; QTc monitoring
- MOA
- μ-opioid agonism with NMDA receptor antagonism and monoamine reuptake inhibition
Black Box Warning
- Life-threatening QT interval prolongation and torsades de pointes; life-threatening respiratory depression (can occur later and last longer than analgesic effect); addiction, abuse and misuse; accidental ingestion; neonatal opioid withdrawal; interactions with CYP450 modulators and CNS depressants; opioid analgesic REMS and opioid treatment program requirements for OUD
Indications
- Pain severe enough to require an opioidFDA-labeled
- Detoxification and maintenance treatment of opioid use disorderFDA-labeled
Off-Label Uses
- Neuropathic and refractory cancer pain (NMDA antagonism)Off-label
Mechanism of Action
- Full mu-opioid agonist with NMDA receptor antagonism and monoamine reuptake inhibition; hepatic metabolism (CYP2B6, 3A4, 2C19, 2D6)
Full Dosing
Adult / usual
- Pain (specialist-guided): start 2.5mg every 8-12 hours; titrate no more often than every 3-5 days because of accumulation and a long half-life (8-59 hours)
- Conversion from other opioids is nonlinear and dose-dependent — use a validated protocol and reduce the calculated dose; seek palliative or pain specialist guidance
- Baseline ECG, then within 30 days and annually; repeat with dose above 100mg/day
Contraindications
- Significant respiratory depression
- Acute or severe bronchial asthma in an unmonitored setting
- Known or suspected gastrointestinal obstruction
- Hypersensitivity to methadone
Drug Interactions
- QT-prolonging drugs (antipsychotics, ondansetron, macrolides, fluoroquinolones, citalopram)
- CYP3A4/2B6 inducers (carbamazepine, phenytoin, rifampin) lower levels and may cause withdrawal; inhibitors raise levels
- Benzodiazepines and CNS depressants; serotonergic drugs
Adverse Effects
- QT prolongation and torsades
- Respiratory depression (delayed)
- Constipation, nausea, sedation
- Hypotension, hypoglycemia, sweating
Monitoring Parameters
- ECG and QTc
- Potassium and magnesium
- Sedation and respiratory rate; careful titration intervals
Pregnancy & Lactation
- Neonatal opioid withdrawal syndrome; used in pregnancy for OUD under specialist care
- Present in milk in low amounts