Clinical safety rating: safe
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Methadone is a mu-opioid receptor agonist with high affinity. It also acts as an NMDA receptor antagonist and inhibits serotonin and norepinephrine reuptake, contributing to its analgesic and maintenance effects.
| Metabolism | Primarily hepatic via CYP3A4, CYP2B6, and CYP2D6. Metabolites include EDDP (inactive) and EMDP. Undergoes N-demethylation and cyclization. Enterohepatic circulation may contribute to prolonged half-life. |
| Excretion | Primarily renal (20-40% as unchanged drug, with urine pH-dependent elimination; 50% as metabolites including EDDP and EMDP). Biliary/fecal excretion accounts for approximately 10-15%. |
| Half-life | Terminal elimination half-life: 24-36 hours following single dose; 13-50 hours with chronic dosing (due to tissue redistribution). Context: prolonged half-life supports once-daily dosing for opioid use disorder but requires careful titration to avoid accumulation. |
| Protein binding | 85-90% bound, primarily to alpha-1-acid glycoprotein (AGP) and albumin. |
| Volume of Distribution | 3-6 L/kg. Clinical meaning: extensive tissue binding and redistribution; Vd increases with tolerance and chronic use. |
| Bioavailability | Oral: 80-95% (range 40-99% due to first-pass metabolism). |
| Onset of Action | Oral: 30-60 minutes. Intravenous: 5-10 minutes (rarely used clinically). Intramuscular: 10-20 minutes. |
| Duration of Action | Duration of analgesia: 4-6 hours (single dose) to 6-8 hours (chronic dosing). Duration of suppression of withdrawal: 24-36 hours (steady state). Context: long duration facilitates once-daily maintenance. |
| Molecular Weight | 309.45 |
Initial: 20-30 mg orally once daily, titrated to effect. Maintenance: 10-120 mg orally once daily. Route: oral (tablet, liquid). Frequency: once daily.
| Renal impairment | GFR 30-60 mL/min: no adjustment; GFR <30 mL/min: use with caution, consider 50% dose reduction; hemodialysis: no supplemental dose; monitor for toxicity. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid or reduce by 75% with close monitoring. |
| Pediatric use | Use not recommended generally; if necessary, initial 0.1-0.2 mg/kg/dose orally every 12-24 hours, titrate to effect; max 10 mg/dose; limited data. |
| Geriatric use | Start with 2.5-5 mg orally every 8-12 hours; titrate slowly; monitor for CNS depression and QT prolongation; reduce maintenance dose by 25-50%. |
| 1st trimester | Limited human data; may cause neural tube defects at high doses; use only if benefit outweighs risk. |
| 2nd trimester | Continued use recommended for opioid use disorder to prevent withdrawal; risk of preterm birth and low birth weight. |
| 3rd trimester | Continued use recommended; risk of neonatal abstinence syndrome (NAS); monitor neonate for withdrawal. |
Clinical note
Standard-of-care MOUD for opioid use disorder in pregnancy. Methadone maintenance therapy reduces illicit drug use, stabilizes maternal physiology, and improves prenatal care engagement and fetal outcomes. Longer-established than buprenorphine in pregnancy with extensive outcome data. Requires daily observed dosing at an opioid treatment program (OTP). Associated with more severe and longer NOWS than buprenorphine. Dose changes required throughout pregnancy due to altered pharmacokinetics. Not the same as analgesic methadone use.
| Placental transfer | High; readily crosses the placenta with fetal concentrations approximately 50-100% of maternal levels. |
| Breastfeeding |
■ FDA Black Box Warning
Risk of respiratory depression, potentially fatal, especially during treatment initiation and dose titration. QT interval prolongation and life-threatening cardiac arrhythmias (Torsade de Pointes). Risk of opioid addiction, abuse, and misuse. Accidental ingestion, especially in children, can be fatal. Concomitant use with benzodiazepines or CNS depressants increases risk of profound sedation, respiratory depression, coma, and death.
| Serious Effects |
Severe respiratory depressionAcute or severe bronchial asthmaHypersensitivity to methadoneProlonged QT interval (congenital or acquired)Concurrent use of MAO inhibitors (within 14 days)
| Precautions | Risk of QT prolongation; monitor ECG if risk factors present. Respiratory depression risk, especially with concomitant CNS depressants. Use caution in elderly, cachectic, or debilitated patients. Adrenal insufficiency and androgen deficiency with prolonged use. Serotonin syndrome risk with concomitant serotonergic drugs. Severe hypotension, including orthostatic hypotension. Seizures in patients with seizure disorders. Avoid abrupt discontinuation; taper to prevent withdrawal. |
| Food/Dietary |
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| Methadone is excreted in breast milk in low concentrations; generally considered compatible with breastfeeding. However, monitor infant for sedation and respiratory depression. Avoid abrupt weaning to prevent withdrawal in the infant. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Methadone is not a major teratogen. First trimester use is associated with a small increased risk of neural tube defects (NTDs) (RR ~1.3) but absolute risk low (0.2-0.5%). Second/third trimester: risk of neonatal abstinence syndrome (NAS) ~60-80%, preterm birth, low birth weight. No major structural malformations consistently attributed. |
| Fetal Monitoring | Maternal: baseline LFTs, ECG (QTc), toxicology screens, adherence monitoring. Fetal: third trimester ultrasound for growth, fetal movement counts, non-stress tests (NSTs) weekly from 32 weeks. Neonatal: NAS scoring (Finnegan) every 3-4 hours for 72-96 hours postpartum. |
| Fertility Effects | Methadone may cause menstrual irregularities and reduced fertility due to hyperprolactinemia and hypothalamic-pituitary-adrenal axis disruption. In males, may reduce libido and sperm quality. Effects are dose-dependent and generally reversible upon dose reduction or discontinuation. |
| Avoid grapefruit and grapefruit juice as they inhibit CYP3A4, increasing methadone levels and risk of toxicity. High-fat meals may slightly delay absorption but have no clinical significance. No other specific food interactions. |
| Clinical Pearls | Methadone has a long and variable half-life (24-36 hours), requiring careful dose titration to avoid accumulation and respiratory depression. QTc interval prolongation is dose-dependent; obtain baseline ECG and monitor for >500 ms. Due to high protein binding, methadone is not significantly removed by hemodialysis. CYP3A4 and CYP2B6 inducers (e.g., rifampin, carbamazepine, phenytoin) can precipitate withdrawal; inhibitors (e.g., fluconazole, macrolides) increase toxicity. Pain management may require divided doses (TID-QID) despite once-daily MOUD dosing. |
| Patient Advice | Take exactly as prescribed; do not alter dose without consulting provider. · Do not consume alcohol, benzodiazepines, or other CNS depressants without medical approval. · Report symptoms of sleepiness, confusion, slow heartbeat, or difficulty breathing immediately. · Store securely out of reach of others; methadone can cause fatal overdose if taken by someone else. · Carry a medication list and inform all healthcare providers of methadone use. · QT prolongation risk: report palpitations, fainting, or family history of sudden cardiac death. · Do not stop suddenly; withdrawal may be severe and delayed. · Pregnancy: methadone is preferred over withdrawal; consult obstetrics for neonatal abstinence syndrome monitoring. |