METHADONE HYDROCHLORIDE
Clinical safety rating: avoid
CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.
Mu-opioid receptor agonist; also NMDA receptor antagonist and serotonin/norepinephrine reuptake inhibitor.
| Metabolism | Hepatic via CYP3A4, CYP2B6, and to a lesser extent CYP2D6 and CYP2C19; metabolite EDDP inactive. |
| Excretion | Renal (80-90% as methadone and metabolites; ~30% unchanged), biliary/fecal (minor ~10%) |
| Half-life | Terminal half-life 24-36 hours (range 13-50 hours) for active l-isomer; clinical context: once-daily dosing possible but cautious due to prolonged QT interval risk. |
| Protein binding | 85-90% bound to alpha1-acid glycoprotein (AAG), also albumin to lesser extent; increased free fraction in chronic use. |
| Volume of Distribution | Vd 3-5 L/kg; extensive tissue binding; clinical meaning: high, reflecting accumulation in tissues (lungs, liver, kidney, muscle). |
| Bioavailability | Oral: 40-100% (average 80%); rectal: similar to oral; IM: ~100%. |
| Onset of Action | Oral: 30-60 min; IM: 10-20 min; IV: 5-10 min; onset of analgesia and respiratory depression. |
| Duration of Action | Analgesic duration: 4-8 hours (oral/IV) initially; with repeated use, duration extends to 12-24 hours due to accumulation. Note: Longer half-life does not correspond to analgesic duration. |
Oral: 20-30 mg daily for induction, then 20-120 mg daily for maintenance; IV: 2.5-10 mg every 8-12 hours for acute pain, titrated; IM/SC: same as IV. Frequency: daily for maintenance, every 8-12 hours for pain.
| Dosage form | INJECTABLE |
| Renal impairment | eGFR 15-60 mL/min: No dose adjustment; caution for accumulation. eGFR <15 mL/min: Consider 50% dose reduction or extend interval to every 12-24 hours. Dialysis: not significantly removed; reduce dose as for severe renal impairment. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose by 20-30%. Child-Pugh C: Reduce dose by 50% or administer every 12-16 hours. Avoid in severe hepatic impairment if possible. |
| Pediatric use | Not FDA-approved for pediatric use; limited data: For opioid dependence, initiate 0.1-0.2 mg/kg/dose orally daily, titrate to effect; max 5 mg/dose for induction. For pain, 0.1-0.2 mg/kg every 6-12 hours IV/IM, max 10 mg/dose. |
| Geriatric use | Initiate at lower doses (2.5-5 mg every 8-12 hours orally for pain, 10 mg daily for maintenance) and titrate slowly due to increased sensitivity and reduced clearance. Monitor for QT prolongation and CNS effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.
| FDA category | Positive |
| Breastfeeding | Methadone is excreted into breast milk with a milk-to-plasma (M/P) ratio of approximately 0.5-0.9. Concentrations are low and generally not sufficient to prevent NAS in the infant, but may reduce severity. American Academy of Pediatrics considers methadone compatible with breastfeeding if mother is stable and not using illicit drugs. Infant should be monitored for drowsiness and adequate weight gain. |
| Teratogenic Risk |
■ FDA Black Box Warning
Risk of respiratory depression, addiction, abuse, misuse, life-threatening QT prolongation, and neonatal opioid withdrawal syndrome. Concomitant use with benzodiazepines or CNS depressants may cause profound sedation, respiratory depression, coma, and death.
| Common Effects | opioid use disorder |
| Serious Effects |
Hypersensitivity to methadone; significant respiratory depression; acute or severe bronchial asthma; GI obstruction; concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days; prolonged QT interval (QTc > 470 ms in females, > 450 ms in males); concurrent use of drugs known to prolong QT interval or precipitate torsade de pointes.
| Precautions | Risk of QT prolongation and torsade de pointes; respiratory depression; opioid-induced hyperalgesia; adrenal insufficiency; severe hypotension; seizures; serotonin syndrome; withdrawal upon abrupt discontinuation; increased intracranial pressure; impaired mental/physical abilities; risk of overdose with accidental or intentional exposure; tolerance and dependence; potential for drug interactions with CYP3A4 inducers/inhibitors; monitoring of ECG, respiratory status, and adherence required. |
Loading safety data…
| First trimester: Limited human data; animal studies show no teratogenicity at clinically relevant doses; risk of neural tube defects not established. Second and third trimesters: Chronic use may lead to neonatal abstinence syndrome (NAS); risk of preterm birth and low birth weight; no consistent evidence of major malformations. Use only if benefit outweighs risk. |
| Fetal Monitoring | Maternal: Regular assessment of respiratory rate, sedation level, and signs of withdrawal or toxicity; liver function tests periodic; ECG for QTc interval prolongation at baseline and during dose titration. Fetal: Ultrasound monitoring for growth parameters and amniotic fluid volume; fetal heart rate monitoring during labor. Neonatal: Monitor for NAS using standardized scoring system for at least 72 hours after birth. |
| Fertility Effects | Methadone may cause hormonal alterations: in males, reduced testosterone levels leading to decreased libido, erectile dysfunction, and reduced sperm count; in females, menstrual irregularities, anovulation, and reduced fertility. These effects are generally reversible with dose reduction or cessation. Patients should be counseled about contraception if pregnancy not desired. |