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. |
| Molecular Weight | 345.91 |
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 | Use only if benefit outweighs risk; associated with neonatal abstinence syndrome (NAS) and neural tube defects; avoid if possible. |
| 2nd trimester | Continue if opioid-dependent; risk of preterm labor and low birth weight; monitor for NAS. |
| 3rd trimester | Continue if opioid-dependent; high risk of severe NAS requiring prolonged treatment; risk of respiratory depression at delivery. |
Clinical note
CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.
| FDA category | Positive |
| Placental transfer | Extensive placental transfer; crosses readily to reach fetal levels similar to maternal. |
| Breastfeeding |
■ 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 |
Known hypersensitivity to methadone or any componentSignificant respiratory depressionAcute or severe bronchial asthmaParalytic ileusUse of MAO inhibitors or within 14 daysQTc interval >500 ms (unless extreme benefit)
| 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. |
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| Expected to pass into breast milk; low absolute doses in milk; monitor infant for sedation and respiratory depression; generally considered compatible if mother is stable on maintenance therapy. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | 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. |
| Food/Dietary | Grapefruit juice may inhibit CYP3A4 metabolism of methadone, potentially increasing serum levels and risk of toxicity; avoid concurrent use. High-fat meals can delay absorption but do not significantly affect total exposure. Maintain consistent dietary habits to minimize variability in methadone levels. |
| Clinical Pearls | Methadone has a long and variable half-life (8-59 hours), requiring careful titration. QT interval prolongation is dose-dependent; obtain baseline ECG and monitor. Due to N-methyl-D-aspartate (NMDA) receptor antagonism, methadone may be effective for neuropathic pain. Observe for respiratory depression especially during initiation and dose adjustments. Drug interactions with CYP3A4, CYP2B6, and CYP2D6 inducers/inhibitors can significantly alter methadone levels. Provide naloxone prescription for rescue. Use in pregnancy may cause neonatal abstinence syndrome; taper slowly to avoid withdrawal. |
| Patient Advice | Take exactly as prescribed; do not change dose or stop abruptly without consulting your doctor. · Methadone can cause serious breathing problems, especially when starting or increasing dose; seek emergency help if you have slow/shallow breathing. · Do not drink alcohol or use other drugs (including benzodiazepines, sedatives, other opioids) without doctor approval, as this increases risk of fatal overdose. · This medication may cause dizziness or drowsiness; avoid driving or operating machinery until you know how it affects you. · Report any symptoms of irregular heartbeat (palpitations, dizziness, fainting) immediately. · Store methadone safely out of reach of children and pets; dispose of unused medication via drug take-back program. · If pregnant or planning pregnancy, discuss risks with your prescriber; do not stop abruptly as withdrawal can harm the fetus. · You may experience constipation; increase fluid and fiber intake, and ask your doctor about stool softeners. |