METHADOSE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for METHADOSE (METHADOSE).
Methadone is a mu-opioid receptor agonist; it also acts as an NMDA receptor antagonist and inhibits serotonin and norepinephrine reuptake, contributing to its analgesic and detoxification effects. It has a long half-life and reduces opioid craving and withdrawal symptoms.
| Metabolism | Primarily metabolized by CYP3A4, with contributions from CYP2B6 and CYP2D6; N-demethylation to inactive metabolites (EDDP). |
| Excretion | Primarily renal (approximately 80%) as inactive metabolites, with about 20% eliminated via feces. Less than 10% excreted unchanged. |
| Half-life | Terminal elimination half-life range: 8–59 hours (mean ~20–35 hours). In chronic use, half-life may increase due to accumulation. Context: The long half-life supports once-daily dosing for opioid dependence but requires careful titration to avoid accumulation. |
| Protein binding | Approximately 85–90% bound to plasma proteins, primarily alpha-1-acid glycoprotein and, to a lesser extent, albumin. |
| Volume of Distribution | Apparent volume of distribution (Vd) approximately 1–8 L/kg (mean 4 L/kg). High Vd indicates extensive tissue distribution, with slow release from tissues contributing to long half-life. |
| Bioavailability | Oral: 36–100% (mean ~50–60%) due to variable first-pass metabolism. Rectal: similar to oral. Parenteral routes (IM, SC, IV): 100%. |
| Onset of Action | Oral: 30–60 minutes; intramuscular: 10–20 minutes; subcutaneous: 15–30 minutes; intravenous: 5–10 minutes. Rectal: similar to oral. |
| Duration of Action | Duration of analgesia: 4–8 hours after single dose. Suppression of withdrawal symptoms: 24–36 hours with repeated dosing, allowing once-daily administration for maintenance therapy. |
Oral: 20-40 mg once daily, titrated to effect; for opioid dependence, typical maintenance 80-120 mg/day. IV: 2.5-10 mg every 8-12 hours.
| Dosage form | CONCENTRATE |
| Renal impairment | CrCl <10 mL/min: increase dosing interval to every 12-24 hours; monitor for accumulation. No specific GFR-based dose reduction defined; use caution. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: avoid or reduce dose by 75% and monitor; long half-life increases risk of toxicity. |
| Pediatric use | Neonatal abstinence syndrome: 0.05-0.2 mg/kg/dose oral every 12-24 hours, titrated. For pain: not FDA-approved in children; expert consultation required. |
| Geriatric use | Initiate at lower end of dosing range (2.5-5 mg every 8-12 hours for pain); titrate slowly due to increased sensitivity, prolonged half-life, and risk of respiratory depression. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for METHADOSE (METHADOSE).
| Breastfeeding | Methadone is excreted into breast milk with an average milk-to-plasma (M/P) ratio of approximately 0.5 to 1.0. Concentrations in milk are low (typically < 0.1 mg/L) and are unlikely to cause adverse effects in the nursing infant, provided the mother is on a stable dose. However, monitoring for neonatal sedation and respiratory depression is recommended. Breastfeeding is encouraged in mothers on methadone maintenance therapy due to benefits outweighing risks. |
| Teratogenic Risk | Methadone is classified as FDA Pregnancy Category C. First trimester: Potential for neural tube defects and congenital abnormalities, though absolute risk is low; opioid withdrawal syndrome may occur neonatally. Second/third trimester: Chronic use may lead to fetal dependence, preterm labor, intrauterine growth restriction, and neonatal abstinence syndrome (NAS) after delivery. No clear evidence of major malformations at therapeutic doses. |
■ FDA Black Box Warning
Risk of respiratory depression, especially during initiation and dose titration; risk of QT interval prolongation and serious arrhythmias; risk of misuse, abuse, and addiction; risk of neonatal opioid withdrawal syndrome with prolonged use during pregnancy.
| Serious Effects |
Hypersensitivity to methadone; significant respiratory depression; acute or severe bronchial asthma; suspected or known paralytic ileus; concurrent use with MAOIs or within 14 days of stopping MAOIs; prolonged QT interval or history of torsades de pointes.
| Precautions | Life-threatening respiratory depression; QT prolongation; serotonin syndrome with serotonergic drugs; adrenal insufficiency; severe hypotension; risks with use in elderly, cachectic, or debilitated patients; risks with hepatic or renal impairment; risk of opioid withdrawal with abrupt discontinuation; risk of accumulation due to long half-life. |
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| Fetal Monitoring | Maternal: Liver function tests, ECG for QT prolongation (especially at high doses), respiratory rate, sedation level, and urine drug screens. Fetal/neonatal: Serial ultrasound for fetal growth, non-stress tests in third trimester, and monitoring for neonatal abstinence syndrome (NAS) using standardized scoring systems (e.g., Finnegan score) after delivery. Also monitor for preterm labor and placental insufficiency. |
| Fertility Effects | Chronic methadone use may cause menstrual irregularities, anovulation, and reduced fertility in women due to hypothalamic-pituitary-gonadal axis suppression. In men, decreased libido and erectile dysfunction are possible, but these effects are generally reversible upon dose reduction or discontinuation. Methadone does not directly impair gamete quality but may disrupt hormonal regulation. |