METHADONE HYDROCHLORIDE INTENSOL

Clinical safety rating: avoid

CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.

How it works

Methadone is a mu-opioid receptor agonist. It also acts as an NMDA receptor antagonist and inhibits serotonin and norepinephrine reuptake. Its long duration of action is due to high protein binding and tissue sequestration.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP2B6, with minor contributions from CYP2C9, CYP2C19, and CYP2D6. Metabolites are inactive. Methadone exhibits high protein binding and undergoes enterohepatic recirculation.
Excretion	Methadone is primarily eliminated via feces (about 50-60%) and urine (about 20-30%), with approximately 10% as unchanged drug in urine. Biliary excretion contributes to fecal elimination.
Half-life	Terminal elimination half-life ranges from 15 to 60 hours (mean ~24-36 hours). The long half-life allows for once-daily dosing in maintenance therapy but risk of accumulation and delayed toxicity during initiation.
Protein binding	Approximately 85-90% bound, primarily to alpha-1-acid glycoprotein (AAG) and, to a lesser extent, albumin.
Volume of Distribution	Vd is approximately 4-7 L/kg. Large Vd indicates extensive tissue distribution (e.g., lungs, liver, kidneys, and brain), contributing to long terminal half-life.
Bioavailability	Oral: 80-95% (mean ~85%).
Onset of Action	Oral: 30-60 minutes; Peak effect at 2-4 hours.
Duration of Action	Analgesic effect lasts 4-8 hours after single dose, but with repeated dosing, duration extends due to long half-life. For opioid dependence, effects last 24-36 hours.

Classification & Brands

Dosing & administration

Oral: 2.5-10 mg every 8-12 hours; titrate slowly. Typical adult dose: 5-10 mg PO every 8-12 hours.

Dosage form	CONCENTRATE
Renal impairment	GFR ≥30 mL/min: no adjustment. GFR 15-29 mL/min: use with caution, reduce dose or increase interval. GFR <15 mL/min: consider alternative or reduce dose by 50%, monitor closely.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% and monitor. Child-Pugh C: avoid use or use extreme caution with 75% dose reduction.
Pediatric use	Weight-based: 0.1-0.2 mg/kg/dose PO every 6-12 hours; maximum initial dose 10 mg. Titrate slowly.
Geriatric use	Start at 2.5 mg PO every 12 hours; increase slowly. Use lower initial doses, monitor for CNS and respiratory depression.

Use during pregnancy

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 enters breast milk in low concentrations (M/P ratio approximately 0.5-1.0). The American Academy of Pediatrics considers it compatible with breastfeeding if the mother is stable on methadone maintenance. However, monitor infant for sedation and withdrawal. Avoid abrupt cessation.
Teratogenic Risk

Warnings & precautions

■ FDA Black Box Warning

WARNING: RISK OF RESPIRATORY DEPRESSION, QT PROLONGATION, AND LIFE-THREATENING CARDIAC ARRHYTHMIAS; ADDICTION, ABUSE, AND MISUSE; NEONATAL OPIOID WITHDRAWAL SYNDROME; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; AND RISK OF ADRENAL INSUFFICIENCY.

Side Effect Profile

Common Effects	opioid use disorder
Serious Effects

Absolute Contraindications

Hypersensitivity to methadone or any component; significant respiratory depression; acute or severe bronchial asthma; paralytic ileus; concurrent use of MAOIs or within 14 days.

Clinical Precautions

Precautions

Respiratory depression, QTc prolongation and torsades de pointes, opioid withdrawal syndrome, adrenal insufficiency, serotonin syndrome, severe hypotension, and risks of concomitant use with CNS depressants.

Clinical Tips & Counseling

Drug interactions

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METHADONE HYDROCHLORIDE INTENSOL

Clinical safety rating: avoid

CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.

How it works

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP2B6, with minor contributions from CYP2C9, CYP2C19, and CYP2D6. Metabolites are inactive. Methadone exhibits high protein binding and undergoes enterohepatic recirculation.
Excretion	Methadone is primarily eliminated via feces (about 50-60%) and urine (about 20-30%), with approximately 10% as unchanged drug in urine. Biliary excretion contributes to fecal elimination.
Half-life	Terminal elimination half-life ranges from 15 to 60 hours (mean ~24-36 hours). The long half-life allows for once-daily dosing in maintenance therapy but risk of accumulation and delayed toxicity during initiation.
Protein binding	Approximately 85-90% bound, primarily to alpha-1-acid glycoprotein (AAG) and, to a lesser extent, albumin.
Volume of Distribution	Vd is approximately 4-7 L/kg. Large Vd indicates extensive tissue distribution (e.g., lungs, liver, kidneys, and brain), contributing to long terminal half-life.
Bioavailability	Oral: 80-95% (mean ~85%).
Onset of Action	Oral: 30-60 minutes; Peak effect at 2-4 hours.
Duration of Action	Analgesic effect lasts 4-8 hours after single dose, but with repeated dosing, duration extends due to long half-life. For opioid dependence, effects last 24-36 hours.

Classification & Brands

Dosing & administration

Oral: 2.5-10 mg every 8-12 hours; titrate slowly. Typical adult dose: 5-10 mg PO every 8-12 hours.

Dosage form	CONCENTRATE
Renal impairment	GFR ≥30 mL/min: no adjustment. GFR 15-29 mL/min: use with caution, reduce dose or increase interval. GFR <15 mL/min: consider alternative or reduce dose by 50%, monitor closely.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% and monitor. Child-Pugh C: avoid use or use extreme caution with 75% dose reduction.
Pediatric use	Weight-based: 0.1-0.2 mg/kg/dose PO every 6-12 hours; maximum initial dose 10 mg. Titrate slowly.
Geriatric use	Start at 2.5 mg PO every 12 hours; increase slowly. Use lower initial doses, monitor for CNS and respiratory depression.

Use during pregnancy

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 enters breast milk in low concentrations (M/P ratio approximately 0.5-1.0). The American Academy of Pediatrics considers it compatible with breastfeeding if the mother is stable on methadone maintenance. However, monitor infant for sedation and withdrawal. Avoid abrupt cessation.
Teratogenic Risk

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Common Effects	opioid use disorder
Serious Effects

Absolute Contraindications

Hypersensitivity to methadone or any component; significant respiratory depression; acute or severe bronchial asthma; paralytic ileus; concurrent use of MAOIs or within 14 days.