METHADONE HYDROCHLORIDE INTENSOL
Clinical safety rating: avoid
CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.
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.
| 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. |
| Molecular Weight | 345.9 |
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. |
| 1st trimester | Methadone is associated with a risk of neural tube defects and other congenital anomalies, though absolute risk is low. Use only if benefit outweighs risk. Consider alternative therapy if possible. |
| 2nd trimester | Continue if patient is on methadone maintenance; risks include preterm birth and small for gestational age. Monitor for withdrawal symptoms in neonate. |
| 3rd trimester | Continued use may cause neonatal abstinence syndrome (NAS). Tapering is not recommended due to risk of relapse and fetal distress. Monitor neonate for NAS. |
Clinical note
CYP450 inducers or inhibitors can significantly alter levels Can cause QT prolongation and life-threatening respiratory depression.
| FDA category | Positive |
| Placental transfer | Methadone crosses the placenta readily, achieving fetal serum concentrations approximately 50-100% of maternal levels. Transfer is primarily via passive diffusion. |
■ 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.
| Common Effects | opioid use disorder |
| Serious Effects |
Hypersensitivity to methadone or any componentRespiratory depression (in unmonitored setting or absence of resuscitative equipment)Acute or severe bronchial asthmaKnown or suspected gastrointestinal obstruction (including paralytic ileus)Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy
| 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. |
| Food/Dietary |
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| Breastfeeding | Methadone is excreted into breast milk in low concentrations, but may cause sedation or respiratory depression in the infant. Benefits of breastfeeding generally outweigh risks if mother is stable on methadone maintenance. Monitor infant for signs of sedation, poor feeding, or withdrawal. Avoid concurrent use of other CNS depressants. |
| Lactation Rating | L3 - Moderate Safety |
| Teratogenic Risk | First trimester: Associated with neural tube defects (increased risk in animal studies, limited human data). Second/third trimester: Risk of neonatal abstinence syndrome (NAS), preterm birth, low birth weight. Chronic use in third trimester may cause fetal dependence and withdrawal postnatally. |
| Fetal Monitoring | Maternal: Monitor for respiratory depression, QTc prolongation, sedation, and signs of opioid withdrawal. Fetal: Ultrasound for growth restriction, antenatal testing (non-stress tests, biophysical profile) in third trimester. Neonatal: Monitor for NAS for at least 48-72 hours after birth. |
| Fertility Effects | Chronic use may disrupt menstrual cycles and reduce fertility due to hypothalamic-pituitary-gonadal axis suppression. In males, may cause hypogonadism and erectile dysfunction. Effects are reversible upon dose reduction or discontinuation. |
| Grapefruit and grapefruit juice may increase methadone levels and should be avoided. Food does not significantly alter methadone absorption, but taking with food may reduce gastrointestinal upset. Avoid alcohol consumption. |
| Clinical Pearls | Methadone has a long and variable half-life (mean 24-36 hours, up to 120 hours in some patients). Accumulation can occur over the first week, leading to delayed toxicity. Use with caution in patients with prolonged QTc interval (corrected QT >450 ms). Do not use methadone for breakthrough pain; it is long-acting. When converting from other opioids, use an initial dose ratio of 10:1 (oral morphine:oral methadone) for chronic pain, but adjust based on individual response. Monitor ECG at baseline and after dose increases. Methadone can cause respiratory depression and death, especially during initiation or dose adjustment. |
| Patient Advice | Take methadone exactly as prescribed. Do not change your dose without talking to your doctor. · Methadone can cause serious breathing problems, especially in the first few days or if your dose is changed. · This medication may be habit-forming. Do not share it with others. · Avoid alcohol and other drugs that make you sleepy, such as benzodiazepines or other opioids. · Methadone can cause a life-threatening heart rhythm problem called QT prolongation. Tell your doctor if you have a history of heart disease or if you faint or have a fast or irregular heartbeat. · Do not stop taking methadone suddenly without your doctor's supervision, as withdrawal symptoms may occur. · Store this medication in a safe place away from children and pets. · If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Do not double the dose. |