Methadone

Indications

• FDA-approved for detoxification and maintenance treatment of opioid use disorder in adults, which outside hospital may be dispensed only by certified opioid treatment programs.
• FDA-approved for pain severe enough to require daily around-the-clock long-term opioid treatment when alternative options are inadequate.
• For pain, any DEA-registered prescriber may write for methadone; the opioid treatment program restriction applies only to addiction treatment.
• Any hospital may administer methadone to an admitted patient already in treatment, or for withdrawal while treating another condition.
• Retention in treatment and mortality reduction at least equal buprenorphine, with better retention at doses of 60 mg/day or more.
• The 2024 revision of 42 CFR Part 8 made pandemic take-home flexibilities permanent and allows audio-visual telehealth initiation.

Mechanism of action

• Full mu-opioid receptor agonist with no ceiling effect, so respiratory depression rises steadily with dose and with any added sedative.
• NMDA receptor antagonism contributes to analgesia in neuropathic and opioid-tolerant pain and may blunt the development of tolerance.
• Inhibits serotonin and norepinephrine reuptake, which underlies a real if uncommon serotonin syndrome risk with serotonergic agents.
• Blocks the hERG potassium channel in a dose-dependent way, prolonging the QT interval and creating torsades de pointes risk.
• Long and variable elimination greatly outlasts analgesia, so tissue stores build for days after each dose increase before the effect plateaus.

Pharmacokinetics

• Oral bioavailability is high at roughly 70-80% and highly variable, with extensive binding to alpha-1-acid glycoprotein in plasma.
• Elimination half-life ranges from 8 to 59 h across patients while analgesia lasts only 4-8 h, the mismatch that drives fatal dose stacking.
• Steady state is not reached for 3-10 days, so the full effect of any increase is not visible when the next increase is usually considered.
• Metabolized by CYP3A4, 2B6, 2C19, 2D6 and 2C9 to inactive EDDP; CYP2B6 genotype shifts levels of the more cardiotoxic S-enantiomer.
• Excreted in urine and feces with pH-dependent renal clearance; methadone is not removed by hemodialysis, so dialysis does not rescue overdose.

Dosing

• Opioid use disorder induction: first dose 20-30 mg, no single dose above 30 mg, and no more than 40 mg total on day 1 with reassessment at 2-4 h.
• Increase by no more than 5-10 mg every 3-5 days at the fastest, because deaths cluster in the first two weeks when levels are still accumulating.
• Effective maintenance is usually 60-120 mg/day as a single daily dose; some patients need more, guided by response, not by an arbitrary ceiling.
• Chronic pain in an opioid-naive adult starts at 2.5 mg every 8 h; never dose every 4-6 h, and never convert from morphine using a fixed ratio.
• Rotation from another opioid requires published dose-dependent tables and a 75-90% reduction from the calculated equianalgesic dose.
• Taper slowly if stopping, on the order of 10% per month for maintenance patients; indefinite maintenance is a legitimate and usually preferable outcome.

Adverse effects

• Constipation, sweating in up to 45%, sedation, nausea, weight gain, dry mouth and peripheral edema are the routine ongoing complaints.
• QTc prolongation is dose-related and clinically important above roughly 100 mg/day, with torsades de pointes reported at maintenance doses.
• Respiratory depression and death occur most often during induction and after dose increases, and often at night during sleep.
• Central and obstructive sleep apnea appear in a substantial minority at higher doses and worsen nocturnal hypoxemia.
• Opioid-induced androgen deficiency causes low libido, erectile dysfunction, amenorrhea, fatigue and reduced bone density over time.
• Neonatal opioid withdrawal syndrome is expected after third-trimester exposure and is treatable, but requires delivery where neonatology is available.

Monitoring

• ECG at baseline, at about 30 days, then annually and after any dose exceeding 100 mg/day or the addition of a QT-prolonging drug.
• Potassium and magnesium, particularly in patients on diuretics, with vomiting or diarrhea, or with cardiac or hepatic disease.
• Observed daily dosing at first, with take-home doses granted according to the 42 CFR Part 8 criteria as stability is established.
• Sedation and respiratory rate reassessed 2-4 h after dosing during induction, plus screening questions for snoring and witnessed apnea.
• Urine drug testing, prescription drug monitoring program review, and testosterone or menstrual history when symptoms suggest hypogonadism.

Interactions

• Benzodiazepines, alcohol, gabapentinoids and other CNS depressants markedly raise overdose risk, though FDA warns against withholding methadone for benzodiazepine use alone.
• CYP inducers such as rifampin, carbamazepine, phenytoin, efavirenz and St. John's wort cause withdrawal, and overdose when the inducer is stopped.
• CYP inhibitors including fluvoxamine, fluconazole, ciprofloxacin, clarithromycin and some antiretrovirals raise levels and QT risk.
• Additive QT prolongation with ondansetron, haloperidol, citalopram, quetiapine, azoles, macrolides and fluoroquinolones warrants ECG review.
• Buprenorphine, naltrexone and other antagonists or partial agonists precipitate withdrawal, and MAOIs are contraindicated within 14 days.

Special populations

• Pregnancy: methadone remains a standard of care; dose requirements usually rise in the third trimester and split twice-daily dosing often helps.
• Lactation: milk concentrations are low and breastfeeding is encouraged in stable patients, with the infant watched for sedation and poor feeding.
• Pediatric: safety and effectiveness for opioid use disorder are not established under 18, and federal rules add consent requirements for minors.
• Geriatric patients are more sensitive to respiratory depression, QT effects and falls; start at the low end and lengthen the titration interval.
• Hepatic or renal impairment: reduce the dose and titrate more slowly in severe disease; hemodialysis does not remove methadone from the body.

Clinical pearls

• Analgesia lasts 4-8 h but the drug lingers for days; every 4 h pain dosing stacks and kills.
• Deaths cluster in the first two weeks: raise by 5-10 mg no faster than every 3-5 days.
• Outpatient dosing for opioid use disorder is legal only through a certified treatment program.