Generic Name

Methadone

Mechanism

• Mu‑opioid receptor agonist – provides analgesia and substitution therapy through sustained activation of central mu receptors.
• NMDA receptor antagonist – reduces tolerance and opioid‑induced hyperalgesia.
• Serotonin & norepinephrine reuptake inhibition – contributes to analgesic and mood‑stabilizing effects.
• Long‑acting pharmacodynamics → steady plasma concentration, reducing craving and withdrawal symptoms.

Pharmacokinetics

• Absorption – oral bioavailability 65–80 %; delayed peak (1–4 h).
• Distribution – large volume of distribution (~400 L), lipophilic, >90 % protein‑bound (mainly albumin).
• Metabolism – hepatic CYP3A4, CYP2B6, CYP2C19; first‑pass effect significant.
• Half‑life – 8–48 h (average 24 h); highly variable with steady‑state achieved in 3–4 weeks.
• Elimination – 60–70 % fecal (biliary), remainder renal in the form of metabolites.

Indications

• Treatment of opioid dependence (maintenance/withdrawal).
• Chronic pain management in patients intolerant to short‑acting opioids.
• Adjunct for opioid‑related neuropathic pain and non‑opioid analgesia in specialized settings.

Contraindications

• QT prolongation or arrhythmia (QTC >480 ms, ventricular tachycardia).
• Severe hepatic dysfunction (ALT > 3× ULN).
• Concurrent use of CYP3A4 inhibitors or serotonergic agents (risk of serotonin syndrome, cardiac toxicity).
• Hypersensitivity to methadone or components.
• Pregnancy – category D; avoid unless benefit outweighs risk.

Dosing

• Administer with food to reduce GI upset but beware delayed absorption.
• Check QTc baseline, ≥2 wk after titration, and at any dose change.
• Reformulated tablets prevent “dose‑splitting” errors.

Monitoring

• Baseline: CBC, CMP, liver enzymes, QTc, opioid urine screen.
• During therapy:
• QTc at baseline, 2 wk, then quarterly; immediately if symptoms.
• Drug levels only in special cases (treatment failure, detox).
• Renal & hepatic function quarterly.
• Physical exam: weight, vital signs, pain score, signs of withdrawal or overdose.
• Education: patient advised on constipation management, safe storage, and dosage adherence.

Clinical Pearls

• Titration Pace – err on the slow side; a 15‑mg increase per week is safer than 30 mg, decreasing withdrawal and QT risk.
• Avoid Liquid Methadone – if formulation is available, use tablet/gel to prevent dosing errors.
• Drug‑Drug Interactions:
• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) can double blood levels; consider dose reduction.
• Serotonergic drugs + methadone = serotonin‑syndrome risk; monitor agitation, hyperthermia, autonomic instability.
• Pregnancy & Lactation – use only if no alternatives; monitor neonate for respiratory depression.
• Withdrawal Assessment – use Clinical Opiate Withdrawal Scale (COWS); methadone may mask symptoms; be vigilant for low pain thresholds.
• Toxicology Screening – methadone is lipophilic; urine screens may be negative early – confirm with plasma if suspicion persists.

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• Key Takeaway

Methadone’s unique long‑acting mu‑agonist action, NMDA antagonism, and serotonergic effects make it a cornerstone for opioid dependence and complex pain regimens—but careful titration, cardiac monitoring, and vigilance for drug interactions are essential to minimize toxicity.