BSN Tracker

methadone

Brand: Dolophine, Methadose

⚠ BBW ISMP High Alert TDM Required Prototype: morphine
Drug Class: opioid analgesic / opioid use disorder treatment
Drug Family: opioid
Subclass: synthetic long-acting mu-opioid agonist
Organ Systems: cns

Mechanism of Action

Full mu-opioid agonist with additional NMDA receptor antagonism (contributing to efficacy in neuropathic pain and reducing opioid tolerance) and weak monoamine reuptake inhibition. Unique among opioids: highly lipophilic, very long and unpredictable half-life (8-59 hours), and substantial QT prolongation risk.

mu-opioid receptor (MOR)NMDA receptor (antagonist)SERT (serotonin transporter)NET (norepinephrine transporter)

Indications

  • opioid use disorder (OUD) — maintenance and detoxification
  • severe chronic pain (when other options inadequate)
  • neonatal opioid withdrawal syndrome (off-label)

Contraindications

  • concurrent QT-prolonging agents (relative)
  • severe respiratory compromise
  • concomitant MAOI use

Adverse Effects

Common

  • sedation
  • constipation
  • sweating
  • nausea
  • sexual dysfunction

Serious

  • QT prolongation and torsades de pointes
  • respiratory depression (delayed with accumulation)
  • fatal overdose (particularly during dose initiation/rotation)
  • diaphoresis and hypogonadism

Pharmacokinetics (ADME)

Absorption well absorbed orally; bioavailability ~36-100% (highly variable)
Distribution highly lipophilic; protein binding ~86%; large Vd ~4-5 L/kg; accumulates in tissues and released slowly
Metabolism primarily CYP3A4 and CYP2B6; inactive metabolites; CYP2B6 genetic polymorphisms significantly affect levels
Excretion primarily fecal
Half-life 8-59 hours (average ~24 hours, but range extraordinarily wide); tissue accumulation extends effective duration
Onset 30-60 minutes oral; analgesia 2-4 hours
Peak 2.5-4 hours (analgesic effect); tissue accumulation continues for days
Duration analgesic 4-8 hours; total drug effect 24-36 hours due to accumulation
Protein Binding 86%
Vd 4-5 L/kg

Drug Interactions

Drug / Agent Mechanism Severity
QT-prolonging drugs (multiple) additive QT prolongation; torsades de pointes major
CYP3A4 inducers (rifampin, carbamazepine) precipitate withdrawal by reducing methadone levels major
CYP3A4 inhibitors increase methadone levels; respiratory depression and QT prolongation major
CNS depressants additive respiratory depression major

Nursing Considerations

  1. Baseline ECG required before initiating methadone; QTc >450 ms warrants cardiology consultation; QTc >500 ms is a relative contraindication; reassess ECG after dose escalations.
  2. Methadone for OUD in the US can only be dispensed by federally licensed opioid treatment programs (OTPs); prescribing rules are different from those for pain management — verify the clinical context of the order.
  3. Dose accumulation occurs over 3-5 days of initiation; overdose deaths cluster in the first week; 'start low, go slow' and reassess sedation daily during initiation.
  4. Monitor for signs of respiratory depression throughout the 24-36 hour effective duration, not just at the first few hours post-dose; this is the most common fatal error with methadone.

Clinical Pearls

  • Methadone's uniquely wide variation in half-life (8-59 hours, average 24 hours) makes it treacherous for opioid rotation; what appears to be an equianalgesic dose can accumulate to toxic levels over 3-5 days — methadone conversions should be managed only by experienced pain or addiction specialists.
  • For opioid use disorder, methadone's long half-life prevents withdrawal symptoms for 24-36 hours, eliminating the cycle of repeated withdrawals; its high lipophilicity and tissue accumulation contribute to its pharmacological suitability as a maintenance agent.

Safety Profile

Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Required

Concordance Terms

Cross-referenced clinical concepts — click any term to see all content where it appears.

Neonatal Opioid Withdrawal Syndrome (off-label) Opioid Analgesic / Opioid Use Disorder Treatment Opioid Use Disorder (OUD) — Maintenance And Detoxification Severe Chronic Pain (when Other Options Inadequate)
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