Methadone (Dolophine®)

Methadone
Brand Names	Dolophine®, Methadose®
Drug Class	Opioid (Full μ-agonist)
Primary Indication	Opioid Use Disorder, Severe Pain
Receptor Activity	Full μ agonist + NMDA antagonist
Relative Potency	Variable (nonlinear)
QT Prolongation	Yes
Half-Life	24–36+ hours
Controlled Substance	Schedule II
FDA Approval	1947

Overview

Methadone is a synthetic full μ-opioid receptor agonist with additional NMDA receptor antagonism.

It is used for both severe chronic pain and medication-assisted treatment of opioid use disorder (MOUD).

Methadone has a long and variable half-life, which increases risk for delayed respiratory depression and accumulation.

Mechanism of Action

Receptor Activity

Full μ-opioid receptor agonist
NMDA receptor antagonist
Weak inhibition of serotonin and norepinephrine reuptake

Clinical Implications

Potent analgesia
Beneficial in neuropathic pain (NMDA blockade)
No ceiling effect (full agonist)

Indications

Opioid Use Disorder (maintenance therapy)
Chronic severe pain
Cancer-related pain

In OUD:

Dispensed through certified opioid treatment programs

Contraindications

Absolute:

Significant respiratory depression
Known QT prolongation
Torsades de pointes

Relative / Caution:

Concomitant QT-prolonging medications
Hepatic impairment
Electrolyte abnormalities (hypokalemia, hypomagnesemia)
Concomitant CNS depressants

Dosing

Pain:

Low initial doses (e.g., 2.5–10 mg every 8–12 hours)
Slow titration required

Opioid Use Disorder:

Initial: 20–30 mg
Titrate carefully
Maintenance typically 60–120 mg/day

Important:

Analgesic duration shorter than elimination half-life
Risk of accumulation with repeated dosing

See:

Equianalgesic Dosing Guide

Pharmacokinetics

Absorption:

Oral

Bioavailability:

High (~70–90%)

Metabolism:

Hepatic (CYP3A4, CYP2B6, CYP2D6)

Half-life:

24–36 hours (may exceed 50 hours in some patients)

Elimination:

Hepatic metabolism with biliary and renal excretion

Half-life is much longer than analgesic duration.

Adverse Effects

Common:

Sedation
Constipation
Nausea

Serious:

Respiratory depression
QT prolongation
Torsades de pointes
Physical dependence

Delayed respiratory depression can occur due to accumulation.

Drug Interactions

QT-prolonging drugs:

Fluoroquinolones
Macrolides
Antipsychotics

CYP3A4 inhibitors (↑ levels):

Azoles
Protease inhibitors

CYP inducers (↓ levels):

Rifampin
Carbamazepine

CNS depressants:

Benzodiazepines
Alcohol

Monitoring

Clinical:

Sedation
Respiratory rate

Cardiac:

Baseline ECG
Periodic QT interval monitoring

Electrolytes:

Potassium
Magnesium

Clinical Pearls

Long half-life → risk of delayed respiratory depression.
Analgesic duration shorter than elimination half-life.
QT prolongation is dose-related.
Useful in neuropathic pain due to NMDA antagonism.
No ceiling effect (full μ agonist).
Used in structured opioid treatment programs for OUD.

Toxicity

Overdose:

CNS depression
Respiratory depression
Prolonged QT interval

Treatment:

Naloxone
Cardiac monitoring

Reversal may require repeated naloxone dosing due to long half-life.

Comparison Within Class

Compared to Morphine:

Much longer half-life
NMDA antagonism
QT prolongation risk

Compared to Buprenorphine:

Full agonist vs partial
No ceiling effect
Higher overdose risk

Compared to Fentanyl:

Less potent
Much longer duration