Methadone in Chronic Pain

QT Prolongation risk and respiratory depression (especially with conversion from other Narcotic)
1. FDA black box warnings
Methadone accounts for only 2% of Opioid prescriptions
1. Yet Methadone is responsible for 30% of Opioid prescription related deaths
2. Prescribe Naloxone Auto-Injector
Methadone has significant Drug Interactions (see below)
Methadone has a very long Half-Life with significant variability between patients
1. Respiratory depression may be significantly delayed from time of dosing
2. Start at low dose, and increase by no more than 5 mg/day each week
3. Closely monitor, esp. in the first 2 weeks on Methadone, or with dosage increase
Caution patients to be aware of symptoms
1. Sedation that precedes pain relief suggests a dose too high (taper down)
2. Patients should not take extra doses for incomplete relief
3. Avoid Methadone with Alcohol or Benzodiazepines

Bioavailability of oral dosing: 80%
Highly tissue bound (brain, liver, Kidneys, Muscle)
1. Release from tissues continues weeks after stopping
Metabolized by liver
Half-Life: 22 hours (variable)
No adjustment needed for Renal Insufficiency
Duration of action
1. After initial dose: 3 to 6 hours
2. After repeat dosing: 8 to 12 hours

Initial dose for most patients: 2.5 mg orally every 8 hours
Initial dose in frail elderly: 2.5 mg orally once daily
Increase dose as needed every 7 days
1. Increase by no more than 5 mg/day each week

Calculate total Morphine Equivalent dosing per 24 hours
1. See Opioid for conversion ratios
2. Example: Patient uses Oxycontin and Hydrocodone
  1. Oxycontin 80 mg PO every 12 hours
    1. Morphine Equivalent: 160 x30/20 = 240 mg/day
  2. Hydrocodone 20 mg PO every 6 hours
    1. Morphine Equivalent: 80 x 30/30 = 80 mg/day
  3. Total Morphine Equivalent: 320 mg/day
Calculate conversion Morphine to Methadone ratio
1. Current oral Morphine <100 mg/day: 3 to 1 ratio
2. Current oral Morphine <300 mg/day: 5 to 1 ratio
3. Current oral Morphine <600 mg/day: 10 to 1 ratio
4. Current oral Morphine <800 mg/day: 12 to 1 ratio
5. Current oral Morphine <1000 mg/day: 15 to 1 ratio
6. Current oral Morphine >1000 mg/day: 20 to 1 ratio
Calculate daily Methadone dose based on ratio
1. Example: Same patient as above
  1. Methadone equivalent: 320/10 = 32 mg/day
  2. Methadone divided dosing: 10 mg PO q8 hours
Titrate up to effective Methadone dose
1. Provide rescue Analgesics while titrating Methadone
2. Increase Methadone gradually to prevent toxicity
3. Inpatient increases may be made every 1-2 days
4. Outpatient increases should be made only every 5 days

Avoid with medications that prolong QT Interval
1. See Prolonged QT Interval due to Medication
Avoid with CNS Depressants
1. Avoid with Alcohol, Benzodiazepines
Decreased Methadone effect
1. Opioid Agonist-Antagonist (Stadol, Nubain, Talwin)
2. Agents affecting CYP3A4 or CYPD6
Increased Methadone effect (via CYP3A4 or CYPD6)
1. HIV Protease Inhibitors (e.g. Ritonavir, Amprenavir)
2. Nevirapine
3. Phenobarbital
4. Phenytoin
5. Rifampin

By far the least expensive long acting Narcotic agent
1. One month costs <$10 contrasted with >$100 for others