Methadone in Chronic Pain

Aka: Methadone in Chronic Pain, Methadone

1. See Also
   1. Methadone for Opioid Dependence
2. Definition
   1. Schedule II Narcotic used in Chronic Pain
3. Indications
   1. Cancer Pain
   2. Chronic Pain
   3. Morphine allergy
4. Precautions
   1. QT Prolongation risk and respiratory depression (especially with conversion from other Narcotic)
      1. FDA black box warnings
   2. 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
   3. Methadone has significant Drug Interactions (see below)
   4. 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
   5. 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
5. Mechanism
   1. Mu-Opioid agonist
      1. More potent than Morphine on repeat dosing
   2. NMDA receptor antagonist
      1. Decreases risk of developing tolerance
6. Pharmacokinetics
   1. Bioavailability of oral dosing: 80%
   2. Highly tissue bound (brain, liver, Kidneys, Muscle)
      1. Release from tissues continues weeks after stopping
   3. Metabolized by liver
   4. Half-life: 22 hours (variable)
   5. No adjustment needed for Renal Insufficiency
   6. Duration of action
      1. After initial dose: 3 to 6 hours
      2. After repeat dosing: 8 to 12 hours
7. Dosing: Patient new to Opioids
   1. Initial dose for most patients: 2.5 mg orally every 8 hours
   2. Initial dose in frail elderly: 2.5 mg orally once daily
   3. Increase dose as needed every 7 days
      1. Increase by no more than 5 mg/day each week
8. Dosing: Converting to Methadone from other Narcotics
   1. 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
   2. 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
   3. 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
   4. 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
9. Drug Interactions
   1. Avoid with medications that prolong QT Interval
      1. See Prolonged QT Interval due to Medication
   2. Avoid with CNS Depressants
      1. Avoid with Alcohol, Benzodiazepines
   3. Decreased Methadone effect
      1. Opioid agonist-antagonist (Stadol, Nubain, Talwin)
      2. Agents affecting CYP3A4 or CYPD6
         1. Ciprofloxacin
         2. Diazepam
         3. Alcohol Intoxication
         4. Fluconazole
   4. Increased Methadone effect (via CYP3A4 or CYPD6)
      1. HIV Protease Inhibitors (e.g. Ritonavir, Amprenavir)
      2. Nevirapine
      3. Phenobarbital
      4. Phenytoin
      5. Rifampin
10. Adverse Effects
    1. Pruritus
    2. Nausea
    3. Constipation
    4. Sedation to confusion
       1. Observe for respiratory depression
    5. Excessive sweating of Flushing
11. Advantages
    1. By far the least expensive long acting Narcotic agent
       1. One month costs <$10 contrasted with >$100 for others
12. References
    1. Ayonrinde (2000) Med J Aust 173:536-40 [PubMed]
    2. Indelicato (2002) J Clin Oncol 20:348-52 [PubMed]
    3. Toombs (2005) Am Fam Physician 71:1353-8 [PubMed]