II. Definition

  1. Schedule II Narcotic used in Chronic Pain

III. Indications

IV. 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

V. Mechanism

  1. Mu-Opioid agonist
    1. More potent than Morphine on repeat dosing
  2. NMDA receptor antagonist
    1. Decreases risk of developing tolerance

VI. 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

VII. 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

VIII. 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

IX. 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

X. Adverse Effects

  1. Pruritus
  2. Nausea
  3. Constipation
  4. Sedation to confusion
    1. Observe for respiratory depression
  5. Excessive sweating of Flushing

XI. Advantages

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

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Cost: Medications

methadone (on 8/17/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
METHADONE 10 MG/ML ORAL CONC Generic $0.69 per ml
METHADONE 5 MG/5 ML SOLUTION Generic $0.07 per ml
METHADONE HCL 10 MG TABLET Generic $0.13 each
METHADONE HCL 5 MG TABLET Generic $0.19 each
METHADONE INTENSOL 10 MG/ML Generic $0.69 per ml

Ontology: Methadone (C0025605)

Definition (MSH) A synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. It has actions and uses similar to those of MORPHINE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1082-3)
Definition (CHV) a narcotic drug used to treat drug addiction
Definition (NCI) A synthetic opioid with analgesic activity. Methadone mimics the actions of endogenous peptides at CNS opioid receptors, primarily on the mu-receptor and has actions similar to those of morphine and morphine-like agents. The characteristic morphine-like effects include analgesia, euphoria, sedation, respiratory depression, miosis, bradycardia and physical dependence. However, the detoxification symptoms between morphine-like agents and methadone differ in that the onset of methadone's withdrawal symptoms is slower, the course is more prolonged and the symptoms are less severe.
Definition (CSP) synthetic narcotic possessing pharmacologic actions similar to those of morphine and heroin and almost equal addiction liability; used as an analgesic and as a narcotic abstinence syndrome suppressant in the treatment of heroin addition.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D008691
SnomedCT 387286002, 51758009
LNC LP15015-8, MTHU001002
English Methadone, 3-Heptanone, 6-(dimethylamino)-4,4-diphenyl-, Methadone [Chemical/Ingredient], methadone, METHADONE, Methadone (product), Methadone (substance)
Swedish Metadon
Czech methadon, metadon
Finnish Metadoni
Russian FENADON, METADON, AMIDON, АМИДОН, МЕТАДОН, ФЕНАДОН
Japanese フェナドン, 塩酸メタドン, メタドン, アミドン
Croatian METADON
Polish Amidon, Metadon
Spanish metadona (producto), metadona (sustancia), metadona, Metadona
French Méthadone
German Methadon
Italian Metadone
Portuguese Metadona