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methadone (Dolophine, Methadose, Physeptone, Algolysin)

Tradenames: Dolophine, Methadose. (methadone hydrochloride) DEA-controlled substance: class 2. Indications: 1) treatment of moderate to severe chronic pain* 2) continued maintenance for opiate detoxification 3) NOT for acute pain or pain requiring rapid titration 4) NOT FDA-approved as cough suppressant 5) opioid dependence, opiate withdrawal * policies discouraging use of methadone for treating pain have reduced opioid overdoses [16] Contraindications: - structural heart disease, arrhythmia, syncope (caution) [13] - not recommended if QTc > 500 msec - mild, acute, or breakthrough pain, or PRN [14] - opioid-naive patients [14] - coadministration with benzodiazepine [14] Dosage: 1) analgesia: 2.5-10 mg PO/IM/SC every 3-4 hours 2) opiate withdrawal: 15-40 mg QD 3) maintenance of dependence: 20-120* mg PO QD * minimum lethal dose is 50 mg; opiate addicts may tolerate > 200 mg Tabs: 5 & 10 mg; 40 mg tablets (opiate withdrawal only)* * methadone 40 mg is only available to hospitals & facilities authorized for detoxification & maintenance treatment of patients with opioid addiction * patients taking methadoned for maintenance treatment are more likely to maintain remission & less likely to experience overdose if they continue methadone [17] Solution: 5 & 10 mg/5 mL. Injection: 10 mg/mL (20 mL). 10 mg PO = 30 mg morphine PO Pharmacokinetics: 1) well absorbed orally 2) onset of analgesia: withing 30-60 minutes 3) peak effect within 1-2 hours 4) with repeated dosing, duration of action increases to 24 hours 5) respiratory depressant effects can persist for 36-48 hours 6) highly protein-bound 7) 1/2life averages 25 hours, variable 8) metabolized in the liver by cyt P450 3A4 9) excreted in urine & feces 10) urine excretion is saturable 11) acidification of the urine increases rate of excretion Monitor: - EKG for QTc [8,11] (all patients when daily dose > 30 mg) [17] a) before treatment begins b) after 30 days c) annually during treatment - more often if daily dose is > 100 mg, QTc is 450-500 ms, or if unexplained syncope or seizures develop d) with dose increase e) consider discontinuation, reducing the dose, or eliminating contributing factors if QTc > 500 ms [13] Adverse effects: 1) common (> 10%) - weakness, tiredness, nausea/vomiting, hypotension, drowsiness, dizziness, histamine release, constipation - QT prolongation (2-16% in one study) [8,11,13] - QT prolongation in HIV patients associated with higher methodone doses, hepatitis C & being antiretroviral-naive [15] - R-isomer associated with less QT prolongation than S-isomer [12] 2) less common (1-10%) - ureteral spasms, pain at site of injection, nervousness, headache, restlessness, anorexia, malaise, stomach cramps, dry mouth, biliary spasm, decreased urination, confusion, dyspnea 3) uncommon (< 1%) - paralytic ileus, mental depression, hallucinations, paradoxical CNS stimulation, rash, urticaria, increased intracranial pressure, physical & psychologic dependence 4) other - dependence less than that with other opioids - accumulation can cause severe respiratory depression - sweating - respiratory depression [10] - cardiac arrhythmias [10] Drug interactions: 1) additive effects with other sedatives - benzodiazepines, barbiturates, alcohol, phenothiazines, tricyclic antidepressants (TCA) in combination increase CNS adverse effects 2) naloxone: direct opiate antagonist 3) carbamazepine, phenytoin, rifampin increase metabolism of methadone & decrease plasma levels 4) diazepam, erythromycin, fluvoxamine decrease metabolism of methadone & increase plasma levels 5) any drug that inhibits cyt P450 3A4 may increase levels of methadone 6) any drug that induces cyt P450 3A4 may diminish levels of methadone 7) drugs that prolong the QT interval - amiodarone, erythromycin, quinidine ... Laboratory: 1) specimen: serum, plasma (EDTA), urine 2) methods: a) serum/plasma: GLC, RIA, EIA, HPLC, fluorometry, GC-MS, color b) urine: TLC, EMIT 3) labs with Loincs - methadone in specimen - methadone in hair - methadone in saliva - methadone in gastric fluid - methadone in bile - methadone in stool - methadone in meconium - methadone in blood - methadone in serum/plasma - methadone in urine - methadone in milk - methadone in vitreous fluid Mechanism of action: 1) primarily a mu opioid agonist 2) produces less euphoria than morphine 3) produces greater respiratory depression with cumulative doses 4) has some NMDA receptor agonist activity [13] -> may be agonist or antagonist [7] 5) inhibits reuptake of both serotonin & norepinephrine [13]

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) methadone clinic NMDA receptor

General

opiate opioid receptor agonist (narcotic)

Properties

MISC-INFO: elimination route LIVER 1/2life 15-25 HOURS therapeutic-range 100-400 NG/ML toxic-range >2000 NG/ML protein-binding 88-90% elimination by hemodialysis - peritoneal dialysis - pregnancy-category C + safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  6. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  7. Bruce Ferrell, Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 25-28, 2002
  8. Ehret GB et al, Drug-induced long QT syndrome in injection drug users receiving methadone: High frequency in hospitalized patients and risk factors. Arch Intern Med 2006; 166:1280 PMID: 16801510
  9. Prescriber's Letter 13(9): 2006 Methadone: Focus on Safety Detail-Document#: 220902 (subscription needed) http://www.prescribersletter.com
  10. FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Methadone
  11. Krantz MJ et al QTc interval screening in methadone treatment. Ann Intern Med 2009 Jan 20 PMID: 19153406
  12. Ansermot N et al. Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval. Arch Intern Med 2010 Mar 22; 170:529. PMID: 20308640
  13. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  14. Centers for Disease Control and Prevention (CDC) Vital Signs: Risk for Overdose from Methadone Used for Pain Relief - United States, 1999-2010 MMWR. July 6, 2012 / 61(26);493-497 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6126a5.htm
  15. Vallecillo G et al. Risk of QTc prolongation in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. Clin Infect Dis 2013 Aug 14 PMID: 23899678 http://cid.oxfordjournals.org/content/early/2013/08/14/cid.cit467
  16. Jones CM, Baldwin GT, Manocchio T, White JO, Mack KA Trends in Methadone Distribution for Pain Treatment, Methadone Diversion, and Overdose Deaths - United States, 2002-2014. MMWR Morb Mortal Wkly Rep 2016;65:667-671 https://www.cdc.gov/mmwr/volumes/65/wr/mm6526a2.htm
  17. NEJM Knowledge+ Pain Management and Opioids: Recharge