methadone (Dolophine, Methadose, Physeptone, Algolysin)
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Introduction
Tradenames: Dolophine, Methadose. (methadone hydrochloride) DEA-controlled substance: class 2.
Indications
- treatment of moderate to severe chronic pain*
- continued maintenance for opiate detoxification
- NOT for acute pain or pain requiring rapid titration
- NOT FDA-approved as cough suppressant
- 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]
- mild, acute, or breakthrough pain, or PRN[14]
- opioid-naive patients[14]
- coadministration with benzodiazepine[14]
Dosage
- analgesia: 2.5-10 mg PO/IM/SC every 3-4 hours
- opiate withdrawal: 15-40 mg QD
- 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.
Pharmacokinetics
- well absorbed orally
- onset of analgesia: withing 30-60 minutes
- peak effect within 1-2 hours
- with repeated dosing, duration of action increases to 24 hours
- respiratory depressant effects can persist for 36-48 hours
- highly protein-bound
- 1/2life averages 25 hours, variable
- metabolized in the liver by cyt P450 3A4
- excreted in urine & feces
- urine excretion is saturable
- acidification of the urine increases rate of excretion
elimination via liver
1/2life = 15-25 hours
protein binding = 88-90 %
elimination by hemodialysis = -
elimination by peritoneal dialysis = -
Monitor
Adverse effects
- 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]
- 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
- uncommon (< 1%)
- paralytic ileus, mental depression, hallucinations, paradoxical CNS stimulation, rash, urticaria, increased intracranial pressure, physical & psychologic dependence
- other
- dependence less than that with other opioids
- accumulation can cause severe respiratory depression
- sweating
- respiratory depression[10]
- cardiac arrhythmias[10]
- drug adverse effects of opiates
- drug adverse effects of psychotropic agents
- drug adverse effects of sedatives
Drug interactions
- additive effects with other sedatives
- benzodiazepines, barbiturates, alcohol, phenothiazines, tricyclic antidepressants (TCA) in combination increase CNS adverse effects
- naloxone: direct opiate antagonist
- carbamazepine, phenytoin, rifampin increase metabolism of methadone & decrease plasma levels
- diazepam, erythromycin, fluvoxamine decrease metabolism of methadone & increase plasma levels
- any drug that inhibits cyt P450 3A4 may increase levels of methadone
- any drug that induces cyt P450 3A4 may diminish levels of methadone
- drugs that prolong the QT interval
- amiodarone, erythromycin, quinidine ...
- drug interaction(s) of methadone in combination with benzodiazepines
- drug interaction(s) of benzodiazepine with opiates
- drug interaction(s) of Z-drugs with opiates
- drug interaction(s) of alcoholic beverage with opiates
- drug interaction(s) of pregabalin with opiates
- drug interaction(s) of gabapentin with opiates
Laboratory
Mechanism of action
- primarily a mu opioid agonist
- produces less euphoria than morphine
- produces greater respiratory depression with cumulative doses
- has some NMDA receptor agonist activity[13]
- may be agonist or antagonist[7]
- inhibits reuptake of both serotonin & norepinephrine[13]
More general terms
Additional terms
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
- methadone clinic
- NMDA receptor
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 7.0 7.1 Bruce Ferrell, Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 25-28, 2002
- ↑ 8.0 8.1 8.2 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: https://www.ncbi.nlm.nih.gov/pubmed/16801510
- ↑ Prescriber's Letter 13(9): 2006 Methadone: Focus on Safety Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220902&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 10.2 FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Methadone
- ↑ 11.0 11.1 11.2 Krantz MJ et al QTc interval screening in methadone treatment. Ann Intern Med 2009 Jan 20 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19153406
- ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/20308640
- ↑ 13.0 13.1 13.2 13.3 13.4 13.5 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 - ↑ 14.0 14.1 14.2 14.3 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
- ↑ 15.0 15.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23899678 <Internet> http://cid.oxfordjournals.org/content/early/2013/08/14/cid.cit467
- ↑ 16.0 16.1 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
- ↑ 17.0 17.1 17.2 NEJM Knowledge+ Pain Management and Opioids: Recharge