Description

Simple

A very strong painkiller medication used to treat severe pain. Also used for the treatment of opioid addiction.

Clinical

An opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction.

Overview

Methadone is a potent synthetic analgesic that works as a full µ-opioid receptor (MOR) agonist and N-methyl-d-aspartate (NMDA) receptor antagonist. As a full MOR agonist, methadone mimics the natural effects of the body's opioids, endorphins, and enkephalins through the release of neurotransmitters involved in pain transmission. It also has a number of unique characteristics that have led to its increased use in the last two decades; in particular, methadone has a lower risk of neuropsychiatric toxicity compared to other opioids (due to a lack of active metabolites), minimal accumulation in renal failure, good bioavailability, low cost, and a long duration of action.[21,22,23,14,19,Read more

Pharmacology

Indication

Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination pr... Read more

Pharmacodynamic

Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and cons... Read more

Mechanism of action

Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous... Read more

Absorption

Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administra... Read more

Protein binding

Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly sl... Read more

Volume of distribution

Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L[ Read more

Clearance

Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours[ Read more

Half life

Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours[ Read more

Route of elimination

The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.

Toxicity

In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

Adverse Effects

Contraindications

  • Regions: Canada
  • Patient Conditions:
      • Name: Status Asthmaticus
      • Drugbank Id: DBCOND0001831
  • Regions: Canada
  • Patient Conditions:
      • Name: Acute Pain Management
      • Drugbank Id: DBCOND0056394
      • Modification Of:
        • Base:
          • Name: Pain Management
          • Drugbank Id: DBCOND0037199
        • Severity:
          • Includes:
            • acute
  • Regions: Canada
  • Patient Conditions:
      • Name: Opioid naive
      • Drugbank Id: DBCOND0098668
  • Regions: Canada
  • Patient Conditions:
      • Name: Labor and Delivery
      • Drugbank Id: DBCOND0067235
  • Regions: Canada
  • Patient Conditions:
      • Name: Pregnancy
      • Drugbank Id: DBCOND0018394
  • Regions: Canada
  • Patient Conditions:
      • Name: CNS depression
      • Drugbank Id: DBCOND0094584
  • Regions: Canada
  • Patient Conditions:
      • Name: Cor Pulmonale
      • Drugbank Id: DBCOND0042897
  • Regions: Canada
  • Patient Conditions:
      • Name: Clostridium Difficile Infection-associated Diarrhea and Colitis
      • Drugbank Id: DBCOND0120879
  • Regions: Canada
  • With Categories Coadmin:
      • Name: Monoamine Oxidase Inhibitors
      • Drugbank Id: DBCAT001004
      • Mesh Id: D008996
  • Regions: Canada
  • Patient Conditions:
      • Name: Convulsive disorders
      • Drugbank Id: DBCOND0107830
  • Regions: Canada
  • Patient Conditions:
      • Name: Delirium Tremens (DTs)
      • Drugbank Id: DBCOND0107126
  • Regions: Canada
  • Patient Conditions:
      • Name: Acute alcoholism
      • Drugbank Id: DBCOND0107892
      • Modification Of:
        • Base:
          • Name: Alcoholism
          • Drugbank Id: DBCOND0006017
        • Severity:
          • Includes:
            • acute
  • Regions: Canada
  • Patient Conditions:
      • Name: Suspected surgical abdomen
      • Drugbank Id: DBCOND0107886
  • Regions: US
  • Patient Conditions:
      • Name: Bowel Obstruction
      • Drugbank Id: DBCOND0031840
  • Regions: US
  • Patient Conditions:
      • Name: Acute or severe bronchial asthma
      • Drugbank Id: DBCOND0107797
  • Regions: US
  • Patient Conditions:
      • Name: Paralytic Ileus
      • Drugbank Id: DBCOND0047064
  • Route:
    • Subcutaneous
    • Intramuscular
    • Intravenous
    • Oral
  • Dose Form:
    • Injection
  • Regions: US
  • Patient Conditions:
      • Name: Hypercarbia
      • Drugbank Id: DBCOND0063116
  • Route:
    • Subcutaneous
    • Intramuscular
    • Intravenous
    • Oral
  • Dose Form:
    • Injection
  • Regions: US
  • Patient Conditions:
      • Name: Respiratory Depression
      • Drugbank Id: DBCOND0034868

Food Interactions

  • Avoid alcohol.
  • Take with or without food. Food does not significantly affect absorption.

Interactions

Type in a drug name to check for interaction with Methadone
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  • Paracetamol(acetaminophen)
  • Paxil(paroxetine)
  • Pamelor(nortriptyline)
  • Panadol(acetaminophen)
  • Patanol(olopatadine ophthalmic)
  • Pataday(olopatadine ophthalmic)
  • Parnate(tranylcypromine)
  • Pazeo(olopatadine ophthalmic)
(R)-warfarin
The serum concentration of (R)-warfarin can be increased when it is combined with Methadone.
(S)-Warfarin
The serum concentration of (S)-Warfarin can be increased when it is combined with Methadone.
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine
The metabolism of Methadone can be decreased when combined with 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine.
1,10-Phenanthroline
The therapeutic efficacy of Methadone can be decreased when used in combination with 1,10-Phenanthroline.
2,5-Dimethoxy-4-ethylamphetamine
2,5-Dimethoxy-4-ethylamphetamine may increase the analgesic activities of Methadone.
2,5-Dimethoxy-4-ethylthioamphetamine
The risk or severity of adverse effects can be increased when Methadone is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamine
The risk or severity of adverse effects can be increased when Methadone is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarin
The metabolism of 4-hydroxycoumarin can be decreased when combined with Methadone.
4-Methoxyamphetamine
The risk or severity of adverse effects can be increased when Methadone is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamine
The risk or severity of adverse effects can be increased when Methadone is combined with 5-methoxy-N,N-dimethyltryptamine.
7-Nitroindazole
The risk or severity of adverse effects can be increased when Methadone is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline
The risk or severity of adverse effects can be increased when Methadone is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
9-aminocamptothecin
The metabolism of 9-aminocamptothecin can be decreased when combined with Methadone.
Abacavir
The therapeutic efficacy of Abacavir can be decreased when used in combination with Methadone.
Abatacept
The metabolism of Methadone can be increased when combined with Abatacept.
Abexinostat
The risk or severity of QTc prolongation can be increased when Methadone is combined with Abexinostat.
Abiraterone
The metabolism of Methadone can be decreased when combined with Abiraterone.
Acalabrutinib
The metabolism of Methadone can be decreased when combined with Acalabrutinib.
Acarbose
Acarbose may decrease the excretion rate of Methadone which could result in a higher serum level.
Acebutolol
The metabolism of Acebutolol can be decreased when combined with Methadone.
23 References
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  2. 2 . Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003.PubMed: 12405865
  3. 3 . Joseph H, Stancliff S, Langrod J: Methadone maintenance treatment (MMT): a review of historical and clinical issues. Mt Sinai J Med. 2000 Oct-Nov;67(5-6):347-64.PubMed: 11064485
  4. 4 . Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, Fry-Smith A, Day E, Lintzeris N, Roberts T, Burls A, Taylor RS: Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess. 2007 Mar;11(9):1-171, iii-iv.PubMed: 17313907
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  6. 6 . Haroutiunian S, McNicol ED, Lipman AG: Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012 Nov 14;11:CD008025. doi: 10.1002/14651858.CD008025.pub2.PubMed: 23152251
  7. 7 . Codd EE, Shank RP, Schupsky JJ, Raffa RB: Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995 Sep;274(3):1263-70.PubMed: 7562497
  8. 8 . Bart G, Lenz S, Straka RJ, Brundage RC: Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study. Drug Alcohol Depend. 2014 Dec 1;145:185-93. doi: 10.1016/j.drugalcdep.2014.10.014. Epub 2014 Oct 24.PubMed: 25456329
  9. 9 . Wang SC, Ho IK, Tsou HH, Tian JN, Hsiao CF, Chen CH, Tan HK, Lin L, Wu CS, Su LW, Huang CL, Yang YH, Liu ML, Lin KM, Chen CY, Liu SC, Wu HY, Chan HW, Tsai MH, Lin PS, Liu YL: CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol. 2011 Aug;31(4):463-9. doi: 10.1097/JCP.0b013e318222b5dd.PubMed: 21694616
  10. 10 . Ahmad T, Valentovic MA, Rankin GO: Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics. Biochem Pharmacol. 2018 Jul;153:196-204. doi: 10.1016/j.bcp.2018.02.020. Epub 2018 Feb 16.PubMed: 29458047
  11. 11 . Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8.PubMed: 30205091
  12. 12 . Deng M, Chen SR, Pan HL: Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain. Cell Mol Life Sci. 2019 May;76(10):1889-1899. doi: 10.1007/s00018-019-03047-y. Epub 2019 Feb 20.PubMed: 30788514
  13. 13 . Ferri M, Minozzi S, Bo A, Amato L: Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD009879. doi: 10.1002/14651858.CD009879.pub2.PubMed: 23740540
  14. 14 . Toombs JD, Kral LA: Methadone treatment for pain states. Am Fam Physician. 2005 Apr 1;71(7):1353-8.PubMed: 15832538
  15. 15 . Kahan M, Wilson L, Mailis-Gagnon A, Srivastava A: Canadian guideline for safe and effective use of opioids for chronic noncancer pain: clinical summary for family physicians. Part 2: special populations. Can Fam Physician. 2011 Nov;57(11):1269-76, e419-28.PubMed: 22084456
  16. 16 . Crews JC, Sweeney NJ, Denson DD: Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer. 1993 Oct 1;72(7):2266-72. doi: 10.1002/1097-0142(19931001)72:7<2266::aid-cncr2820720734>3.0.co;2-p.PubMed: 7690683
  17. 17 . Hewitt DJ: The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain. 2000 Jun;16(2 Suppl):S73-9.PubMed: 10870744
  18. 18 . Bruera E, Neumann CM: Role of methadone in the management of pain in cancer patients. Oncology (Williston Park). 1999 Sep;13(9):1275-82; discussion 1285-8, 1291.PubMed: 10509323
  19. 19 . Mercadante S: Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain. 1998 Jan;74(1):5-9.PubMed: 9514554
  20. 20 . Sarhill N, Davis MP, Walsh D, Nouneh C: Methadone-induced myoclonus in advanced cancer. Am J Hosp Palliat Care. 2001 Jan-Feb;18(1):51-3. doi: 10.1177/104990910101800113.PubMed: 11406880
  21. 21 . FDA Label - Methadone File
  22. 22 . Health Canada Label - Metadol File
  23. 23 . Health Canada Label - Methadose File