Editing Methadone

{{Short description|Opioid medication}}
{{Use dmy dates|date=September 2023}}
{{Distinguish|methedrone|mephedrone|methedrine|mephedrene|methylone|methcathinone|ephedrone}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 420419989
| image = Methadone enantiomers labelled.svg
| image_class = skin-invert-image
| width = 350
| caption = [[Skeletal formula]] of methadone's [[w:enantiomers|enantiomers]]. (''S'') corresponds to the D-enantiomer, and (''R'') corresponds to the L-enantiomer.
| imageL = Dextromethadone ball-and-stick model from xtal 1958.png
| widthL = 175
| altL = Ball-and-stick model of the less active dextromethadone.
| imageR = Levomethadone-xtal-1974-ball-and-stick.png
| widthR = 175
| altR = Ball-and-stick model of the more active levomethadone.

<!-- Clinical data -->| pronounce = 
| tradename = Dolophine, Methadose, Methatab,<ref>https://www.medsafe.govt.nz/consumers/cmi/m/Methatabs.pdf {{Bare URL PDF|date=August 2024}}</ref> others
| Drugs.com = {{drugs.com|monograph|methadone-hydrochloride}}
| MedlinePlus = a682134
| DailyMedID = Methadone
| pregnancy_AU = C
| pregnancy_AU_comment = 
| pregnancy_category = 
| dependency_liability = 
| addiction_liability = High<ref>{{cite book | vauthors = Bonewit-West K, Hunt SA, Applegate E |title=Today's Medical Assistant: Clinical and Administrative Procedures |date=2012|page=571 |publisher=Elsevier Health Sciences |isbn=9781455701506 |url=https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |language=en}}</ref>
| routes_of_administration = [[By mouth]], [[intravenous]], [[insufflation (medicine)|insufflation]], [[sublingual administration|sublingual]], [[rectal administration|rectal]]
| class = [[Opioid]]
| ATCvet = 
| ATC_prefix = N02
| ATC_suffix = AC52
| ATC_supplemental = {{ATC|N07|BC02}} {{ATCvet|N02|AC90}}

<!-- Legal status -->| legal_AU = Schedule 8
| legal_AU_comment = 
| legal_BR = A1
| legal_BR_comment = 
| legal_CA = Schedule I
| legal_CA_comment = 
| legal_DE = Anlage III
| legal_DE_comment = 
| legal_NZ = Class B
| legal_NZ_comment = 
| legal_UK = Class A
| legal_UK_comment = 
| legal_US = Schedule II
| legal_US_comment = 
| legal_EU = 
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->| bioavailability = Rectal: 76% 
SC: 79% <ref name="acta08">{{cite journal | vauthors = Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, Dale O | title = Clinical pharmacology of methadone for pain | journal = Acta Anaesthesiologica Scandinavica | volume = 52 | issue = 7 | pages = 879–889 | date = August 2008 | pmid = 18331375 | doi = 10.1111/j.1399-6576.2008.01597.x | s2cid = 25626479 }}</ref><br />
Oral: 41–99% <ref name="acta08" />
IV/IM: 100% <ref name="acta08" />
| protein_bound = 85–90%<ref name="acta08" />
| metabolism = [[Liver]] ([[CYP3A4]], [[CYP2B6]] and [[CYP2D6]]-mediated)<ref name="acta08" /><ref name=PMJ04>{{cite journal | vauthors = Brown R, Kraus C, Fleming M, Reddy S | title = Methadone: applied pharmacology and use as adjunctive treatment in chronic pain | journal = Postgraduate Medical Journal | volume = 80 | issue = 949 | pages = 654–659 | date = November 2004 | pmid = 15537850 | pmc = 1743125 | doi = 10.1136/pgmj.2004.022988 | url = http://pmj.bmj.com/content/80/949/654.full.pdf | url-status = live | archive-url = https://web.archive.org/web/20140502005223/http://pmj.bmj.com/content/80/949/654.full.pdf | archive-date = 2 May 2014 }}</ref>
| metabolites = 
| onset = Rapid<ref name=AHFS2015/>
| elimination_half-life = 15–55 hours<ref name = PMJ04/>
| duration_of_action = Single dose: 4–8 h<br />Prolonged use:<br /> • Withdrawal prevention: 1–2 days<ref name=AHFS2015/><br /> • Pain relief: 8–12 hours<ref name=AHFS2015/><ref name="DurPain"/>
| excretion = Urine, faeces<ref name = PMJ04/>

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 76-99-3
| CAS_supplemental = 
| PubChem = 4095
| IUPHAR_ligand = 5458
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00333
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3953
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = UC6VBE7V1Z
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08195
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 6807
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 651
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = <!-- Chemical and physical data -->
| IUPAC_name = (''RS'')-6-(dimethylamino)-4,4-diphenylheptan-3-one
| C = 21
| H = 27
| N = 1
| O = 1
| SMILES = CCC(C(C1=CC=CC=C1)(C2=CC=CC=C2)CC(N(C)C)C)=O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = USSIQXCVUWKGNF-UHFFFAOYSA-N
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Methadone''', sold under the brand names '''Dolophine''' and '''Methadose''' among others, is a synthetic [[opioid]] used medically to treat [[chronic pain]] and [[opioid use disorder]].<ref name=AHFS2015>{{cite web|title=Methadone Hydrochloride|url=https://www.drugs.com/monograph/methadone-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=22 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151223011324/http://www.drugs.com/monograph/methadone-hydrochloride.html|archive-date=23 December 2015}}</ref> Prescribed for daily use, the medicine relieves cravings and [[opioid withdrawal]] symptoms.<ref name="JosephStancliffLangrod" /> Withdrawal management using methadone can be accomplished in less than a month,<ref>{{Cite book |last=World Health Organization |title=Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. |date=2009 |publisher=World Health Organization |isbn= |location=Geneva |publication-date=2009 |language=en}}</ref> or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life.<ref name="AHFS2015" /> While a single dose has a rapid effect, maximum effect can take up to five days of use.<ref name="AHFS2015" /><ref name="Gris2011">{{cite journal | vauthors = Grissinger M | title = Keeping patients safe from methadone overdoses | journal = P & T | volume = 36 | issue = 8 | pages = 462–466 | date = August 2011 | pmid = 21935293 | pmc = 3171821 }}</ref> After long-term use, in people with normal liver function, effects last 8 to 36 hours.<ref name="AHFS2015" /><ref name="DurPain">{{cite journal | vauthors = Toombs JD, Kral LA | title = Methadone treatment for pain states | journal = American Family Physician | volume = 71 | issue = 7 | pages = 1353–1358 | date = April 2005 | pmid = 15832538 | url = http://www.aafp.org/afp/2005/0401/p1353.html | url-status = live | archive-url = https://web.archive.org/web/20170905230511/http://www.aafp.org/afp/2005/0401/p1353.html | archive-date = 5 September 2017 }}</ref> Methadone is usually taken [[by mouth]] and rarely by [[intramuscular|injection into a muscle]] or [[intravenous|vein]].<ref name=AHFS2015/>

<!-- Side effects and mechanism -->
Side effects are similar to those of other opioids.<ref name=AHFS2015/> These frequently include [[dizziness]], [[Somnolence|sleepiness]], [[nausea]], [[vomiting]], and [[Perspiration|sweating]].<ref name=AHFS2015/><ref>{{cite web|title=Methadone|date=16 June 2015 |publisher=The Substance Abuse and Mental Health Services Administration|url=https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/methadone|access-date=14 October 2020}}</ref> Serious risks include [[opioid abuse]] and [[respiratory depression]].<ref name=AHFS2015/> [[Heart arrhythmia|Abnormal heart rhythms]] may also occur due to a prolonged [[QT interval]].<ref name=AHFS2015/> The number of deaths in the United States involving methadone poisoning declined from 4,418 in 2011<ref>{{cite web|title=Data table for Figure 1. Age-adjusted drug-poisoning and opioid-analgesic poisoning death rates: United States, 1999–2011|url=https://www.cdc.gov/nchs/data/databriefs/db166_table.pdf#2|website=CDC|access-date=22 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151123200249/http://www.cdc.gov/nchs/data/databriefs/db166_table.pdf#2|archive-date=23 November 2015}}</ref> to 3,300 in 2015.<ref>{{cite journal | vauthors = Rudd RA, Seth P, David F, Scholl L | title = Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 65 | issue = 50–51 | pages = 1445–1452 | date = December 2016 | pmid = 28033313 | doi = 10.15585/mmwr.mm655051e1 | doi-access = free | title-link = doi }}</ref> Risks are greater with higher doses.<ref>{{cite journal | vauthors = Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA | title = The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop | journal = Annals of Internal Medicine | volume = 162 | issue = 4 | pages = 276–286 | date = February 2015 | pmid = 25581257 | doi = 10.7326/M14-2559 | doi-access =  | title-link = doi | s2cid = 207538295 }}</ref> Methadone is made by [[chemical synthesis]] and acts on [[opioid receptors]].<ref name=AHFS2015/>

<!-- History, society, and culture -->
Methadone was developed in Germany in the late 1930s by [[Gustav Ehrhart]] and [[Max Bockmühl]].<ref>{{cite book|title=Methadone Matters: Evolving Community Methadone Treatment of Opiate Addiction|date=2003|publisher=CRC Press|isbn=9780203633090|page=13|url=https://books.google.com/books?id=A8ObB64ZKWoC&pg=PA13|url-status=live|archive-url=https://web.archive.org/web/20151223052336/https://books.google.com/books?id=A8ObB64ZKWoC&pg=PA13|archive-date=23 December 2015}}</ref><ref>{{cite book|title=Encyclopedia of Drug Policy|date=2011|isbn=9781506338248|chapter-url=https://books.google.com/books?id=OePnCgAAQBAJ&pg=PT662|chapter=Diphenypropylamine Derivatives|url-status=live|archive-url=https://web.archive.org/web/20151223050127/https://books.google.com/books?id=OePnCgAAQBAJ&pg=PT662|archive-date=23 December 2015| vauthors = Kleiman MA, Hawdon JE |publisher=SAGE Publications }}</ref> It was approved for use as an [[analgesic]] in the United States in 1947, and has been used in the treatment of addiction since the 1960s.<ref name=AHFS2015/><ref>Kuehn, B. M. (2005). ''Methadone Treatment Marks 40 Years. JAMA: The Journal of the American Medical Association, 294(8), 887–889.'' doi:10.1001/jama.294.8.887</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

{{TOC limit}}

== Medical uses ==
[[File:Methadone 40mg.jpg|thumb|40&nbsp;mg of methadone]]
[[File:Chlorydrate de Méthadone.jpg|thumb|Two single-dose bottles of Methadone Hydrochloride syrup for oral administration (two different dosages: 10mg and 20mg)]]

=== Opioid addiction ===
Methadone is used for the treatment of [[opioid use disorder]].<ref>{{cite web |url= https://www.lecturio.com/concepts/opioid-use-disorder/ | title= Opioid Use Disorder | website= The Lecturio Medical Concept Library | access-date=25 June 2021}}</ref>
It may be used as maintenance therapy or in shorter periods to manage opioid withdrawal symptoms. Its use for the treatment of addiction is usually strictly regulated. In the US, outpatient treatment programs must be certified by the federal [[Substance Abuse and Mental Health Services Administration]] (SAMHSA) and registered by the [[Drug Enforcement Administration]] (DEA) to prescribe methadone for opioid addiction.

A 2009 [[Cochrane review]] found methadone was effective in retaining people in treatment and the reduction or cessation of heroin use as measured by self-report and urine/hair analysis and did not affect criminal activity or risk of death.<ref>{{cite journal | vauthors = Mattick RP, Breen C, Kimber J, Davoli M | title = Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD002209 | date = July 2009 | volume = 2009 | pmid = 19588333 | pmc = 7097731 | doi = 10.1002/14651858.CD002209.pub2 | veditors = Mattick RP }}</ref>

Treatment of opioid-dependent persons with methadone follows one of two routes: maintenance or withdrawal management.<ref>{{cite journal | vauthors = Stotts AL, Dodrill CL, Kosten TR | title = Opioid dependence treatment: options in pharmacotherapy | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 11 | pages = 1727–1740 | date = August 2009 | pmid = 19538000 | pmc = 2874458 | doi = 10.1517/14656560903037168 }}</ref> Methadone maintenance therapy (MMT) usually takes place in outpatient settings. It is usually prescribed as a single daily dose medication for those who wish to abstain from illicit opioid use. Treatment models for MMT differ. It is not uncommon for treatment recipients to be administered methadone in a specialized clinic, where they are observed for around 15–20 minutes post-dosing, to reduce the risk of diversion of medication.<ref>{{cite book | vauthors=((World Health Organization)) | year=2009 | title=Clinical guidelines for withdrawal management and treatment of drug dependence in closed settings. Manila : WHO Regional Office for the Western Pacific | hdl=10665/207032 | hdl-access=free | isbn=9789290614302 | chapter=Methadone maintenance treatment | publisher=WHO Regional Office for the Western Pacific }}</ref>

The duration of methadone treatment programs ranges from a few months to years. Given opioid dependence is characteristically a chronic relapsing/remitting disorder, MMT may be lifelong. The length of time a person remains in treatment depends on a number of factors. While starting doses may be adjusted based on the amount of opioids reportedly used, most clinical guidelines suggest doses start low (e.g., at doses not exceeding 40&nbsp;mg daily) and are incremented gradually.<ref name="JosephStancliffLangrod" /><ref name="Connock">{{cite journal | vauthors = 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 | title = Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation | journal = Health Technology Assessment | volume = 11 | issue = 9 | pages = 1–171, iii–iv | date = March 2007 | pmid = 17313907 | doi = 10.3310/hta11090 | doi-access = free | title-link = doi }}</ref> It has been found that doses of 40&nbsp;mg per day were sufficient to help control the withdrawal symptoms but not enough to curb the cravings for the drug. Doses of 80 to 100&nbsp;mg per day have shown higher rates of success in patients and less illicit [[heroin]] use during the maintenance therapy.<ref name="Anderson_2000">{{cite journal |vauthors=Anderson IB, Kearney TE |date=January 2000 |title=Use of methadone |journal=The Western Journal of Medicine |volume=172 |issue=1 |pages=43–46 |doi=10.1136/ewjm.172.1.43 |pmc=1070723 |pmid=10695444}}</ref> However, higher doses do put a patient more at risk for overdose than a moderately low dose (e.g. 20&nbsp;mg/day).<ref name="Gris2011"/>

Methadone [[Maintenance dose|maintenance]] has been shown to reduce the transmission of bloodborne viruses associated with opioid injection, such as hepatitis B and C, and/or HIV.<ref name="JosephStancliffLangrod" /> The principal goals of methadone maintenance are to relieve opioid cravings, suppress the abstinence syndrome, and block the euphoric effects associated with opioids.

Chronic methadone dosing will eventually lead to neuroadaptation, characterised by [[Drug tolerance|tolerance]] and [[Substance dependence|dependence]]. However, when used correctly in treatment, maintenance therapy is medically safe, non-sedating, and can provide a slow recovery from opioid addiction.<ref name="JosephStancliffLangrod" /> Methadone has been widely used for pregnant women addicted to opioids.<ref name="JosephStancliffLangrod">{{cite journal | vauthors = Joseph H, Stancliff S, Langrod J | title = Methadone maintenance treatment (MMT): a review of historical and clinical issues | journal = The Mount Sinai Journal of Medicine, New York | volume = 67 | issue = 5–6 | pages = 347–364 | year = 2000 | pmid = 11064485 }}</ref>

=== Pain ===
Methadone is used as an [[analgesic]] in chronic pain, often in [[opioid rotation|rotation with other opioids]].<ref name="Kraychete_2012">{{cite journal | vauthors = Kraychete DC, Sakata RK | title = Use and rotation of opioids in chronic non-oncologic pain | journal = Revista Brasileira de Anestesiologia | volume = 62 | issue = 4 | pages = 554–562 | date = July 2012 | pmid = 22793972 | doi = 10.1016/S0034-7094(12)70155-1 | doi-access = free | title-link = doi }}</ref><ref name="Mercadante_2016">{{cite journal | vauthors = Mercadante S, Bruera E | title = Opioid switching in cancer pain: From the beginning to nowadays | journal = Critical Reviews in Oncology/Hematology | volume = 99 | pages = 241–248 | date = March 2016 | pmid = 26806145 | doi = 10.1016/j.critrevonc.2015.12.011 }}</ref> Due to its activity at the [[NMDA receptor]], it may be more effective against [[neuropathic pain]]; for the same reason, tolerance to the analgesic effects may be less than that of other opioids.<ref>{{cite journal | vauthors = Leppert W | title = The role of methadone in cancer pain treatment--a review | journal = International Journal of Clinical Practice | volume = 63 | issue = 7 | pages = 1095–1109 | date = July 2009 | pmid = 19570126 | doi = 10.1111/j.1742-1241.2008.01990.x | s2cid = 205875314 }}</ref><ref>{{cite journal | vauthors = Nicholson AB, Watson GR, Derry S, Wiffen PJ | title = Methadone for cancer pain | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 3 | pages = CD003971 | date = February 2017 | pmid = 28177515 | pmc = 6464101 | doi = 10.1002/14651858.CD003971.pub4 }}</ref>

== Adverse effects ==
[[File:HarmCausedByDrugsTable.svg|class=skin-invert-image|thumb|upright=1.35|Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Methadone was found to be the 12th overall most dangerous drug.<ref name="Nutt_2010">{{cite journal | vauthors = Nutt DJ, King LA, Phillips LD | title = Drug harms in the UK: a multicriteria decision analysis | journal = Lancet | volume = 376 | issue = 9752 | pages = 1558–1565 | date = November 2010 | pmid = 21036393 | doi = 10.1016/S0140-6736(10)61462-6 | s2cid = 5667719 | citeseerx = 10.1.1.690.1283 }}</ref>]]
[[File:Rational harm assessment of drugs radar plot.svg|thumb|Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in [[Delphi method|delphic analysis]] regarding 20 popular recreational drugs. Street methadone was ranked 4th in dependence, 5th in physical harm, and 5th in social harm.<ref>{{cite journal | vauthors = Nutt D, King LA, Saulsbury W, Blakemore C | title = Development of a rational scale to assess the harm of drugs of potential misuse | journal = Lancet | volume = 369 | issue = 9566 | pages = 1047–1053 | date = March 2007 | pmid = 17382831 | doi = 10.1016/s0140-6736(07)60464-4 | s2cid = 5903121 }}</ref>]]

Adverse effects of methadone include:<ref>{{cite web |url=https://www.webmd.com/drugs/2/drug-2671-1278/methadone-oral/methadone-concentrate-oral/details | title=Methadone Oral: Side Effects | website= WebMD |access-date=25 June 2021}}</ref>
* [[Sedation]]
* [[Constipation]]<ref name=Drugs.com/><ref name=medlineplus-archive/>
* [[Flushing (physiology)|Flushing]]<ref name=medlineplus-archive/>
* [[Perspiration]]<ref name=medlineplus-archive/>
* [[Heat intolerance]]
* [[Dizziness]] or [[fainting]]<ref name=Drugs.com/><ref name=RxList/><ref name=MedicineNet/>
* [[Weakness]]<ref name=medlineplus-archive/>
* [[Fatigue (medical)#Chronic fatigue|Fatigue]]<ref name=medlineplus-archive/>
* [[Drowsiness]]<ref name=Drugs.com/>
* [[Miotic|Constricted pupils]]
* [[Xerostomia|Dry mouth]]<ref name=Drugs.com/><ref name=medlineplus-archive/>
* [[Nausea]] and [[vomiting]]<ref name=Drugs.com/><ref name=medlineplus-archive/>
* [[Hypotension|Low blood pressure]]
* [[Headache]]<ref name=medlineplus-archive>{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682134.html|archive-url=https://web.archive.org/web/20080227025738/http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682134.html |archive-date=27 February 2008 |title=Methadone| website=MedlinePlus}}</ref>
* Heart problems such as chest pain<ref name=Drugs.com/><ref name=RxList/> or fast heartbeat<ref name=Drugs.com/><ref name=RxList/><ref name=MedicineNet/>
* [[Cardiac arrhythmia|Abnormal heart rhythms]]<ref name=MedicineNet/><ref name="pmc3021856">{{cite journal | vauthors = John J, Amley X, Bombino G, Gitelis C, Topi B, Hollander G, Ghosh J | title = Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection | journal = Cardiology Research and Practice | volume = 2010 | pages = 524764 | date = December 2010 | pmid = 21253542 | pmc = 3021856 | doi = 10.4061/2010/524764 | doi-access = free | title-link = doi }}</ref>
* Respiratory problems such as trouble breathing,<ref name=Drugs.com/><ref name=RxList/> slow or shallow breathing ([[hypoventilation]]),<ref name=Drugs.com>{{cite web |url=https://www.drugs.com/methadone.html |title=Methadone |publisher=Drugs.com |url-status=live |archive-url=https://web.archive.org/web/20170729133154/https://www.drugs.com/methadone.html |archive-date=29 July 2017 }}</ref><ref name=RxList>{{cite web |url=http://www.rxlist.com/cgi/generic/methdone.htm |title=Dolophine: Drug Description |website=RxList |url-status=dead |archive-url=https://web.archive.org/web/20080903135222/http://www.rxlist.com/cgi/generic/methdone.htm |archive-date=3 September 2008 }}</ref> [[lightheadedness]],<ref name=Drugs.com/><ref name=RxList/><ref name=MedicineNet>{{cite web |url=http://www.medicinenet.com/methadone-dispersible_tablet/article.htm |title=Methadone |publisher=MedicineNet |url-status=live |archive-url=https://web.archive.org/web/20160304040715/http://www.medicinenet.com/methadone-dispersible_tablet/article.htm |archive-date=4 March 2016 }}</ref> or fainting<ref name=Drugs.com/><ref name=RxList/>
*[[Weight gain]]<ref name=medlineplus-archive/>
* Memory loss
* [[Itching]]
* [[Difficulty urinating]]<ref name=medlineplus-archive/>
* [[Swelling (medical)|Swelling]] of the hands, arms, feet, and legs<ref name=medlineplus-archive/>
* [[Mood changes]],<ref name=medlineplus-archive/> (e.g., [[euphoria]], [[disorientation]])
* [[Blurred vision]]<ref name=medlineplus-archive/>
* Decreased [[libido]],<ref name=Drugs.com/><ref name=medlineplus-archive/> difficulty in reaching [[orgasm]],<ref name=Drugs.com/> or [[impotence]]<ref name=Drugs.com/><ref name=medlineplus-archive/>
* [[Amenorrhea|Missed menstrual periods]]<ref name=medlineplus-archive/>
* [[Skin rash]]
* Central sleep apnea

=== Withdrawal symptoms ===
Methadone withdrawal symptoms are reported as being significantly more protracted than withdrawal from opioids with shorter half-lives.

When used for opioid maintenance therapy, Methadone is generally administered as an oral liquid. Methadone has been implicated in contributing to significant [[tooth decay]]. Methadone causes [[xerostomia|dry mouth]], reducing the protective role of [[saliva]] in preventing decay. Other putative mechanisms of methadone-related tooth decay include craving for carbohydrates related to opioids, poor dental care, and a general decrease in personal hygiene. These factors, combined with sedation, have been linked to the causation of extensive dental damage.<ref>{{cite journal | vauthors = Brondani M, Park PE | title = Methadone and oral health--a brief review | journal = Journal of Dental Hygiene | volume = 85 | issue = 2 | pages = 92–98 | date = 16 May 2011 | pmid = 21619737 }}</ref><ref>{{cite journal | vauthors = Graham CH, Meechan JG | title = Dental management of patients taking methadone | journal = Dental Update | volume = 32 | issue = 8 | pages = 477–8, 481–2, 485 | date = October 2005 | pmid = 16262036 | doi = 10.12968/denu.2005.32.8.477 }}</ref>

====Physical symptoms====
* [[Lightheadedness]]<ref name=michael>{{cite web | url = https://www.nhtsa.gov/sites/nhtsa.gov/files/809725-drugshumanperformfs.pdf | title = National Highway Traffic Safety Administration. Methadone. Drugs and Human Performance Fact Sheets. | publisher = NHTSA }}</ref>
* [[Lacrimation|Tearing]] of the eyes<ref name=michael/><ref name=sadovsky/>
* [[Mydriasis]] (dilated pupils)<ref name=michael/>
* [[Photophobia]] (sensitivity to light)
* [[Hyperventilation]] (breathing that is too fast/deep)
* [[Rhinorrhea|Runny nose]]<ref name=sadovsky/>
* Yawning
* Sneezing<ref name=sadovsky/>
* [[Nausea]],<ref name=michael/><ref name=sadovsky/> vomiting,<ref name=michael/><ref name=sadovsky/> and [[diarrhea]]<ref name=michael/>
* [[Fever]]<ref name=sadovsky/>
* [[Sweating]]<ref name=michael/>
* Chills<ref name=sadovsky/>
* [[Tremor]]s<ref name=michael/><ref name=sadovsky/>
* [[Akathisia]] (restlessness)
* [[Tachycardia]] (fast heartbeat)<ref name=sadovsky/>
* Aches<ref name=michael/> and pains, often in the joints or legs
* Elevated pain sensitivity
* Blood pressure that is too high ([[hypertension]], may cause a stroke)

====Cognitive symptoms====
* [[Suicidal ideation]]
* Susceptibility to cravings<ref name=michael/>
* [[Depression (mood)|Depression]]<ref name=michael/>
* Spontaneous [[orgasm]]
* Prolonged [[insomnia]]
* [[Delirium]]
* [[Auditory hallucinations]]
* [[Visual hallucinations]]
* Increased perception of odors ([[olfaction]]), real or imagined
* Marked increase in [[Libido|sex drive]]
* [[Psychomotor agitation|Agitation]]
* [[Anxiety]]<ref name=michael/>
* [[Panic disorder]]
* Nervousness<ref name=michael/>
* [[Paranoia]]
* [[Delusions]]
* [[Apathy]]
* [[Anorexia (symptom)]]

=== Black box warning ===
Methadone has the following U.S. FDA [[black box warning]]:<ref>{{cite web|url=https://www.drugs.com/pro/methadone.html|title=Methadone Black Box Warnings - Drugs.com|website=drugs.com|access-date=20 November 2018}}</ref>

* Risk of addiction and abuse
* Potentially fatal respiratory depression
* Lethal overdose in accidental ingestion
* QT prolongation<ref name="pmid33157550">{{cite journal | vauthors = Tran PN, Sheng J, Randolph AL, Baron CA, Thiebaud N, Ren M, Wu M, Johannesen L, Volpe DA, Patel D, Blinova K, Strauss DG, Wu WW | title = Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block | journal = PLOS ONE | volume = 15 | issue = 11 | pages = e0241362 | date = 2020 | pmid = 33157550 | pmc = 7647070 | doi = 10.1371/journal.pone.0241362 | doi-access = free | title-link = doi | bibcode = 2020PLoSO..1541362T }}</ref>
* Neonatal opioid withdrawal syndrome in children of pregnant women
* CYP450 drug interactions
* Risks when used with [[alcohol (drug)|alcohol]], [[benzodiazepine]]s, and other CNS depressants.
* A certified opioid treatment program is required under federal law (42 CFR 8.12) when dispensing methadone for the treatment of opioid addiction.

=== Overdose ===
Most people who overdose on methadone show some of the following symptoms:
* [[Miosis]] (constricted pupils)<ref name=medline-methadone>{{cite web | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682134.html | title = Methadone (meth' a done) | publisher = National Institutes of Health | work = MedlinePlus | date = 1 February 2009 | access-date = 23 October 2013 | url-status = live | archive-url = https://web.archive.org/web/20131017172738/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682134.html | archive-date = 17 October 2013 }}</ref>
* Vomiting<ref name=MedlinePlusOverdose>{{cite web|title=Methadone overdose|url=https://medlineplus.gov/ency/article/002679.htm|website=MedlinePlus|date=3 October 2017}}</ref>
*[[Spasm]]s of the stomach and intestines<ref name="medlineplus.gov">{{cite web|title=Methadone overdose: MedlinePlus Medical Encyclopedia|url=https://medlineplus.gov/ency/article/002679.htm|access-date=13 November 2021|website=medlineplus.gov|language=en}}</ref>
* [[Hypoventilation]] (breathing that is too slow/shallow)<ref name=medline-methadone/>
* [[Drowsiness]],<ref name=medline-methadone/> sleepiness, disorientation, sedation, unresponsiveness
* Skin that is cool, clammy (damp), and pale<ref name=medline-methadone/>
*Blue fingernails and lips<ref name="medlineplus.gov"/>
* Limp muscles,<ref name=medline-methadone/> trouble staying awake, nausea
* [[Unconsciousness]]<ref name=medline-methadone/> and [[coma]]<ref name=medline-methadone/>

The respiratory depression of an overdose can be treated with [[naloxone]].<ref name=sadovsky>{{cite journal | url = http://www.aafp.org/afp/2000/0715/p428.html | title = Tips from Other Journals – Public Health Issue: Methadone Maintenance Therapy | vauthors = Sadovsky R | journal = American Family Physician | date = 15 July 2000 | volume = 62 | pages = 428–432 | issue = 2 | url-status = live | archive-url = https://web.archive.org/web/20150904004312/http://www.aafp.org/afp/2000/0715/p428.html | archive-date = 4 September 2015 }}</ref> Naloxone is preferred to the newer, longer-acting antagonist [[naltrexone]]. Despite methadone's much longer duration of action compared to heroin and other shorter-acting agonists and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half-life, it is more difficult to titrate. If too large a dose of the opioid antagonist is given to a dependent person, it will result in withdrawal symptoms (possibly severe). When using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short-lived. Doses of methadone take longer to be eliminated from the person's system. A common problem in treating methadone overdoses is that given the short action of naloxone (versus the extremely longer-acting methadone), a dosage of naloxone given to a methadone-overdosed person will initially work to bring the person out of overdose, but once the naloxone wears off, if no further naloxone is administered, the person can go right back into overdose (based upon time and dosage of the methadone ingested).

=== Tolerance and dependence ===
As with other opioid medications, tolerance and dependence usually develop with repeated doses. There is some clinical evidence that tolerance to analgesia is less with methadone compared to other opioids; this may be due to its activity at the [[NMDA]] receptor. Tolerance to the different physiological effects of methadone varies; tolerance to analgesic properties may or may not develop quickly, but tolerance to euphoria usually develops rapidly, whereas tolerance to constipation, sedation, and respiratory depression develops slowly (if ever).<ref name="SE">{{cite journal | url = http://www.atforum.com/pdf/DosingandSafetyWP.pdf | journal = Addiction Treatment Forum | date = September 2003 | title = Methadone Dosing & Safety in the Treatment of Opioid Addiction | vauthors = Leavitt SB }}</ref>

=== Driving ===
Methadone treatment may impair driving ability.<ref>{{cite journal | vauthors = Giacomuzzi SM, Ertl M, Vigl A, Riemer Y, Günther V, Kopp M, Pilsz W, Haaser W | title = Driving capacity of patients treated with methadone and slow-release oral morphine | journal = Addiction | volume = 100 | issue = 7 | pages = 1027 | date = July 2005 | pmid = 15955021 | doi = 10.1111/j.1360-0443.2005.01148.x | doi-access = free }}</ref> Drug abusers had significantly more involvement in serious crashes than non-abusers in a study by the University of Queensland. In the study of a group of 220 drug abusers, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other people randomly selected having no involvement in fatal crashes.<ref>{{cite journal | vauthors = Reece AS | title = Experience of road and other trauma by the opiate dependent patient: a survey report | journal = Substance Abuse Treatment, Prevention, and Policy | volume = 3 | pages = 10 | date = May 2008 | pmid = 18454868 | pmc = 2396610 | doi = 10.1186/1747-597X-3-10 | doi-access = free | title-link = doi }}</ref> However, there have been multiple studies verifying the ability of methadone maintenance patients to drive.<ref>{{cite web | url = http://www.methadonesupport.org/Driving%20Article%20Abstracts.doc | archive-url = https://web.archive.org/web/20111103044844/http://www.methadonesupport.org/Driving%20Article%20Abstracts.doc | url-status = dead | archive-date = 3 November 2011 | format = DOC | title = Methadone and Driving Article Abstracts: Brief Literature Review | publisher = Institute for Metropolitan Affairs, Roosevelt University | date = 14 February 2008 }}</ref> In the UK, persons who are prescribed oral methadone can continue to drive after they have satisfactorily completed an independent medical examination which will include a urine screen for drugs. The license will be issued for 12 months at a time and even then, only following a favourable assessment from their own doctor.<ref name="rcgp.org.uk-PDF-drug_meth%20guidance.pdf">{{cite book | url = http://www.rcgp.org.uk/PDF/drug_meth%20guidance.pdf | archive-url = https://web.archive.org/web/20120521080204/http://www.rcgp.org.uk/PDF/drug_meth%20guidance.pdf | archive-date = 21 May 2012 | title = Guidance for the use of methadone for the treatment of opioid dependence in primary care | location = London| publisher = Royal College of General Practitioners | edition = 1st | year = 2005 | vauthors = Ford C, Barnard J, Bury J, Carnwath T, Gerada C, Joyce A, Keen J, Lowe C, Nelles B, Roberts K, Sander-Hess C, Schofield P, Scott J, Watson R, Wolff K }}</ref> Individuals who are prescribed methadone for either IV or IM administration cannot drive in the UK, mainly due to the increased sedation effects that this route of use can cause.

=== Mortality ===
In the United States, deaths linked to methadone more than quadrupled in the five-year period between 1999 and 2004. According to the U.S. National Center for Health Statistics,<ref>{{cite web |url=https://www.cdc.gov/nchs/products/pubs/pubd/hestats/methadone1999-04/methadone1999-04.htm |title=Increases in Methadone-Related Deaths:1999–2004 |url-status=live |archive-url=https://web.archive.org/web/20100411213556/http://cdc.gov/nchs/products/pubs/pubd/hestats/methadone1999-04/methadone1999-04.htm |archive-date=11 April 2010 |date=4 September 2018 }}</ref> as well as a 2006 series in the ''Charleston Gazette'' (West Virginia),<ref name="http://www.wvgazette.com/section/Series/The+Killer+Cure">[http://www.wvgazette.com/section/Series/The+Killer+Cure "The Killer Cure"] {{webarchive|url=https://web.archive.org/web/20060618125503/http://wvgazette.com/section/Series/The+Killer+Cure |date=18 June 2006 }} ''The Charleston Gazette'' 2006</ref> medical examiners listed methadone as contributing to 3,849 deaths in 2004. That number was up from 790 in 1999. Approximately 82 percent of those deaths were listed as accidental, and most deaths involved combinations of methadone with other drugs (especially [[benzodiazepines]]).

Although deaths from methadone are on the rise{{update inline|date=January 2024}}, methadone-associated deaths are not being caused primarily by methadone intended for methadone treatment programs, according to a panel of experts convened by the [[Substance Abuse and Mental Health Services Administration]], which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remains incomplete, National Assessment meeting participants concurred that methadone tablets or Diskets distributed through channels other than opioid treatment programs most likely are the central factors in methadone-associated mortality."<ref>{{cite web |url=http://alcoholism.about.com/cs/heroin/a/blsam040209.htm |title=Methadone-Associated Mortality, Report of a National Assessment |url-status=live |archive-url=https://web.archive.org/web/20160101081924/http://alcoholism.about.com/cs/heroin/a/blsam040209.htm |archive-date=1 January 2016 }}</ref>

In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled "Methadone Use for Pain Control May Result in Death." The FDA also revised the drug's package insert. The change deleted previous information about the usual adult dosage. The ''Charleston Gazette'' reported, "The old language about the 'usual adult dose' was potentially deadly, according to pain specialists."<ref>{{cite news | url = http://wvgazette.com/News/TheKillerCure/200611280003 | newspaper = Charleston Gazette | title = New warning issued on methadone | date = 28 November 2006 | vauthors = Finn S, Tuckwiller T | url-status = live | archive-url = https://web.archive.org/web/20100213212647/http://wvgazette.com/News/TheKillerCure/200611280003 | archive-date = 13 February 2010 }}</ref>

== Pharmacology ==
{{Methadone at opioid receptors, monoamine transporters, and the NMDA receptor}}
Methadone acts by binding to the [[μ-opioid receptor]], but also has some [[affinity (pharmacology)|affinity]] for the [[NMDA receptor]], an [[ionotropic glutamate receptor]]. Methadone is [[metabolism|metabolized]] by [[CYP3A4]], [[CYP2B6]], [[CYP2D6]], and is a [[substrate (biochemistry)|substrate]], or in this case target, for the [[P-glycoprotein]] efflux protein, a protein which helps pump foreign substances out of cells, in the [[intestine]]s and [[brain]]. The [[bioavailability]] and [[elimination half-life]] of methadone are subject to substantial [[interindividual variability]]. Its main [[route of administration]] is [[oral administration|oral]]. Adverse effects include sedation, [[hypoventilation]], [[constipation]], and [[miosis]], in addition to tolerance, dependence, and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opioids, spanning anywhere from two weeks to several months.

The metabolic half-life of methadone differs from its duration of action. The metabolic half-life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours for opioid-naive people), as opposed to a half-life of 1 to 5 hours for morphine.<ref name="Gris2011"/> The length of the half-life of methadone allows for the exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.<ref name=Gris2011/>

Methadone at therapeutic concentrations is known to prolong the [[QTc interval]], which indicates that the heart muscle repolarizes more slowly. This QTc prolongation tends to increase the risk of [[torsades de pointes]] (TdP), a heart rhythm disturbance that can lead to [[Syncope (medicine)|syncope]] or sudden death. In a large observational study in Sweden, methadone was associated with a particularly high [[Incidence (epidemiology)|incidence]] of TdP, especially in younger patients. The incidence of TdP was 41.9 cases per 100,000 users of methadone in the 18-64 year old age group.<ref name="sweden-2020">{{cite journal |author1=Bengt Danielsson |author2=Julius Collin |author3=Anastasia Nyman |author4=Annica Bergendal |author5=Natalia Borg |author6=Maria State |author7=Lennart Bergfeldt |author8=Johan Fastbom |title=Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study |journal=BMJ Open |date=2020-03-12 |volume=10 |issue=3 |page=e034560 |doi=10.1136/bmjopen-2019-034560 |pmid=32169926 |ref=sweden-2020 |pmc=7069257}}</ref> In this study of TdP, methadone was the highest-risk drug in the 18-64 year-old group, with the sole exception of the [[antiarrhythmic]] drug [[amiodarone]], which was associated with 66.5 cases of TdP per 100,000 amiodarone users.<ref name="sweden-2020" /> The high incidence of TdP in amiodarone-treated patients may indicate correlation and not causation because amiodarone is often prescribed to patients with preexisting heart conditions that independently increase the risk of TdP. Methadone likely causes cardiac arrhythmias (such as TdP) via two mechanisms.<ref name="Na-channels-2014">{{cite journal | vauthors = Schulze V, Stoetzer C, O'Reilly AO, Eberhardt E, Foadi N, Ahrens J, Wegner F, Lampert A, de la Roche J, Leffler A | title = The opioid methadone induces a local anaesthetic-like inhibition of the cardiac Na<sup>+</sup> channel, Na(v)1.5 | journal = British Journal of Pharmacology | volume = 171 | issue = 2 | pages = 427–437 | date = January 2014 | pmid = 24117196 | pmc = 3904262 | doi = 10.1111/bph.12465 | quote = "the clinical relevance of a Na+ channel blocker is probably better estimated from recordings on inactivated channels (IC50 ~10 μM in our study)." }}</ref> Like many other [[cardiotoxic]] drugs, methadone blocks the [[hERG|hERG K+ channel]]. The two enantiomers of methadone inhibit hERG channels with different potency. [[Dextromethadone]], which is less potent as an opioid, is more potent at blocking the hERG channel with an IC<sub>50</sub> of ~12 μM. [[Levomethadone]] has a lower affinity, with an IC<sub>50</sub> of ~29 μM at the hERG channel.<!-- This data comes from Eap et al. (2002) and is quoted fully in the following citation. --><ref name="Na-channels-2014" /> Methadone is also known to block the [[SCN5A|Na<sub>v</sub>1.5 voltage-gated Na+ channel]] (SCN5A) with an IC<sub>50</sub> of ~10 μM, which is similar to the local anesthetic [[bupivacaine]]. Both enantiomers of methadone block the Na<sub>v</sub>1.5 channel with similar affinities.<ref name="Na-channels-2014" /> Bupivacaine is especially cardiotoxic among local anesthetics, and it is believed to act via this same sodium channel. Plasma concentrations of methadone in recovering addicts can reach 4 μM during therapy, so the actions of methadone at both the hERG potassium channel and the Na<sub>v</sub>1.5 sodium channel are possibly clinically relevant in producing cardiac side effects.<ref name="Na-channels-2014" /> This also suggests that [[levomethadone]] is not completely free of cardiac toxicity.

=== Mechanism of action ===
[[Levomethadone]] (the ''R''-(–)-methadone enantiomer) is a [[μ-opioid receptor]] agonist with higher [[intrinsic activity]] than morphine, but lower affinity.<ref>{{cite book| veditors = Davis MP, Glare P, Hardy JR, Columba Q |title= Opioids in Cancer Pain|date=2009|publisher=Oxford University Press|location=Oxford, UK|isbn=978-0-19-923664-0|edition=2nd|pages=211–212}}</ref> [[Dextromethadone]] (the ''S''-(+)-methadone enantiomer) has a much lower affinity to the μ-opioid receptor than levomethadone. Both enantiomers bind to the [[glutamatergic]] [[NMDA]] (''N''-methyl-{{Small|D}}-aspartate) receptor, acting as noncompetitive antagonists. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism.{{Citation needed|date=December 2022}} NMDA antagonists such as [[dextromethorphan]], [[ketamine]], [[tiletamine]] and [[ibogaine]] are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal,{{Citation needed|date=December 2022}} possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain.{{Citation needed|date=May 2024}} Methadone also acted as a potent, [[noncompetitive]] [[alpha-3 beta-4 nicotinic receptor|α<sub>3</sub>β<sub>4</sub>]] neuronal [[nicotinic acetylcholine receptor]] [[nicotinic antagonist|antagonist]] in rat receptors, expressed in human embryonic kidney cell lines.<ref>{{cite journal | vauthors = Xiao Y, Smith RD, Caruso FS, Kellar KJ | title = Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 299 | issue = 1 | pages = 366–371 | date = October 2001 | doi = 10.1016/S0022-3565(24)29338-1 | pmid = 11561100 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11561100 | access-date = 21 June 2011 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828170410/https://jpet.aspetjournals.org/content/299/1/366.long | url-status = dead | url-access = subscription }}</ref>

=== Metabolism ===
Methadone has a slow metabolism and very high [[Lipophilicity|fat solubility]], making it longer lasting than morphine-based drugs. Methadone has a typical elimination [[half-life]] of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100,<ref name="Kell">{{cite journal | vauthors = Kell MJ | title = Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting | journal = Journal of Addictive Diseases | volume = 13 | issue = 1 | pages = 5–26 | year = 1994 | pmid = 8018740 | doi = 10.1300/J069v13n01_02 }}</ref><ref name=Europad>{{cite journal | vauthors = Eap CB, Déglon JJ, Baumann P |title=Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance |journal=Heroin Addiction and Related Clinical Problems |volume=1 |issue=1 |pages=19–34 |year=1999 |url=http://atforum.com/pdf/europad/HeroinAdd1-1.pdf#page=25}}</ref> ranging from as few as 4 hours to as many as 130 hours,<ref name="EapI">{{cite journal | vauthors = Eap CB, Buclin T, Baumann P | title = Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence | journal = Clinical Pharmacokinetics | volume = 41 | issue = 14 | pages = 1153–1193 | year = 2002 | pmid = 12405865 | doi = 10.2165/00003088-200241140-00003 | s2cid = 1396257 }}</ref> or even 190 hours.<ref>{{cite journal | vauthors = Manfredonia JF | title = Prescribing methadone for pain management in end-of-life care | journal = The Journal of the American Osteopathic Association | volume = 105 | issue = 3 Suppl 1 | pages = S18–S21 | date = March 2005 | pmid = 18154194 | url = http://www.jaoa.org/cgi/content/full/105/3_suppl/18S | url-status = dead | archive-url = https://web.archive.org/web/20070520062222/http://www.jaoa.org/cgi/content/full/105/3_suppl/18S | archive-date = 20 May 2007 }}</ref> This variability is apparently due to genetic variability in the production of the associated cytochrome enzymes [[CYP3A4]], [[CYP2B6]] and [[CYP2D6]]. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half-life frequently allows for administration only once a day in opioid [[Drug detoxification|withdrawal management]] and maintenance programs. People who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.<ref name="EapI"/> This can also allow lower total doses in some such people. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day normally dividing daily dosage for administration at 8-hour intervals.<ref>Medscape Methadone Dosage. [https://reference.medscape.com/drug/methadose-dolophine-methadone-343317].</ref>

The main metabolic pathway involves ''N''-demethylation by CYP3A4 in the liver and intestine to give [[2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine]] (EDDP).<ref name=acta08/><ref>{{cite journal | vauthors = Preston KL, Epstein DH, Davoudzadeh D, Huestis MA | title = Methadone and metabolite urine concentrations in patients maintained on methadone | journal = Journal of Analytical Toxicology | volume = 27 | issue = 6 | pages = 332–341 | date = September 2003 | pmid = 14516485 | doi = 10.1093/jat/27.6.332 | doi-access = free | title-link = doi }}</ref> This inactive product, as well as the inactive 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), produced by a second ''N''-demethylation, are detectable in the urine of those taking methadone.
<div class="skin-invert-image"><gallery caption="Methadone and its two main metabolites" perrow="3">
File:Methadone.svg|Methadone
File:EDDP.png|EDDP
File:EDMP.png|EDMP
</gallery></div>

=== Route of administration ===
The most common [[route of administration]] at a methadone clinic is in a [[racemic]] oral solution, though in Germany, only the ''R'' [[enantiomer]] (the [[levorotatory|L]] optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects.<ref name="EapI"/> The single-isomer form is becoming less common due to the higher production costs.

Methadone is available in traditional pills, [[sublingual]] tablets, and two different formulations designed for the person to drink. Drinkable forms include ready-to-dispense liquid (sold in the [[United States]] as Methadose), and Diskets (known on the street as "wafers" or "biscuits") tablets which are dispersible in water for oral administration, used similarly to [[Alka-Seltzer]]. The liquid form is the most common as it allows for smaller dose changes. Methadone is almost as effective when administered orally as by injection. Oral medication is usually preferable because it offers safety, and simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs.<ref name="ReferenceA">Code of Federal Regulations, Title 42, Sec 8.</ref> Injecting methadone pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects. Methadone pills often contain talc that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots.<ref>{{cite web |url=http://www.vistapharm.com/methadone_tablets.pdf |title=Methadone Hydrochloride Tablets, USP |publisher=VistaPharm |url-status=dead |archive-url=https://web.archive.org/web/20130511224428/http://www.vistapharm.com/methadone_tablets.pdf |archive-date=11 May 2013 }}</ref><ref>{{cite journal | vauthors = Murphy SB, Jackson WB, Pare JA | title = Talc retinopathy | journal = Canadian Journal of Ophthalmology. Journal Canadien d'Ophtalmologie | volume = 13 | issue = 3 | pages = 152–156 | date = July 1978 | pmid = 698886 }}</ref> These particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as [[pulmonary hypertension]], an irreversible and progressive disease.<ref>{{cite journal | vauthors = Hill AD, Toner ME, FitzGerald MX | title = Talc lung in a drug abuser | journal = Irish Journal of Medical Science | volume = 159 | issue = 5 | pages = 147–148 | date = May 1990 | pmid = 2397985 | doi = 10.1007/BF02937408 | s2cid = 41611298 }}</ref><ref>{{cite journal | vauthors = Cappola TP, Felker GM, Kao WH, Hare JM, Baughman KL, Kasper EK | title = Pulmonary hypertension and risk of death in cardiomyopathy: patients with myocarditis are at higher risk | journal = Circulation | volume = 105 | issue = 14 | pages = 1663–1668 | date = April 2002 | pmid = 11940544 | doi = 10.1161/01.CIR.0000013771.30198.82 | doi-access =  | title-link = doi | s2cid = 298931 }}</ref><ref>{{cite journal | vauthors = Humbert M | title = Improving survival in pulmonary arterial hypertension | journal = The European Respiratory Journal | volume = 25 | issue = 2 | pages = 218–220 | date = February 2005 | pmid = 15684283 | doi = 10.1183/09031936.05.00129604 | doi-access = free | title-link = doi }}</ref> The formulation sold under the brand name Methadose (flavored liquid suspension for oral dosing, commonly used for [[Methadone maintenance|maintenance purposes]]) should not be injected either.<ref>{{cite journal | vauthors = Lintzeris N, Lenné M, Ritter A | title = Methadone injecting in Australia: a tale of two cities | journal = Addiction | volume = 94 | issue = 8 | pages = 1175–1178 | date = August 1999 | pmid = 10615732 | doi = 10.1046/j.1360-0443.1999.94811757.x | doi-access = free }}</ref>

Information leaflets included in packs of UK methadone tablets state that the tablets are for oral use only and that use by any other route can cause serious harm. In addition to this warning, additives have now been included in the tablet formulation to make the use of them by the IV route more difficult.<ref>Dales pharmaceuticals patients information leaflet revision 09/10{{verify source|date=December 2013}}</ref>

Methadone is also available in ampoules with strength of 50mg/ml & 10mg/ml for IV/IM/SC use in the UK.<ref>{{cite web |title=BNF |url=https://bnf.nice.org.uk/drugs/methadone-hydrochloride/medicinal-forms/#solution-for-injection |website=NICE}}</ref> Prescribing the injectable formulation was more common in the 90s with prescribers reporting that up to 9-10% of all methadone prescription were for ampoules. This practice is much less common nowadays  <ref>{{cite journal | vauthors = Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M | title = The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales | journal = The British Journal of General Practice | volume = 55 | issue = 515 | pages = 444–451 | date = June 2005 | pmid = 15970068 | pmc = 1472740 }}</ref>

== Chemistry ==

=== Detection in biological fluids ===
Methadone and its major metabolite, [[2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine]] (EDDP), are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naïve individual. Chronic users often have high methadone and EDDP baseline values.<ref>{{cite book | vauthors = Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |edition=8th |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |pages=941–5}}</ref>

=== Conformation ===
The protonated form of methadone takes on an extended conformation, while the free base is more compact. In particular, it was found that there is an interaction between the tertiary amine and the carbonyl carbon of the ketone function (R<sub>3</sub>N ••• >C=O) that limits the molecule's conformation freedom, though the distance (291 pm by X-ray) is far too long to represent a true chemical bond. However, it does represent the initial trajectory of attack of an amine on a carbonyl group and was an important piece of experimental evidence for the proposal of the [[Bürgi–Dunitz angle]] for carbonyl addition reactions.<ref>{{cite journal | vauthors = Bürgi HB, Dunitz JD, Shefter E | title = Pharmacological implications of the conformation of the methadone base | journal = Nature | volume = 244 | issue = 136 | pages = 186–187 | date = August 1973 | pmid = 4516455 | doi = 10.1038/newbio244186b0 }}</ref>

== History ==
Methadone was developed in 1937 in Germany by scientists working for [[I.G. Farbenindustrie AG]] at the [[Hoechst AG|Farbwerke Hoechst]] who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's [[opium]] and [[morphine]] shortage problem.<ref name=JanssenHist>{{cite journal | vauthors = López-Muñoz F, Alamo C | title = The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice | journal = Brain Research Bulletin | volume = 79 | issue = 2 | pages = 130–141 | date = April 2009 | pmid = 19186209 | doi = 10.1016/j.brainresbull.2009.01.005 | s2cid = 7720401 }}</ref><ref>{{cite journal |doi=10.1002/jlac.19495610107 |title=Über eine neue Klasse von spasmolytisch und analgetisch wirkenden Verbindungen, I |trans-title=On a new class of spasmolytic and analgesic compounds, I |language=de |year=1949 | vauthors = Bockmühl M, Ehrhart G |journal=Justus Liebigs Annalen der Chemie |volume=561 |issue=1 |pages=52–86}}</ref> On 11 September 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany)<ref>{{cite web |title=Polamidon: Wirkung, Legalität, Substitution, Erfolgschancen & Entzug |url=https://www.mywaybettyford.de/suchtkompendium/polamidon/ |access-date=2 March 2023 |website=My Way Betty Ford Klinik |language=de-DE}}</ref> and whose structure had little relation to morphine or other "true opiates" such as [[Heroin|diamorphine]] (Heroin), [[desomorphine]] (Permonid), [[nicomorphine]] (Vilan), [[codeine]], [[dihydrocodeine]], [[oxymorphone]] (Opana), [[hydromorphone]] (Dilaudid), [[oxycodone]] (OxyContin), [[hydrocodone]] (Dicodid), and other closely related opium alkaloid derivatives and analogues.<ref>{{cite book | vauthors = Bockmühl M, Ehrhart G, Schaumann O |date= 1948 |title= Über eine neue Klasse von spasmolytisch und analgetisch wirkenden (About a new class of compounds with a spasmolytic and analgesic effect) |url= https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_1_page006.html |location= |publisher= Justus Liebigs Ann. | volume=561 |pages= 561, 52–85 |isbn=}}</ref> It was brought to market in 1943 and was widely used by the German army during WWII as a substitute for morphine.<ref name=JanssenHist/>

In the 1930s, [[pethidine]] (meperidine) went into production in Germany; however, the production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research.<ref>{{cite journal | vauthors = Defalque RJ, Wright AJ | title = The early history of methadone. Myths and facts | journal = Bulletin of Anesthesia History | volume = 25 | issue = 3 | pages = 13–16 | date = October 2007 | pmid = 20506765 | doi = 10.1016/S1522-8649(07)50035-1 }}</ref> After the war, all German patents, trade names, and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US.<ref name=JanssenHist/> The report published by the committee noted that while methadone itself was potentially addictive, it produced "considerably" less [[euphoria]], sedation, and respiratory depression than morphine at equianalgesic doses and was thus interesting as a commercial drug. The same report also compared methadone to pethidine. German researchers reported that methadone was capable of producing strong morphine-like physical dependence, which is characterized by [[Opioid withdrawal|opioid withdrawal symptoms]] which are lesser in severity and intensity compared to morphine, but methadone was associated with a considerably prolonged or protracted withdrawal syndrome when compared to morphine.<ref name="SE"/><ref name=JanssenHist/> Morphine produced higher rates of self-administration and reinforcing behaviour in both human and animal subjects when compared to both methadone and pethidine. In comparison to equianalgesic doses of pethidine (Demerol), methadone was shown to produce less euphoria, but higher rates of constipation, and roughly equal levels of respiratory depression and sedation.<ref name=JanssenHist/>

In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.<ref name="pmid41087">{{cite journal | vauthors = Overton DA, Batta SK | title = Investigation of narcotics and antitussives using drug discrimination techniques | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 211 | issue = 2 | pages = 401–408 | date = November 1979 | doi = 10.1016/S0022-3565(25)31847-1 | pmid = 41087 | pmc = 8331839 }}</ref>

[[Isomethadone]], [[noracymethadol]], [[levacetylmethadol|LAAM]], and [[normethadone]] were first developed in Germany, the United Kingdom, Belgium, Austria, Canada, and the United States in the thirty or so years after the 1937 discovery of pethidine, the first synthetic opioid used in medicine. These synthetic opioids have increased length and depth of satiating any opiate cravings and generate very strong analgesic effects due to their long metabolic half-life and strong receptor affinity at the mu-opioid receptor sites. Therefore, they impart much of the satiating and anti-addictive effects of methadone by suppressing drug cravings.<ref>Morphine & Allied Drugs, Reynolds et al. 1957 Ch 8</ref>

It was only in 1947 that the drug was given the generic name "methadone" by the Council on Pharmacy and Chemistry of the American Medical Association. Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected, each pharmaceutical company interested in the formula could buy the rights for the commercial production of methadone for just one dollar (MOLL 1990).

Methadone was introduced into the United States in 1947 by [[Eli Lilly and Company]] as an analgesic under the trade name Dolophine.<ref name=JanssenHist/> An [[urban myth]] later arose that [[Nazi Germany|Nazi]] leader [[Adolf Hitler]] ordered the manufacture of methadone or that the brand name 'Dolophine' was named after him, probably based on the similarity of "doloph" with "Adolph". (The pejorative term "adolphine" would appear in the early 1970s.<ref>{{cite web|url=http://www.exchangesupplies.org/publications/methadone_briefing/section1.html|archive-url=https://web.archive.org/web/20031120200050/http://www.exchangesupplies.org/publications/methadone_briefing/section1.html |title=Methadone Briefing|archive-date=20 November 2003|access-date=9 July 2007}}</ref><ref>[http://www.indro-online.de/discovery.pdf Indro-Online.de] {{webarchive|url=https://web.archive.org/web/20160113172231/http://www.indro-online.de/discovery.pdf |date=13 January 2016 }} ([[PDF]] format)</ref>) However, the name "Dolophine" was a contraction of "Dolo" from the Latin word ''dolor'' (pain), and ''finis'', the Latin word for "end". Therefore, Dolophine literally means "pain end".<ref>{{cite book|chapter=The History of Methadone and Methadone Prescribing. | vauthors = Preston A, Bennett G |title=In: Methadone Matters. Evolving Community Methadone Treatment of Opiate Addiction. | veditors = Tober G, Strang E |date=2003|publisher=Taylor and Francis Group.}}</ref>

Methadone was studied as a treatment for opioid addiction at the Addiction Research Center of the [[Narcotic Farm|Narcotics Farm]] in Lexington, Kentucky in the 1950s, and by Rockefeller University physicians Robert Dole and Marie Nyswander in the 1960s in New York City.<ref name="Browne-Miller_2009">{{cite book| vauthors = Browne-Miller A |url=https://books.google.com/books?id=MwannQGBS9cC&dq=methadone+lexington&pg=PA305|title=The Praeger International Collection on Addictions|date=2009|publisher=ABC-CLIO|isbn=978-0-275-99605-5|language=en}}</ref> By 1976, methadone clinics had opened in cities including Chicago, New York, and New Haven, with some 38,000 patients treated in New York City alone.<ref name="Browne-Miller_2009" /><ref>{{cite journal | vauthors = Dole VP, Nyswander ME | title = Methadone maintenance treatment. A ten-year perspective | journal = JAMA | volume = 235 | issue = 19 | pages = 2117–2119 | date = May 1976 | pmid = 946538 | doi = 10.1001/jama.1976.03260450029025 }}</ref>

== Society and culture ==

=== Brand names ===
Brand names include Dolophine, Symoron, Amidone, Methadose, Physeptone, Metadon, Metadol, Metadol-D, Heptanon and Heptadon among others.

=== Economics ===
In the US, generic methadone tablets are inexpensive, with retail prices ranging from $0.25 to $2.50 per [[defined daily dose]].<ref>Based on:

* {{cite web|url=http://www.goodrx.com/methadone?form=tablet&dosage=5mg&quantity=150&days_supply=&label_override=methadone|title=Methadone Prices and Methadone Coupons » 5 mg|publisher=GoodRx, Inc|archive-url=https://web.archive.org/web/20160911110432/http://www.goodrx.com/methadone?form=tablet&dosage=5mg&quantity=150&days_supply=&label_override=methadone|archive-date=11 September 2016|url-status=dead|access-date=30 August 2016}}{{Unreliable source?|date=September 2023}}
* {{cite web|url=http://www.goodrx.com/methadone?form=tablet&dosage=40mg&quantity=19&days_supply=&label_override=methadone|title=Methadone Prices and Methadone Coupons » 40 mg|publisher=GoodRx, Inc|archive-url=https://web.archive.org/web/20160911115830/http://www.goodrx.com/methadone?form=tablet&dosage=40mg&quantity=19&days_supply=&label_override=methadone|archive-date=11 September 2016|url-status=dead|access-date=30 August 2016}}{{Unreliable source?|date=September 2023}}
* {{cite web|url=http://www.whocc.no/atc_ddd_index/?code=N07BC02|title=WHOCC – ATC/DDD Index|publisher=WHO Collaborating Centre for Drug Statistics Methodology|archive-url=https://web.archive.org/web/20160919085353/http://www.whocc.no/atc_ddd_index/?code=N07BC02|archive-date=19 September 2016|url-status=live|access-date=30 August 2016}}</ref>

Methadone maintenance clinics in the US may be covered by private insurance, [[Medicaid]], or [[Medicare (United States)|Medicare]].<ref>{{cite web|url=https://www.samhsa.gov/medication-assisted-treatment/treatment/insurance-payments|title=Insurance and Payments| vauthors = Walsh L |date=16 June 2015 |website=www.samhsa.gov |language=en|access-date=2 November 2018}}</ref> Medicare covers methadone under the prescription drug benefit, Medicare Part D, when it is prescribed for pain, but not when it is used for opioid dependence treatment because it cannot be dispensed in a retail pharmacy for this purpose.<ref>{{cite web|url=https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/downloads/SE1604.pdf|title=Medicare Coverage of Substance Abuse Services|access-date=3 November 2018|archive-date=23 October 2020|archive-url=https://web.archive.org/web/20201023225139/https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/SE1604.pdf|url-status=dead}}</ref> In California methadone maintenance treatment is covered under the medical benefit. Patients' eligibility for methadone maintenance treatment is most often contingent on them being enrolled in substance abuse counseling. People on methadone maintenance in the US either have to pay cash or if covered by insurance must complete a pre-determined number of hours per month in therapeutic groups or counseling.<ref>{{cite web|url=https://www.asam.org/docs/default-source/advocacy/state-medicaid-reports/state-medicaid-reports_ca.pdf?sfvrsn=6|title=Medicaid Coverage of Medications for the Treatment of Opioid Use Disorder}}</ref> The United States Department of Veteran's Affairs (VA) Alcohol and Drug Dependence Rehabilitation Program offers methadone services to eligible veterans enrolled in the VA health care system.<ref>{{cite web|url=https://www.benefits.gov/benefit/307|title=Veterans Alcohol and Drug Dependence Rehabilitation Program|date=1 November 2018}}</ref>

[[Methadone maintenance|Methadone maintenance treatment]] (MMT) cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.<ref>{{cite web|url=http://www.drugpolicy.org/library/research/methadone.cfm|title=Methadone Maintenance Treatment|publisher=Drug Policy Alliance Lindesmith Library|archive-url=https://web.archive.org/web/20030511203202/http://www.drugpolicy.org/library/research/methadone.cfm#note3|archive-date=11 May 2003}}</ref><ref>{{cite web|url=http://international.drugabuse.gov/collaboration/guide_methadone/partb_question15.html|title=Methadone Research Web Guide|publisher=NIDA|archive-url=https://web.archive.org/web/20100215142535/http://international.drugabuse.gov/collaboration/guide_methadone/partb_question15.html|archive-date=15 February 2010|url-status=live}}</ref> A preliminary cost analysis conducted in 2016 by the US Department of Defense determined that methadone treatment, which includes psychosocial and support services, may cost an average of $126.00 per week or $6,552.00 per year.<ref>{{cite web|url=https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-addiction/how-much-does-opioid-treatment-cost|title=How Much Does Opioid Treatment Cost?| author = National Institute on Drug Abuse |date=June 2018 |language=en|access-date=2 November 2018}}</ref> The average cost for one full year of methadone maintenance treatment is approximately $4,700 per patient, whereas one full year of imprisonment costs approximately $24,000 per person.<ref>{{cite web|url=https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/frequently-asked-questions/drug-addiction-treatment-worth-its-cost|title=Is drug addiction treatment worth its cost?|access-date=29 December 2019|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728024409/https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/frequently-asked-questions/drug-addiction-treatment-worth-its-cost|url-status=dead}}</ref>

== Regulation ==

=== United States and Canada ===
Methadone is a [[Controlled Drugs and Substances Act|Schedule I]] controlled substance in Canada and Schedule II in the United States, with an ACSCN of 9250 and a 2014 annual aggregate manufacturing quota of 31,875 kilos for sale. [[Methadone intermediate]] is also controlled, under [[ACSCN]] 9226 also under Schedule II, with a quota of 38,875 kilos. In most countries of the world, methadone is similarly restricted. The salts of methadone in use are the hydrobromide (free base conversion ratio 0.793), hydrochloride (0.894), and HCl monohydrate (0.850).<ref>{{cite web |url=http://www.deadiversion.usdoj.gov/quotas/conv_factor/index.html |title=DEA Diversion Control Division |access-date=28 February 2016 |url-status=live |archive-url=https://web.archive.org/web/20160302162948/http://deadiversion.usdoj.gov/quotas/conv_factor/index.html |archive-date=2 March 2016 }}</ref> Methadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.<ref>{{cite web |url=http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |title=DEA Diversion Control Division |access-date=28 February 2016 |url-status=live |archive-url=https://web.archive.org/web/20160304053357/http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |archive-date=4 March 2016 }}</ref><ref name="Nordegren2002">{{cite book | vauthors = Nordegren T | title = The A-Z Encyclopedia of Alcohol and Drug Abuse | url = https://books.google.com/books?id=4yaGePenGKgC&pg=PA366 | access-date = 16 May 2012 | date = 1 March 2002 | publisher = Universal-Publishers | isbn = 978-1-58112-404-0 | page = 366 | url-status = live | archive-url = https://web.archive.org/web/20140101085353/http://books.google.com/books?id=4yaGePenGKgC&pg=PA366 | archive-date = 1 January 2014 }}</ref>

==== Methadone clinics ====
In the United States, prescription of methadone requires intensive monitoring and must be obtained in-person from an Opioid Treatment Program—colloquially known as a 'methadone clinic'—when prescribed for [[opioid use disorder]] (OUD).<ref name="Anderson_2000"/> According to federal laws, methadone cannot be prescribed by a doctor and obtained from a pharmacy to treat addiction. Because of its long half-life, methadone is almost invariably prescribed to be taken in a single daily dose. At nearly all methadone clinics in the US, patients must visit a clinic to receive and take their dose under the supervision of a nurse. Both patients who are new to methadone treatment and high-risk patients—such as those who are using drugs and alcohol, including cannabis in some states—must visit the clinic daily.<ref>{{cite web|title=Methadone|url=https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/methadone|access-date=15 February 2021|website=www.samhsa.gov|date=16 June 2015 |language=en}}</ref><ref>{{cite web|title=42 CFR § 8.12 – Federal opioid treatment standards.|url=https://www.law.cornell.edu/cfr/text/42/8.12|access-date=15 February 2021|website=LII / Legal Information Institute|language=en}}</ref>

=== Other countries ===
In [[Russia]], methadone treatment is illegal. In 2008, the Chief Sanitary Inspector of Russia [[Gennadiy Onishchenko]], stated that Russian health officials were not convinced of methadone's efficacy in treating heroin and/or opioid addiction. Instead of replacement therapy and gradual reduction of illicit drug use, Russian doctors encouraged immediate cessation and withdrawal. People who use drugs were generally given [[sedative]]s and non-opioid [[analgesic]]s to cope with withdrawal symptoms.<ref>{{cite news | vauthors = Schwirtz M |title=Russia Scorns Methadone for Heroin Addiction |work=The New York Times |date=22 July 2008 |url=https://www.nytimes.com/2008/07/22/health/22meth.html |url-status=live |archive-url=https://web.archive.org/web/20161207145850/http://www.nytimes.com/2008/07/22/health/22meth.html |archive-date=7 December 2016 }}</ref>

As of 2015, China had the largest methadone maintenance treatment program with over 250,000 people in over 650 clinics in 27 provinces.<ref>{{cite journal | vauthors = Sullivan SG, Wu Z, Rou K, Pang L, Luo W, Wang C, Cao X, Yin W, Liu E, Mi G | title = Who uses methadone services in China? Monitoring the world's largest methadone programme | journal = Addiction | volume = 110 | issue = Suppl 1 | pages = 29–39 | date = January 2015 | pmid = 25533862 | doi = 10.1111/add.12781 | doi-access = free | title-link = doi }}</ref>

==Veterinary use==
Methadone is a common perioperative analgesic in cats and dogs with a variety of routes of administration. Methadone in combination with [[acepromazine]] provides greater sedation than the equivalent combination involing [[morphine]] or [[butorphanol]]. Methadone's depressive effect on the cardiovascular system is approximately twice as strong as morphine. Methadone is contradicated for [[gastroduodenoscopy]]. Methadone provides greater analgesia than [[buprenorphine]] for orthopaedic and [[Dog neutering|ovariohysterectomy]] procedures in dogs. [[Fluconazole]] and methadone given concurrently as a subcutaneous administration twice over a 6 hour period can provide analgesia for 12–24 hours. Methadone can be used for sedation in horses but is less effective than [[butorphanol]], it can be combined with [[detomidine]], which improves efficacy but can cause [[ataxia]] although the combination with detomidine has significantly less cardiovascular depressive effects than a combination with [[acepromazine]]. Methadone may be more effective as an analgesic in horses when adiminstered parenterally or epidurally as opposed to intravenously. Opioids are uncommon for livestock due to legislation surrounding usage but intravenous methadone is an effective analgesic in sheep and epidural methadone is an effective analgesic in cattle and sheep.<ref>{{cite book | vauthors = Simon BT, Lizarraga I |chapter=Opioids | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C |title=Veterinary Anesthesia and Analgesia | edition = 6th Edition of Lumb and Jones|pages=376–378|publisher=Wiley Blackwell |isbn=978-1-119-83027-6}}</ref>

== References ==
{{Reflist}}

== External links ==
* [https://web.archive.org/web/20110707090824/http://www.aegisuniversity.com/Aegis%20Documents/Tapering%20off%20of%20Methadone%20Maintenance%205-24-02.pdf Tapering off of methadone maintenance]
* {{cite patent |country=DE |number=711069 |status=patent |title=Verfahren zur Darstellung von basischen Estern |pubdate=1941-09-25 |gdate=1941-09-25 |fdate=1938-09-11 |pridate=1938-09-11 |inventor= |invent1=Dr Max Bockmuehl |invent2=Dr Gustav Ehrhart |assign1=IG Farbenindustrie AG |url=https://worldwide.espacenet.com/publicationDetails/biblio?II=13&ND=3&adjacent=true&locale=en_EP&FT=D&date=19410925&CC=DE&NR=711069C&KC=C}}

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