Editing Methadone (section)

== 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 naltrexone 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>