Editing Methadone (section)

== 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 }}</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>