Methadone

Effects

EuphoriaDry MouthMood liftItchinessRelaxantConstipationPupil constrictionAnalgesia TS

Overview

Methadone (sold under trade names such as Dolophine and Methadose) is a synthetic opioid analgesic used for the treatment of moderate to severe pain and for the treatment of opioid addiction. It is commonly used to treat and manage the symptoms of opioid addiction. The subjective effects are similar to those of other synthetic opioids such as fentanyl, however, most users note a significantly stronger euphoria. Like dextropropoxyphene, the use of methadone is associated with cardiac arrhythmia, however it is more common with dextropropoxyphene than it is with methadone. PW

A synthetic opioid drug used as an analgesic and is often used in detoxification off of other opioids. As it has a much longer half-life.[1] TS

Methadone, sold under the brand names Dolophine and Methadose, among others, is a potent synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.[2–6] WP

Side effects are similar to those of other opioids. These frequently include dizziness, sleepiness, nausea, vomiting, and sweating. Serious risks include opioid abuse and respiratory depression. Abnormal heart rhythms may also occur due to a prolonged QT interval. The number of deaths in the United States involving methadone poisoning declined from 4,418 in 2011 to 3,300 in 2015. Risks are greater with higher doses. Methadone is made by chemical synthesis and acts on opioid receptors.[2][7–10] WP

Methadone was developed in Germany in the late 1930s by Gustav Ehrhart and Max Bockmühl. 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. It is on the World Health Organization's List of Essential Medicines.[2][11–14] WP

History

History

Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the 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. 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) and whose structure had little relation to morphine or other "true opiates" such as 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. It was brought to market in 1943 and was widely used by the German army during WWII as a substitute for morphine.[17–20] WP

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. 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. 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 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. 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.[17][21][22] WP

In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.[23] WP

Isomethadone, noracymethadol, 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.[24] WP

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). WP

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic under the trade name Dolophine. An urban myth later arose that 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.) 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".[17][25][26][27] WP

Methadone was studied as a treatment for opioid addiction at the Addiction Research Center of the 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. 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.[28][29] WP

Legal status

• Canada: Methadone is a Schedule I Controlled Substance.[30] PW
• Germany: Methadone is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.[31] PW
• Russia: Methadone is a Schedule I controlled substance.[32] PW
• Switzerland: Methadone is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.[33] PW
• United Kingdom: Methadone is a Class A, Schedule 2 drug in the United Kingdom.[34] PW
• United States: Methadone is a Schedule II Controlled Substance.[35] PW

Brand names

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

Economics

In the US, generic methadone tablets are inexpensive, with retail prices ranging from $0.25 to $2.50 per defined daily dose.[36][37][38] WP

Methadone maintenance clinics in the US may be covered by private insurance, Medicaid, or Medicare. 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. 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. 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.[39–42] WP

Methadone maintenance treatment (MMT) cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use. 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. 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.[43–46] WP

United states and canada

Methadone is a 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). Methadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.[47][48][49] WP

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). 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. Patients earn take home bottles with their daily dose, by providing clean drug tests and doing therapy. These bottles will be taken away if they provide a dirty drug test, or break clinic rules. They can be earned back. 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.[7][50][51] WP

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 sedatives and non-opioid analgesics to cope with withdrawal symptoms.[52] WP

As of 2015, China had the largest methadone maintenance treatment program with over 250,000 people in over 650 clinics in 27 provinces.[53] WP

Pharmacology

Pharmacology

Methadone acts by binding to the μ-opioid receptor, but also has some affinity for the NMDA receptor, an ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6, and is a substrate, or in this case target, for the P-glycoprotein efflux protein, a protein which helps pump foreign substances out of cells, in the intestines and brain. The bioavailability and elimination half-life of methadone are subject to substantial interindividual variability. Its main route of administration is 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. WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

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. 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.[5] WP

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 or sudden death. In a large observational study in Sweden, methadone was associated with a particularly high 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. 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. 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. Like many other cardiotoxic drugs, methadone blocks the 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 IC₅₀ of ~12 μM. Levomethadone has a lower affinity, with an IC₅₀ of ~29 μM at the hERG channel. Methadone is also known to block the Naᵥ1.5 voltage-gated Na+ channel (SCN5A) with an IC₅₀ of ~10 μM, which is similar to the local anesthetic bupivacaine. Both enantiomers of methadone block the Naᵥ1.5 channel with similar affinities. 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 Naᵥ1.5 sodium channel are possibly clinically relevant in producing cardiac side effects. This also suggests that levomethadone is not completely free of cardiac toxicity.[54][55] WP

Mechanism of action

Levomethadone (the R-(–)-methadone enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity. 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-D-aspartate) receptor, acting as noncompetitive antagonists. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. 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, 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. Methadone also acted as a potent, noncompetitive α₃β₄ neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[56][57][58] WP⚠ Wikipedia itself has flagged this text: citation needed.

Metabolism

Methadone has a slow metabolism and very high 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, ranging from as few as 4 hours to as many as 130 hours, or even 190 hours. 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 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. 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.[59–63] WP

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). 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. Para-hydroxylation of the aromatic ring at the 4-position is a secondary metabolic pathway of methadone; it did not exhibit opioid activity.[64–67] WP

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.[68] WP

Chemistry

Formula

C21H27NO PC

CAS number

76-99-3 PC

Molar mass (g/mol)

309.4 PC

IUPAC name (computed by PubChem)

6-(dimethylamino)-4,4-diphenylheptan-3-one PC

SMILES

CCC(=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C2=CC=CC=C2 PC

InChIKey

USSIQXCVUWKGNF-UHFFFAOYSA-N PC

PubChem CID

4095

Pop culture

No references added yet.

References

1. Journal / agency Methadone trials have proven successful in treating Heroin addiction
2. Other Methadone Hydrochloride
3. Journal / agency Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT): a review of historical and clinical issues. The Mount Sinai Journal of Medicine, New York. 2000. PMID 11064485
4. Other World Health Organization. Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. 2009
5. Journal / agency Grissinger M. Keeping patients safe from methadone overdoses. P & T. August 2011. PMID 21935293 · PMC3171821
6. Journal / agency Toombs JD, Kral LA. Methadone treatment for pain states. American Family Physician. April 2005. PMID 15832538
7. Other Methadone. 16 June 2015
8. Journal / agency Data table for Figure 1. Age-adjusted drug-poisoning and opioid-analgesic poisoning death rates: United States, 1999–2011
9. Journal / agency Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015. MMWR. Morbidity and Mortality Weekly Report. December 2016. doi:10.15585/mmwr.mm655051e1 · PMID 28033313
10. Journal / agency Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA. 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. Annals of Internal Medicine. February 2015. doi:10.7326/M14-2559 · PMID 25581257
11. Other Methadone Matters: Evolving Community Methadone Treatment of Opiate Addiction. 2003
12. Other Kleiman MA, Hawdon JE. Encyclopedia of Drug Policy. 2011
13. Other 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
14. Other World Health Organization. World Health Organization model list of essential medicines: 22nd list (2021). 2021
15. Other Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider)
16. Journal / agency Siegel, S., Hinson, R. E., Krank, M. D., McCully, J. Heroin “Overdose” Death: Contribution of Drug-Associated Environmental Cues. Science. 23 April 1982. doi:10.1126/science.7200260
17. Journal / agency López-Muñoz F, Alamo C. The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice. Brain Research Bulletin. April 2009. doi:10.1016/j.brainresbull.2009.01.005 · PMID 19186209
18. Journal / agency Bockmühl M, Ehrhart G. Über eine neue Klasse von spasmolytisch und analgetisch wirkenden Verbindungen, I. Justus Liebigs Annalen der Chemie. 1949. doi:10.1002/jlac.19495610107
19. Other Polamidon: Wirkung, Legalität, Substitution, Erfolgschancen & Entzug
20. Harm reduction site Bockmühl M, Ehrhart G, Schaumann O. Über eine neue Klasse von spasmolytisch und analgetisch wirkenden (About a new class of compounds with a spasmolytic and analgesic effect). 1948
21. Journal / agency Defalque RJ, Wright AJ. The early history of methadone. Myths and facts. Bulletin of Anesthesia History. October 2007. doi:10.1016/S1522-8649(07)50035-1 · PMID 20506765
22. Journal / agency Leavitt SB. Methadone Dosing & Safety in the Treatment of Opioid Addiction. Addiction Treatment Forum. September 2003
23. Journal / agency Overton DA, Batta SK. Investigation of narcotics and antitussives using drug discrimination techniques. The Journal of Pharmacology and Experimental Therapeutics. November 1979. doi:10.1016/S0022-3565(25)31847-1 · PMID 41087 · PMC8331839
24. Other Morphine & Allied Drugs, Reynolds et al. 1957 Ch 8
25. Other Methadone Briefing
26. Other Indro-Online.de (PDF format). link 2
27. Other Preston A, Bennett G. In: Methadone Matters. Evolving Community Methadone Treatment of Opiate Addiction. 2003
28. Other Browne-Miller A. The Praeger International Collection on Addictions. 2009
29. Journal / agency Dole VP, Nyswander ME. Methadone maintenance treatment. A ten-year perspective. JAMA. May 1976. doi:10.1001/jama.1976.03260450029025 · PMID 946538
30. Other Branch, L. S. Consolidated federal laws of Canada, Controlled Drugs and Substances Act. 2022
31. Other Anlage III BtMG - Einzelnorm
32. Other Постановление Правительства РФ от 01.10.2012 N 1002 (ред. от 09.08.2019)
33. Other Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien
34. Other List of most commonly encountered drugs currently controlled under the misuse of drugs legislation
35. Other DEA Controlled Substances
36. Other Methadone Prices and Methadone Coupons » 5 mg
37. Other Methadone Prices and Methadone Coupons » 40 mg
38. Other WHOCC – ATC/DDD Index
39. Other Walsh L. Insurance and Payments. 16 June 2015
40. Other Medicare Coverage of Substance Abuse Services
41. Other Medicaid Coverage of Medications for the Treatment of Opioid Use Disorder
42. Other Veterans Alcohol and Drug Dependence Rehabilitation Program. 1 November 2018
43. Other Methadone Maintenance Treatment
44. Other Methadone Research Web Guide
45. Other National Institute on Drug Abuse. How Much Does Opioid Treatment Cost?. June 2018
46. Other Is drug addiction treatment worth its cost?
47. Other DEA Diversion Control Division
48. Other DEA Diversion Control Division
49. Other Nordegren T. The A-Z Encyclopedia of Alcohol and Drug Abuse. 1 March 2002
50. Journal / agency Anderson IB, Kearney TE. Use of methadone. The Western Journal of Medicine. January 2000. doi:10.1136/ewjm.172.1.43 · PMID 10695444 · PMC1070723
51. Other 42 CFR § 8.12 – Federal opioid treatment standards
52. Other Schwirtz M. Russia Scorns Methadone for Heroin Addiction. 22 July 2008
53. Journal / agency Sullivan SG, Wu Z, Rou K, Pang L, Luo W, Wang C, Cao X, Yin W, Liu E, Mi G. Who uses methadone services in China? Monitoring the world's largest methadone programme. Addiction. January 2015. doi:10.1111/add.12781 · PMID 25533862
54. Journal / agency Bengt Danielsson; Julius Collin; Anastasia Nyman; Annica Bergendal; Natalia Borg; Maria State; Lennart Bergfeldt; Johan Fastbom. Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study. BMJ Open. 2020-03-12. doi:10.1136/bmjopen-2019-034560 · PMID 32169926 · PMC7069257
55. Journal / agency Schulze V, Stoetzer C, O'Reilly AO, Eberhardt E, Foadi N, Ahrens J, Wegner F, Lampert A, de la Roche J, Leffler A. The opioid methadone induces a local anaesthetic-like inhibition of the cardiac Na⁺ channel, Na(v)1.5. British Journal of Pharmacology. January 2014. doi:10.1111/bph.12465 · PMID 24117196 · PMC3904262
56. Other Opioids in Cancer Pain. 2009
57. Other Cooperative N-methyl-d-aspartate (NMDA) receptor antagonism and μ-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain
58. Journal / agency Xiao Y, Smith RD, Caruso FS, Kellar KJ. Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs. The Journal of Pharmacology and Experimental Therapeutics. October 2001. doi:10.1016/S0022-3565(24)29338-1 · PMID 11561100
59. Journal / agency Kell MJ. Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting. Journal of Addictive Diseases. 1994. doi:10.1300/J069v13n01_02 · PMID 8018740
60. Journal / agency Eap CB, Déglon JJ, Baumann P. Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance. Heroin Addiction and Related Clinical Problems. 1999
61. Journal / agency Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clinical Pharmacokinetics. 2002. doi:10.2165/00003088-200241140-00003 · PMID 12405865
62. Journal / agency Manfredonia JF. Prescribing methadone for pain management in end-of-life care. The Journal of the American Osteopathic Association. March 2005. PMID 18154194
63. Other Medscape Methadone Dosage
64. Journal / agency Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, Dale O. Clinical pharmacology of methadone for pain. Acta Anaesthesiologica Scandinavica. August 2008. doi:10.1111/j.1399-6576.2008.01597.x · PMID 18331375
65. Journal / agency Preston KL, Epstein DH, Davoudzadeh D, Huestis MA. Methadone and metabolite urine concentrations in patients maintained on methadone. Journal of Analytical Toxicology. September 2003. doi:10.1093/jat/27.6.332 · PMID 14516485
66. Journal / agency Gerardy BM, Kapusta D, Dumont P, Poupaert JH. Synthesis, characterization, and quantitation of para-hydroxymethadone, a metabolite of methadone in the rat. Drug Metabolism and Disposition. 1986. PMID 2873996
67. Journal / agency Garrett ER, Derendorf H, Mattha AG. Pharmacokinetics of morphine and its surrogates. VII: High-performance liquid chromatographic analyses and pharmacokinetics of methadone and its derived metabolites in dogs. Journal of Pharmaceutical Sciences. November 1985. doi:10.1002/jps.2600741114 · PMID 4087182
68. Other Baselt R. Disposition of Toxic Drugs and Chemicals in Man. 2008

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