Methadone

Methadone
The more active R enantiomer of methadone (levomethadone)
Names
Trade namesDolophine, Methadose, others
IUPAC name
  • (RS)-6-(dimethylamino)-4,4-diphenylheptan-3-one
Clinical data
Drug classOpioid
Main usesOpioid maintenance therapy, chronic pain[1]
Side effectsDizziness, sleepiness, vomiting, sweating, opioid abuse, decreased effort to breathe[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Addiction riskHigh[2]
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth, intravenous, insufflation, sublingual, rectal
    Onset of actionRapid[1]
    Duration of actionSingle dose: 4–8 h
    Prolonged use:
    • Withdrawal prevention: 1–2 days[1]
    • Pain relief: 8–12 hours[1][3]
    Defined daily dose25 milligrams (by mouth)
    25 milligram (parenteral)[4]
    Urine detection<7 days[5]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa682134
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability15-20% subcutaneous[6]

    100% intravenous[6]

    41–99% (by mouth)[6]
    Protein binding85–90%[6]
    MetabolismLiver (CYP3A4, CYP2B6 and CYP2D6-mediated)[6][7]
    Elimination half-life15 to 55 hours[7]
    ExcretionUrine, faeces[7]
    Chemical and physical data
    FormulaC21H27NO
    Molar mass309.453 g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture
    SMILES
    • CCC(C(C1=CC=CC=C1)(C2=CC=CC=C2)CC(N(C)C)C)=O
    InChI
    • InChI=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 checkY
    • Key:USSIQXCVUWKGNF-UHFFFAOYSA-N checkY

    Methadone, sold under the brand name Dolophine among others, is an opioid used for opioid maintenance therapy in opioid dependence and for chronic pain management.[1] Detoxification using methadone can be accomplished in less than a month, or it may be done gradually over as long as six months.[1] While a single dose has a rapid effect, maximum effect can take up to five days of use.[1] The pain-relieving effects last about six hours after a single dose.[1][8] After long-term use, in people with normal liver function, effects last 8 to 36 hours.[1][3] Methadone is usually taken by mouth and rarely by injection into a muscle or vein.[1]

    Side effects are similar to those of other opioids.[1] These frequently includes dizziness, sleepiness, vomiting, and sweating.[1] Serious risks include opioid abuse and a decreased effort to breathe.[1] Abnormal heart rhythms may also occur due to a prolonged QT interval.[1] The number of deaths in the United States involving methadone poisoning declined from 4,418 in 2011[9] to 3,300 in 2015.[10] Risks are greater with higher doses.[11] Methadone is made by chemical synthesis and acts on opioid receptors.[1]

    Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl.[12][13] It was approved for use in the United States in 1947.[1] It is on the World Health Organization's List of Essential Medicines.[14] In 2013, about 41,400 kilograms were manufactured globally.[15] It is regulated similarly to other narcotic drugs.[16] It is not particularly expensive in the United States.[17]

    Medical uses

    Methadone maintenance

    Methadone is used for the treatment of opioid use disorder. It may be used as a maintenance therapy or in shorter periods for detoxification to manage opioid withdrawal symptoms.

    A 2009 Cochrane review found methadone was effective in retaining people in treatment and in the reduction or cessation of heroin use as measured by self-report and urine/hair analysis but did not affect criminal activity or risk of death.[18]

    Treatment of opioid-dependent persons with methadone follows one of two routes: maintenance or detoxification.[19] 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 specialist clinic, where they are observed for around 15–20 minutes post dosing, to reduce risk of diversion of medication.[20]

    The duration of methadone treatment programs range from a few months to several 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 mg daily) and are incremented gradually.[21][22]

    Methadone maintenance has been shown to reduce the transmission of blood borne viruses associated with opioid injection, such as hepatitis B and C, and/or HIV.[21] 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 a syndrome of tolerance and withdrawal (dependence). However, when used correctly in treatment, maintenance therapy has been found to be medically safe, non-sedating, and can provide a slow recovery from opioid addiction.[21] Methadone has been widely used for pregnant women addicted to opioids.[21]

    Opioid detoxification

    Methadone is approved in the US, and many other parts of the world, for the treatment of opioid addiction. 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) in order to prescribe methadone for opioid addiction.

    Pain

    Methadone is used as an analgesic in chronic pain, often in rotation with other opioids.[23][24] 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.[25][26]

    Dosage

    Methadone is generally started at 20 to 30 mg per day.[27]

    The defined daily dose is 25 milligrams (by mouth) or 25 milligrams (parenteral).[4]

    If one or two doses are missed, the next dose can be given as per usual.[27] If three or four doses are missed the dose should be decreased by 25% and 50% respectively.[27] If more than four doses are missed one needs to start back at 20 to 30 mg per day.[27]

    Adverse effects

    Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Street methadone was ranked 4th in dependence, 5th in physical harm, and 5th in social harm.[28]

    Adverse effects of methadone include:

    Withdrawal symptoms

    Physical symptoms

    Cognitive symptoms

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

    Methadone is sometimes administered as an oral liquid. Methadone has been implicated in contributing to significant tooth decay. Methadone causes 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 general decrease in personal hygiene. These factors, combined with sedation, have been linked to the causation of extensive dental damage.[36][37]

    Black box warning

    Methadone has the following US FDA black box warning:[38]

    • Risk of addiction and abuse
    • Potentially fatal respiratory depression
    • Lethal overdose in accidental ingestion
    • QT prolongation
    • Neonatal opioid withdrawal syndrome in children of pregnant women
    • CYP450 drug interactions
    • Risks when used with benzodiazepines and other CNS suppressants, including alcohol.
    • A certified opioid treatment program is required under federal law (42 CFR 8.12) when dispensing methadone for the treatment of opioid addiction or detoxification.

    Overdose

    Most people who have overdosed on methadone may show some of the following symptoms:

    The respiratory depression of an overdose can be treated with naloxone.[35] Naloxone is preferred to the newer, longer acting antagonist naltrexone. Despite methadone's much longer duration of action compared to either 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).[41]

    Driving

    Methadone treatment may impair driving ability.[42] 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.[43] However, there have been multiple studies verifying the ability of methadone maintenance patients to drive.[44] 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.[45] 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,[46] as well as a 2006 series in the Charleston Gazette (West Virginia),[47] 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, 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 diskettes distributed through channels other than opioid treatment programs most likely are the central factors in methadone-associated mortality."[48]

    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."[49]

    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.

    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 in opioid-naive people), as opposed to a half life of 1 to 5 hours for morphine.[8] The length of the half life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.[8]

    Mechanism of action

    Levomethadone (the L enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity.[50] Dextromethadone (the S enantiomer) does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM, a cough suppressant), ketamine (a dissociative anaesthetic), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga) 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. The dextrorotary form (dextromethadone), which acts as an NMDA receptor antagonist and is devoid of opioid activity, has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[51]

    Methadone at opioid receptors, monoamine transporters, and the NMDA receptor
    CompoundAffinities (Ki)Ratios
    MORDORKORSERTNETNMDARMOR:DOR:KORSERT:NET
    Methadone1.7 nM435 nM405 nMNDND2,500–8,300 nM1:256:238ND
      Dextromethadone19.7 nM960 nM1,370 nM992 nM12,700 nM2,600–7,400 nM1:49:701:13
      Levomethadone0.945 nM371 nM1,860 nM14.1 nM702 nM2,800–3,400 nM1:393:19681:50
    Sources: See template.

    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,[52][53] ranging from as few as 4 hours to as many as 130 hours,[54] or even 190 hours.[55] 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 detoxification 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.[54] 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.[56]

    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).[6][57] 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.

    • Methadone and its two main metabolites
    • Methadone
      Methadone
    • EDDP
      EDDP
    • EDMP
      EDMP

    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 L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects.[54] The single-isomer form is becoming less common due to the higher production costs.

    Methadone is available in traditional pill, sublingual tablet, 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") which are tablets designed to disperse themselves rapidly in water for oral administration, used in a similar fashion 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, 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.[58] 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.[59][60] 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.[61][62][63] The formulation sold under the brand name Methadose (flavored liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either.[64]

    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 into the tablets formulation to make the use of them by the IV route more difficult.[65]

    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-naive individual. Chronic users often have high methadone and EDDP baseline values.[66]

    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 (R3N ••• >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.[67]

    History

    40 mg of methadone

    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 shortage problem.[68][69] On September 11, 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 only slight relation to morphine or the opiate alkaloids. (Bockmühl and Ehrhart, 1949) It was brought to market in 1943 and was widely used by the German army during WWII.[68]

    In the 1930s, pethidine (meperidine) went into production in Germany; however, production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research.[70] 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.[68] The report published by the committee noted that while methadone was potentially addictive, it produced less sedation and respiratory depression than morphine and was thus interesting as a commercial drug.[68]

    In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.[71]

    Isomethadone, noracymethadol, LAAM, and normethadone were first developed in Germany, 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 means of suppressing drug cravings.[72]

    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.[68]

    The trade name Dolophine was created by Eli Lilly after World War II and used in the United States; the claim that Nazi leader Adolf Hitler ordered the manufacture of methadone or that the brand name 'Dolophine' was named after him is an urban legend. "Dolo" stems from the Latin word for pain, dolor, and finis which means "end". Therefore, Dolophine literally means "pain end".[73] The pejorative term "adolphine" (never a widely used name for the drug) appeared in the United States in the early 1970s as a reference to the aforementioned urban myth that the trade name Dolophine was a reference to Adolf Hitler.[74][75]

    Society and culture

    Brand names

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

    Cost

    In the US, generic methadone tablets are inexpensive, with retail prices ranging from $0.25 to $2.50 per defined daily dose.[76] Brand-name methadone tablets may cost much more.

    Methadone maintenance clinics in the US may be covered by private insurances, Medicaid, or Medicare.[77] 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.[78] 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.[79] 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.[80]

    Methadone maintenance treatment (MMT) cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.[81][82] 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.[83] 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.[84]

    As of 2015 China had the largest methadone maintenance treatment program with over 250,000 people in over 650 clinics in 27 provinces.[85]

    Controversy

    Methadone substitution as a treatment of opioid addiction has been criticized in the social sciences for its role in social control of addicts.[86] It is suggested that methadone does not function as much to curb addiction as to redirect it and maintain dependency on authorised channels. Several authors apply a Foucauldian analysis to the widespread prescription of the drug and use in institutions such as prisons, hospitals and rehabilitation centres.[87] Such critique centers on the notion that substance addiction is reframed with a disease model. Thus methadone, which mimics the effects of opioids and renders the addict compliant, is labeled as a "treatment" and so achieves the disciplinary objectives of managing the "undesirables".[86]

    Regulation

    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).[88] Methadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.[89][90]

    In Russia, methadone treatment is illegal. Gennadiy Onishchenko, Chief Sanitary Inspector of Russia, claimed in 2008 that health officials are not convinced of the treatment's efficacy. Instead, doctors encourage immediate cessation of drug use, rather than the gradual process that methadone substitution therapy entails. People are often given sedatives and non-opioid analgesics to cope with withdrawal symptoms.[91]

    References

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    2. ↑ Bonewit-West, Kathy; Hunt, Sue A.; Applegate, Edith (2012). Today's Medical Assistant: Clinical and Administrative Procedures. Elsevier Health Sciences. p. 571. ISBN 9781455701506. Archived from the original on 28 July 2020. Retrieved 2 August 2020.
    3. 1 2 Toombs, JD; Kral, LA (1 April 2005). "Methadone treatment for pain states". American Family Physician. 71 (7): 1353–8. PMID 15832538. Archived from the original on 5 September 2017.
    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 28 July 2020. Retrieved 22 September 2020.
    5. ↑ "Interpreting Urine Drug Tests (UDT)". Archived from the original on 25 October 2023. Retrieved 24 October 2023.
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    8. 1 2 3 Grissinger, Matthew (August 2011). "Keeping Patients Safe From Methadone Overdoses". Pharmacy and Therapeutics. 36 (8): 462–466. PMC 3171821. PMID 21935293.
    9. ↑ "Data table for Figure 1. Age-adjusted drug-poisoning and opioid-analgesic poisoning death rates: United States, 1999–2011" (PDF). CDC. Archived (PDF) from the original on 23 November 2015. Retrieved 22 December 2015.
    10. ↑ Rudd, Rose A.; Seth, Puja; David, Felicita; Scholl, Lawrence (2016). "Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015". MMWR. Morbidity and Mortality Weekly Report. 65 (5051): 1445–1452. doi:10.15585/mmwr.mm655051e1. ISSN 0149-2195. PMID 28033313.
    11. ↑ Chou, R; Turner, JA; Devine, EB; Hansen, RN; Sullivan, SD; Blazina, I; Dana, T; Bougatsos, C; Deyo, RA (17 February 2015). "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. 162 (4): 276–86. doi:10.7326/M14-2559. PMID 25581257.
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    13. ↑ Kleiman, Mark A. R.; Hawdon, James E. (2011). "Diphenypropylamine Derivatives". Encyclopedia of Drug Policy. ISBN 9781506338248. Archived from the original on 23 December 2015.
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    15. ↑ Narcotic Drugs 2014 (PDF). International Narcotics Control Board. 2015. p. 21. ISBN 9789210481571. Archived (PDF) from the original on 2 June 2015.
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    External sites:
    Identifiers:
    • Methadone Archived 24 July 2020 at the Wayback Machine, Substance Abuse and Mental Health Services Administration, U.S. Department of Health and Human Services
    • Tapering off of methadone maintenance
    • DE patent 711069, Dr Max Bockmuehl & Dr Gustav Ehrhart, "Verfahren zur Darstellung von basischen Estern", published 1941-09-25, issued 1941-09-25, assigned to IG Farbenindustrie AG 
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