|Trade names||Dolophine, Methadose, others|
|Oral, intravenous, insufflation, sublingual, rectal|
|Metabolism||Liver (CYP3A4, CYP2B6 and CYP2D6-mediated)|
|Onset of action||rapid|
|Biological half-life||15 to 55 hours|
|Duration of action||4–8 h (one dose), 1–2 days (prolonged use)|
|Chemical and physical data|
|Molar mass||309.445 g/mol|
|3D model (Jmol)|
|(what is this?)|
Methadone, sold under the brand name Dolophine, among others, is an opioid used to treat pain and as maintenance therapy or to help with detoxification in people with opioid dependence. Detoxification using methadone can either be done relatively rapidly in less than a month or gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take five days of use. The effects last about six hours after a single dose and a day and a half after long-term use in people with normal liver function. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.
Side effects are similar to those of other opioids. Commonly these include dizziness, sleepiness, vomiting, and sweating. Serious risks include opioid abuse or a decreased effort to breathe. Abnormal heart rhythms may also occur including prolonged QT. The number of deaths in the United States involving methadone poisoning was 4,418 in 2011, which was 26% of total deaths from opioid poisoning. Risks are greater with higher doses. Methadone is made by chemical synthesis and acts on opioid receptors.
Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl. It was approved for use in the United States in 1947. Methadone is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Globally in 2013, about 41,400 kilograms were manufactured. It is regulated similarly to other narcotic drugs. In the United States it is not very expensive.
- 1 Medical uses
- 2 Adverse effects
- 3 Detection in biological fluids
- 4 Pharmacology
- 5 History
- 6 Society and culture
- 7 References
- 8 External links
Methadone is indicated for the maintenance treatment of opioid dependency (i.e. opioid use disorder per the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). A 2009 Cochrane review found that methadone was effective in retaining people in treatment and in the suppression of heroin use as measured by self-report and urine/hair analysis but did not affect criminal activity or risk of death.
The treatment of opiate-dependent persons with methadone will follow one of two routes. MMT (methadone maintenance therapy) is prescribed to individuals who wish to abstain from illicit drug use but have failed to maintain abstinence from opiates for significant periods. The duration of methadone maintenance ranges from a few months to lifetime maintenance. Methadone reduction programs are suitable for addicted persons who wish to stop using drugs altogether. The length of the reduction program will depend on the starting dose and speed of reduction, this varies from clinic to clinic and from person to person. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates, however methadone abuse can cause the very opposite of what its original intention is. When used correctly, methadone maintenance has been found to be medically safe and non-sedating, and provide a slow recovery from opiate addiction. It is also indicated for pregnant women addicted to opiates.
In Russia, methadone treatment is illegal. Gennadiy Onishchenko, Chief Sanitary Inspector, 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. Patients are often given sedatives and non-opiate analgesics to cope with withdrawal symptoms.
In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an analgesic in chronic pain. Methadone is a very effective pain medication. 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 lesser compared to other opioids. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than shorter-acting drugs like morphine or hydrocodone. Another factor in the increased usage is the low cost of methadone.
On 29 November 2006, the U.S. Food and Drug Administration issued a Public Health Advisory about methadone titled "Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat". The advisory said that "the FDA has received reports of death and life-threatening side effects in patients taking methadone. These deaths and life-threatening side effects have occurred in patients newly starting methadone for pain control and in patients who have switched to methadone after being treated for pain with other strong narcotic pain relievers. Methadone can cause slow or shallow breathing and dangerous changes in heartbeat that may not be felt by the patient." The advisory urged that physicians use caution when prescribing methadone to patients who are not used to the drug and that patients take the drug exactly as directed.
Patients with long-term pain will sometimes have to perform so-called opioid rotation. What this means is switching from one opioid to another, usually at intervals of between a few weeks, or more commonly, several months. Opioid rotation may allow a lower equivalent dose, and hence fewer side effects may be encountered to achieve the desired effect. Then, over time, tolerance increases with the new opioid, requiring higher doses. This, in turn, increases the possibility of adverse reactions and toxicity. Then it is time to rotate again to another opioid. Such opioid rotation is standard practice for managing patients with tolerance development. Usually when doing opioid rotation, one cannot go down to a completely naive dose, because there is cross-tolerance carried over to the new opioid. However, methadone has a lower cross-tolerance when switching to it from other opioids, than other opioids. This means that methadone can start at a comparatively lower dose than other opiates, and the time for the next switch will be longer.
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.
Adverse effects of methadone include:
- Diarrhea or constipation
- Perspiration and sweating
- Heat intolerance
- Dizziness or fainting
- Chronic fatigue, sleepiness and exhaustion
- Sleep problems such as drowsiness, trouble falling asleep (Insomnia), and trouble staying asleep
- Constricted pupils
- Dry mouth
- Nausea and vomiting
- Low blood pressure
- Hallucinations or confusion
- Heart problems such as chest pain or fast/pounding heartbeat
- Abnormal heart rhythms
- Respiratory problems such as trouble breathing, slow or shallow breathing (hypoventilation), light-headedness, or fainting
- Loss of appetite, and in extreme cases anorexia
- Weight gain
- Memory loss
- Stomach pains
- Difficulty urinating
- Swelling of the hands, arms, feet, and legs
- Feeling restless or agitated
- Mood changes, euphoria, disorientation
- Nervousness or anxiety
- Blurred vision
- Decreased libido, missed menstrual periods, difficulty in reaching orgasm, or impotence
- Skin rash
- Central sleep apnea
Physical symptoms
- Tearing of the eyes
- Mydriasis (dilated pupils)
- Photophobia (sensitivity to light)
- Hyperventilation syndrome (breathing that is too fast/deep)
- Runny nose
- Nausea, vomiting, and diarrhea
- Akathisia (restlessness)
- Tachycardia (fast heartbeat)
- Aches and pains, often in the joints or legs
- Elevated pain sensitivity
- Blood pressure that is too high (hypertension, may cause stroke)
Cognitive symptoms
- Suicidal ideation
- Susceptibility to cravings
- Spontaneous orgasm
- Prolonged insomnia
- Auditory hallucinations
- Visual hallucinations
- Increased perception of odors (olfaction), real or imagined
- Marked decrease or increase in sex drive
- Panic disorder
- Anorexia (symptom)
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 due to these factors combined with sedation have causing extensive dental damage.
Most people who have overdosed on methadone may show some of the following symptoms:
- Miosis (constricted pupils)
- Hypoventilation (breathing that is too slow/shallow)
- Drowsiness, sleepiness, disorientation, sedation, unresponsiveness
- Skin that is cool, clammy, and pale
- Limp muscles, trouble staying awake, nausea
- Unconsciousness and coma
- Excessive vomiting
The respiratory depression of an overdose can be treated with naloxone. 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 patient, 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 patient'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 patient will initially work to bring the patient out of overdose, but once the naloxone wears off, if no further naloxone is administered, the patient 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).
Methadone treatment may impair driving ability. Drug abuse patients had significantly more involvement in serious crashes than non-abuse patients in a study by the University of Queensland. In the study of a group of 220 drug abuse patients, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other patients randomly selected having no involvement in fatal crashes. However, there have been multiple studies verifying the ability of methadone maintenance patients to drive. 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 licence will be issued for 12 months at a time and even then, only following a favourable assessment from their own doctor. 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.
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, as well as a 2006 series in the Charleston Gazette (West Virginia), 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 remain 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."
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."
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.
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6 and is a substrate for the P-Glycoprotein efflux protein in intestine and brain. The bioavailability and elimination half-life of methadone is subject to substantial inter-individual 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 opiates, spanning anywhere from two weeks to several months. Many factors contribute to its metabolism and excretion rate including the individual's body weight, history of use/abuse, metabolic dysfunctions, renal system dysfunction, among others.
In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.
From this research came a generally non-controlled—or controlled for having the same precursors and effects of strong pure agonist agents of the open chain type, this one a phenaloxam derivative, levopropoxyphene with optical isomerism and one of which appeared to have no narcotic properties but was an antitussive which did have dissociative effects if misused; the isomer form which is removed from the racemic salts to yield dextromethorphan, or remove the other isomer to purify a dextropropoxyphene, or left in to finish with a racemic salts mixture dimethorphan. The open chain opioids tend to have at least one isomer that is at some level a strong pure mu opioid receptor agent.
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, prolonging and increasing length and depth of satiating any opiate cravings and generating very strong analgesia (the long metabolic half-life and the strong receptor affinity at the mu opioid receptor sites, therefore imparting much of the satiating and anti-addictive effects of methadone) by means of suppressing drugs cravings and the discovery in the early 1950s of methadone's antitussive properties first tested in dogs in Europe in 1952-1955 with different inert placebos, active placebos like codeine.
Mechanism of action
Levomethadone is a full µ-opioid agonist. Dextromethadone does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA antagonism. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) 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 (d-methadone) acts as an NMDA antagonist and is devoid of opioid activity: it 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.
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 detoxification and maintenance programs. Patients 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 patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.
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.
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. 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 patient to drink. Drinkable forms include ready-to-dispense liquid (sold in the United States as Methadose), and "Diskets" 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. In fact, injection of methadone does not result in a "rush" as with some other strong opioids such as morphine or hydromorphone, because its extraordinarily high volume of distribution causes it to diffuse into other tissues in the body, particularly fatty tissue; the peak concentration in the blood is achieved at roughly the same time, whether the drug is injected or ingested. 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. 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. 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. The formulation sold under the brand name Methadose (flavoured liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either. While it has been done in extremely diluted concentrations, instances of cardiac arrest have been reported, as well as damaged veins from sugars (even sugar-free syrups may cause this damage due to the presence of similarly-damaging artificial sweeteners). Oral medication also 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.
Patient 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.
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. 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[full citation needed]) It was brought to market in 1943 and was widely used by the German army during WWII.
In the 1930s, 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. 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 was potentially addictive, it produced less sedation and respiratory depression than morphine and was thus interesting as a commercial drug.
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, which is now registered to Roxane Laboratories. Since then, it has been best known for its use in treating opioid dependence. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and is not uncommonly used in hospitals and other de-addiction centers to enhance rates of completed opioid withdrawal. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.
Methadone was first manufactured in the US by Eli Lilly, who obtained FDA approval on August 14, 1947, for their Dolophine 5 mg and 10 mg Tablets. Mallinckrodt Pharmaceuticals did not receive approval until December 15, 1947 to manufacture their bulk compounding powder. Mallinckrodt received approval for their branded generic, Methadose, on April 15, 1993 for their 5 mg and 10 mg Methadose Tablets. Mallinckrodt who also makes 5 mg, 10 mg and 40 mg generic tablets in addition to their branded generic Methadose received approval for their plain generic tablets on April 27, 2004.
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 bestowed in honor of Hitler is an urban legend. [clarification needed] The pejorative term "adolphine" (never an actual name of 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.
Society and culture
Brand names include Dolophine, Symoron, Amidone, Methadose, Physeptone, and Heptadon among others.
Methadone maintenance treatment
In Germany, methadone maintenance treatment (MMT) is fully covered by all public and private insurance plans. The annual cost per person is less than 3000 euros, while heroin-assisted treatment costs up to 10,000 euros per year.
As of 2015 China had the largest methadone maintenance treatment program with over 250,000 people in over 650 clinics in 27 provinces.
Methadone substitution as a treatment of opioid addiction has been widely criticized in the social sciences for its role in social control of addicts. 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. 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 obscures the disciplinary objectives of “managing undesirables”.
Methadone is a Schedule II controlled substance 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.
- Fredheim, OM; Moksnes, K; Borchgrevink, PC; Kaasa, S; Dale, O (August 2008). "Clinical pharmacology of methadone for pain.". Acta Anaesthesiologica Scandinavica. 52 (7): 879–89. doi:10.1111/j.1399-6576.2008.01597.x. PMID 18331375.
- Brown, R; Kraus, C; Fleming, M; Reddy, S (November 2004). "Methadone: applied pharmacology and use as adjunctive treatment in chronic pain." (PDF). Postgraduate Medical Journal. 80 (949): 654–9. doi:10.1136/pgmj.2004.022988. PMC . PMID 15537850.
- "Methadone Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Dec 2015. Check date values in:
- "Data table for Figure 1. Age-adjusted drug-poisoning and opioid-analgesic poisoning death rates: United States, 1999–2011" (PDF). CDC. Retrieved 22 December 2015.
- 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.
- Methadone Matters: Evolving Community Methadone Treatment of Opiate Addiction. CRC Press. 2003. p. 13. ISBN 9780203633090.
- "Diphenypropylamine Derivatives". Encyclopedia of Drug Policy. 2011. ISBN 9781506338248.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
- Narcotic Drugs 2014 (pdf). INTERNATIONAL NARCOTICS CONTROL BOARD. 2015. p. 21. ISBN 9789210481571.
- Organization, World Health (2009). Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: World Health Organization. p. 78. ISBN 9789241547543.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 13. ISBN 9781284057560.
- Mattick, Richard P; Breen, Courtney; Kimber, Jo; Davoli, Marina (2009). Mattick, Richard P, ed. "Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence". Cochrane Database of Systematic Reviews (4): CD002209. doi:10.1002/14651858.CD002209.pub2. PMID 19588333.
- Joseph, H; Stancliff, S; Langrod, J (2000). "Methadone maintenance treatment (MMT): A review of historical and clinical issues". The Mount Sinai Journal of Medicine. 67 (5–6): 347–64. PMID 11064485.
- Connock, M; Juarez-Garcia, A; Jowett, S; Frew, E; Liu, Z; Taylor, RJ; Fry-Smith, A; Day, E; Listerine, N; Roberts, T; Burls, A; Taylor, RS (2007). "Methadone and buprenorphine for the management of opioid dependence: A systematic review and economic evaluation". Health Technology Assessment. 11 (9): 1–171, iii–iv. doi:10.3310/hta11090. PMID 17313907.
- Schwirtz, Michael (July 22, 2008). "Russia Scorns Methadone for Heroin Addiction". The New York Times.
- Leppert, W. (2009). "The role of methadone in cancer pain treatment - a review". International Journal of Clinical Practice. 63 (7): 1095–109. doi:10.1111/j.1742-1241.2008.01990.x. PMID 19570126.
- Nicholson, AB (Oct 2007). "Methadone for cancer pain". Cochrane Database Syst Rev. 4: CD003971. doi:10.1002/14651858.CD003971.pub3. PMID 17943808.
- "2006 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements". MedWatch. Food and Drug Administration.
- De Stoutz, Noe´mi D.; Bruera, Eduardo; Suarez-Almazor, Maria (1995). "Opioid rotation for toxicity reduction in terminal cancer patients". Journal of Pain and Symptom Management. 10 (5): 378–84. doi:10.1016/0885-3924(95)90924-C. PMID 7673770.
- Vigano', Antonio; Fan, David; Bruera, Eduardo (1996). "Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators". Pain. 67 (1): 115–9. doi:10.1016/0304-3959(96)03112-0. PMID 8895238.
- Nutt, D; King, LA; Saulsbury, W; Blakemore, C (24 March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse.". Lancet. 369 (9566): 1047–53. doi:10.1016/s0140-6736(07)60464-4. PMID 17382831.
- "Methadone". Drugs.com.
- "Methadone". MedlinePlus. Archived from the original on 2008-02-27.
- "Dolophine: Drug Description". RxList.
- "Methadone". MedicineNet.
- John, Jinu; Amley, Xixi; Bombino, Gabriel; Gitelis, Chaim; Topi, Bernard; Hollander, Gerald; Ghosh, Joydeep (2010). "Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection". Cardiology Research and Practice. 2010: 1–4. doi:10.4061/2010/524764. PMC . PMID 21253542.
- "Methadone Withdrawal Symptoms". Michael's House Drug & Alcohol Treatment Centers. Retrieved 23 October 2013.
- Sadovsky, M.D., Richard (15 July 2000). "Tips from Other Journals – Public Health Issue: Methadone Maintenance Therapy". American Family Physician. 62 (2): 428–432.
- Brondani, M; Park, PE (16 May 2011). "Methadone and oral health--a brief review.". Journal of dental hygiene : JDH / American Dental Hygienists' Association. 85 (2): 92–8. PMID 21619737.
- Graham, CH; Meechan, JG (October 2005). "Dental management of patients taking methadone.". Dental update. 32 (8): 477–8, 481–2, 485. PMID 16262036.
- "Methadone (meth' a done)". MedlinePlus. National Institutes of Health. 1 February 2009. Retrieved 23 October 2013.
- Leavitt, Stewart B. (September 2003). "Methadone Dosing & Safety in the Treatment of Opioid Addiction" (PDF). Addiction Treatment Forum.
- Giacomuzzi, SM; Ertl, M; Vigl, A; Riemer, Y; Günther, V; Kopp, M; Pilsz, W; Haaser, W (2005). "Driving Capacity of Patients Treated with Methadone and Slow-Release Oral Morphine". Addiction. 100 (7): 1027. doi:10.1111/j.1360-0443.2005.01148.x. PMID 15955021.
- Reece, Albert S (2008). "Experience of road and other trauma by the opiate dependent patient: A survey report". Substance Abuse Treatment, Prevention, and Policy. 3: 10. doi:10.1186/1747-597X-3-10. PMC . PMID 18454868.
- "Methadone and Driving Article Abstracts: Brief Literature Review" (DOC). Institute for Metropolitan Affairs, Roosevelt University. 14 February 2008
- Ford, Chris; Barnard, Jim; Bury, Judy; Carnwath, Tom; Gerada, Clare; Joyce, Alan; Keen, Jenny; Lowe, Charlie; Nelles, Bill; Roberts, Kay; Sander-Hess, Carola; Schofield, Penny; Scott, Jenny; Watson, Richard; Wolff, Kim (2005). "Guidance for the use of methadone for the treatment of opioid dependence in primary care" (PDF) (1st ed.). Royal College of General Practitioners. Archived from the original (PDF) on 21 May 2012[dead link]
- "Increases in Methadone-Related Deaths:1999-2004".
- "The Killer Cure" The Charleston Gazette 2006
- "Methadone-Associated Mortality, Report of a National Assessment".
- Finn, Scott; Tuckwiller, Tara (28 November 2006). "New warning issued on methadone". Charleston Gazette.
- Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 941–5.
- J Pharmacol Exp Ther November 1979 211:401-408
- Appleton & Lange's 2003 Nursing Drug Guide, pp 177
- The Oxford Textbook of Pharmacology & Clinical Drug
- Morphine & Allied Drugs, Reynolds et al 1957 Ch 8
- Morphine & Allied Drugs, 1957 Ch 8
- Xiao, Yingxian; Smith, Richard D.; Caruso, Frank S.; Kellar, Kenneth J. (October 2001). "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs". The Journal of Pharmacology and Experimental Therapeutics. 299 (1): 366–71. PMID 11561100.
- Kell, Michael Jon (1994). "Utilization of Plasma and Urine Methadone Concentrations to Optimize Treatment in Maintenance Clinics:". Journal of Addictive Diseases. 13 (1): 5–26. doi:10.1300/J069v13n01_02. PMID 8018740.
- Eap, Chin B. Eap; Déglon, Jean-Jacques; Baumann, Pierre (1999). "Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance" (PDF). Heroin Addiction and Related Clinical Problems. 1 (1): 19–34.
- Eap, Chin B.; Buclin, Thierry; Baumann, Pierre (2002). "Interindividual Variability of the Clinical Pharmacokinetics of Methadone". Clinical Pharmacokinetics. 41 (14): 1153–93. doi:10.2165/00003088-200241140-00003. PMID 12405865.
- Manfredonia, John (March 2005). "Prescribing Methadone for Pain Management in End-of-Life Care". JAOA the Journal of the American Osteopathic Association. 105 (3 suppl): 18S.
- Preston, KL; Epstein, DH; Davoudzadeh, D; Huestis, MA (2003). "Methadone and metabolite urine concentrations in patients maintained on methadone". J Anal Toxicol. 27 (6): 332–341. doi:10.1093/jat/27.6.332. PMID 14516485.
- Code of Federal Regulations, Title 42, Sec 8.
- "Methadone Hydrochloride Tablets, USP" (PDF). VistaPharm.
- Murphy, SB; Jackson, WB; Pare, JA (1978). "Talc retinopathy". Canadian Journal of Ophthalmology. 13 (3): 152–6. PMID 698886.
- Hill, A. D.; Toner, M. E.; Fitzgerald, M. X. (1990). "Talc lung in a drug abuser". Irish Journal of Medical Science. 159 (5): 147–8. doi:10.1007/BF02937408. PMID 2397985.
- Cappola, T. P.; Felker, GM; Kao, WH; Hare, JM; Baughman, KL; Kasper, EK (2002). "Pulmonary Hypertension and Risk of Death in Cardiomyopathy: Patients with Myocarditis Are at Higher Risk". Circulation. 105 (14): 1663–8. doi:10.1161/01.CIR.0000013771.30198.82. PMID 11940544.
- Humbert, M. (2005). "Improving survival in pulmonary arterial hypertension". European Respiratory Journal. 25 (2): 218–20. doi:10.1183/09031936.05.00129604. PMID 15684283.
- Lintzeris, Nicholas; Lenné, Michael; Ritter, Alison (1999). "Methadone injecting in Australia: A tale of two cities". Addiction. 94 (8): 1175–8. doi:10.1046/j.1360-0443.1999.94811757.x. PMID 10615732.
- Dales pharmaceauticles patients information leaflet revision 09/10[verification needed]
- Lopez-Munoz, Francisco; Alamo, Cecilio (2009). "The Consolidation of Neuroleptic Therapy: Janssen, the Discovery of Haloperidol and Its Introduction into Clinical Practice". Brain Research Bulletin. 79: 130–141. doi:10.1016/j.brainresbull.2009.01.005. PMID 19186209.
- Bockmühl, Max; Ehrhart, Gustav (1949). "Über eine neue Klasse von spasmolytisch und analgetisch wirkenden Verbindungen, I" [On a new class of spasmolytic and analgesic compounds, I]. Justus Liebigs Annalen der Chemie (in German). 561 (1): 52–86. doi:10.1002/jlac.19495610107.
- Defalque, Ray J.; Wright, Amon J. (2007). "The early history of methadone. Myths and facts.". Bull Anesth Hist (25(3)): :13–6.
- http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm[full citation needed]
- Preston, A.; Bennett, G. (2003). "The History of Methadone and Methadone Prescribing.". In Tober, G.; Strang, E. In: Methadone Matters. Evolving Community Methadone Treatment of Opiate Addiction. Taylor and Francis Group.
- "Methadone Briefing". Archived from the original on 2003-11-20. Retrieved 2007-07-09.
- Indro-Online.de (PDF format)
- "Methadone Maintenance Treatment". Drug Policy Alliance Lindesmith Library. Archived from the original on 2003-05-11.
- "Methadone Research Web Guide". NIDA.
- Sullivan, Sheena G.; Wu, Zunyou; Rou, Keming; Pang, Lin; Luo, Wei; Wang, Changhe; Cao, Xiaobin; Yin, Wenyuan; Liu, Enwu; Mi, Guodong (January 2015). "Who uses methadone services in China? Monitoring the world's largest methadone programme". Addiction. 110: 29–39. doi:10.1111/add.12781. PMID 25533862.
- Based on:
- Bennett, C (2011). "Methadone Maintenance Treatment: Disciplining the "Addict"". Health and history. 13 (2): 130–57. doi:10.5401/healthhist.13.2.0130. PMID 22329263.
- Bergschmidt V (2004) 'Pleasure, Power, and Dangerous Substances: Applying Foucault to the study of "Heroin Dependence" in Germany' Anthropology and Medicine Vol. 11 (1) pp. 59-73
- Thomas Nordegren (1 March 2002). The A-Z Encyclopedia of Alcohol and Drug Abuse. Universal-Publishers. p. 366. ISBN 978-1-58112-404-0. Retrieved 16 May 2012.
- ONDCP Fact Sheet
- DHHS, Centers for Disease Control and Prevention (CDC)
- Tapering off of methadone maintenance
- BEST PRACTICES: Methadone Maintenance Treatment* Fraser, Suzanne; valentine, kylie (2008). Substance and Substitution: Methadone subjects in liberal societies (1st ed.). Basingstoke: Palgrave Macmillan. p. 216. ISBN 9780230019980.