|Systematic (IUPAC) name|
|Oral, intravenous, insufflation, sublingual, rectal|
|Metabolism||Hepatic (CYP3A4, CYP2B6 and CYP2D6-mediated)|
|(what is this?)|
Methadone (also known as Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon and many other names) is a synthetic opioid. It is used medically as an analgesic and a maintenance anti-addictive and reductive preparation for use by patients with opioid dependence. It was developed in Germany in 1937, mainly because Germany required a reliable internal source of opioids. It is an acyclic analog of morphine and heroin. Methadone acts on the same opioid receptors as these drugs, and has many of the same effects. Methadone is also used in managing severe chronic pain, owing to its long duration of action, strong analgesic effect, and very low cost. Methadone was introduced into the United States in 1947 by Eli Lilly and Company. The number of drug-poisoning deaths involving methadone increased from 784 deaths in 1999 to 5,518 deaths in 2007; then it declined to 4,418 deaths in 2011.
Methadone is listed under Schedule II of the Single Convention On Narcotic Drugs 1961 and is regulated similarly to morphine in most countries. In the United States, it is a Schedule II Narcotic controlled substance with an ACSCN of 9250 and a 2013 annual aggregate manufacturing quota of 25 metric tons, down from just under 30 in 2012. One intermediate in the manufacturing process, 4-cyano-2-dimethylamino-4,4-diphenyl butane, is also listed as a Schedule II Narcotic Intermediate controlled substance with ACSCN 9254 and a quota of 32.5 metric tons. Levomethadone is presumably under Schedule II as an isomer of methadone. The salts of methadone in common medical use are the hydrochloride (free base conversion ratio 0.89) and hydrobromide (0.79); the tartrate was used in the past.
Methadone is mainly used in the treatment of opioid dependence. It has cross-tolerance (tolerance to similar drugs) with other opioids including heroin and morphine, and offers very similar effects but a longer duration of effect. Oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome or making it more tolerable. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.
Methadone is approved for different indications in different countries. Common is approval as an analgesic and approval for the treatment of opioid dependence. It is not intended to reduce the use of non-opioid drugs such as methamphetamine or ethanol (alcohol).
A number of pharmaceutical companies produce and distribute methadone. The racemic hydrochloride is the only form available in most countries, such as the Netherlands, Belgium, France and in the United States, as of March 2008. The dextrorotary enantiomer of methadone, dextromethadone, is an NMDA antagonist rather than an opiate agonist. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
- 1 Medical uses
- 2 Adverse effects
- 3 Detection in biological fluids
- 4 Pharmacology
- 5 History
- 6 Society and culture
- 7 Similar drugs
- 8 References
- 9 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). 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. Methadone helps opioid dependent individuals be more social and productive in life.
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 can be for months or even years. Methadone reduction programs are suitable for addicted persons who wish to stop using drugs altogether. The length of the reduction programme 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. When used correctly, methadone maintenance has been found to be medically safe and non-sedating. It is also indicated for pregnant women addicted to opiates.
In Russia, methadone treatment is illegal. Health officials there 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. 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 went on to say 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 heart beat 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. So then it is time 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 low dose, and the time for the next switch will be longer.
Methadone is also approved in the US for detoxification treatment of opioid addiction; however, its use in this regard must follow strict federal regulations. 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 detoxification.
At dosage levels
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
- Gynecomastia (enlargement of male breast tissue)
- 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, and impotence
- Skin rash
- Central sleep apnea
- Sudden death
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
- Severe itching
- Akathisia (restlessness)
- Tachycardia (fast heartbeat)
- Aches and pains, often in the joints and/or legs
- Elevated pain sensitivity
- Blood pressure that is too low (hypotension) or too high (hypertension, may cause stroke)
- sudden cardiac death
Cognitive symptoms
- Suicidal ideation
- Susceptibility to cravings
- Reduced breathing (may be fatal between 2–4 hours)
- 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)
Withdrawal symptoms are significantly more prolonged but also less intense than withdrawal from opiates with shorter half-lives.
When detoxing at a recommended rate (typically 1–2 mg per week), withdrawal is either minimal or nonexistent, as the patient's body has time to adjust to each reduction in dose. Unlike methadone, buprenorphine produces cognitive dehabilitation in multiple areas of mental function in both memory and timed choice task tests, which may persist after cessation of substitution treatment.
Symptoms of overdose
Patients 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
- Skin that is cool, clammy, and pale
- Limp muscles, trouble staying awake, nausea.
- Unconsciousness and coma
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 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 Queensland University. 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 (West Virginia) Gazette, 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 and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor 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."
Methadone is sometimes administered in a sugary syrup which is swallowed. This preparation can cause significant tooth decay. Methadone also causes dry mouth (xerostomia), reducing the protective role of saliva in preventing decay. Typically individuals taking methadone have low awareness of oral health. These factors combine to often cause extensive damage to the teeth in persons taking methadone.
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.
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 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.
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. This 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, and "Disket" which is a tablet designed to disperse itself 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. 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. Methadose/Methadone 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 sugar and other ingredients (Sugar-Free syrups also should not be injected). Oral medication 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 brought to market in 1943 and was widely used by the German army during WWII.
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 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 USA 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. The pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s. An urban legend claims Dolophine was named for Adolf Hitler.
Society and culture
In Germany the annual cost per patient is less than 3000 euros, while heroin assisted treatment costs up to 10,000 euros per year. Methadone clinics in the U.S. charge anywhere from $5–400 per week, which may be covered by private insurance or Medicaid. MMT cost analysis often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.
Methadone substitution as a treatment of opiate addiction has been widely criticised 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 labelled as a “treatment” and so obscures the disciplinary objectives of “managing undesirables”.
Viktoria Bergschmidt cites Michel Foucault’s concept of Biopower as key to understanding the power relations inherent in methadone treatment programs. Here Foucault describes the historical shift from a sovereign’s power “symbolised by the sword and ultimately articulated in the execution of his subjects” to a power based largely on the concern for life. The mechanisms of Biopower are not those of repression and coercion but rather the normalisation and regulation of the body.
The Biopower model is particularly pertinent in the case of methadone treatments given the unique status of drug addictions in post-industrial society. The image of the "junkie" is instilled with the notion of the “abject other… marked for death” and thus is a singularly dangerous entity, requiring firm control.
There are two methadone isomers that form the racemic mixture which is more common as it is cheaper to produce. The laevorotary isomer, which is isolated by several recrystalisations from racemic methadone, is more expensive to produce than the racemate. It is more potent at the opioid receptor than the racemic mixture and is marketed especially in continental Europe as an analgesic under the trade names Levo-Polamidone, Polamidone, Heptanone, Heptadone, Heptadon and others. It is used as the hydrochloride salt almost exclusively with some uncommon pharmaceuticals and research subjects consisting of the tartrate. The dextrorotary isomer d-methadone is not commercially available. It is devoid of opioid activity and it acts as an NMDA antagonist. It has been shown to be analgesic in experimental models of chronic pain.
The closest chemical relative of methadone in clinical use is levo-α-acetylmethadol or LAAM. It has a longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994, it was approved as a narcotic addiction treatment. In the Netherlands, like methadone and all other strong opioids, LAAM is a List I drug of the Opium Law, and in Schedule II of the United States Controlled Substances Act. LAAM has since been removed from the US and European markets due to reports of rare cardiac side effects.
Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Subutex (buprenorphine) and Suboxone (buprenorphine combined with naloxone). With the Drug Addiction Treatment Act of 2000, qualified physicians in the U.S. were allowed to prescribe buprenorphine and other Schedule III drugs on an outpatient basis. Methadone, which is cheaper than buprenorphine, is only available from methadone clinics in the U.S.
In the Netherlands, Switzerland, the UK and a few other European countries, not only buprenorphine and oral methadone but also injectable methadone and pharmaceutical diamorphine (heroin) or other opioids may be used for outpatient maintenance treatment of opiate addiction, and treatment is generally provided in much less heavily regulated environments than in the United States. In the United Kingdom, diamorphine is used extremely selectively and is not available on prescription to addicts; except in specialist trials which involved no more than 300 participants. A study from Austria indicated that slow release oral morphine (in the form of MS-Contin), under trade names Substitol-Retard and Compensan, provide better results than oral methadone, and studies of heroin maintenance have indicated that a low background dose of methadone combined with heroin maintenance may significantly improve outcomes for less-responsive patients. Since the late 1990s in Austria, slow release oral morphine has been used alongside methadone and buprenorphine for Opioid Substitution Therapy (OST) and more recently it has been approved in Slovenia and Bulgaria, and it has gained approval in other EU nations including the United Kingdom, although its use is not yet as widespread. The more attractive side-effect profile of morphine compared to buprenorphine or methadone has led to the adoption of morphine as an option for OST treatment, and currently in Vienna over 60 percent of substitution therapy utilizes slow release oral morphine. Illicit diversion has been a problem, but to the many proponents of the utilization of morphine for OST, the benefits far outweigh the costs, taking into account the much higher percentage of addicts who are "held" or, from another perspective, satisfied by this treatment option, as opposed to methadone and buprenorphine treated addicts, who are more likely to forgo their treatment and revert to using heroin etc., in many cases by selling their methadone or buprenorphine prescriptions to afford their opiate of choice. Driving impairment tests done in the Netherlands that have shown morphine to have the least negative effects on cognitive ability on a number of mental tasks also suggest morphines use in OST may allow for better psychological functioning and engagement in society. Other opiates such as dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.
Another close relative of methadone is dextropropoxyphene, first marketed in 1957 under the trade name of Darvon. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II of the United States Controlled Substances Act, while preparations containing it are in Schedule IV. More than 100 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. Since dextropropoxyphene produces relatively modest pain relief compared to other opioids but still produces severe respiratory depression at high doses, it is particularly dangerous when abused, as drug users may take dangerously high doses in an attempt to achieve narcotic effects. This narcotic is among the top 10 drugs reported by medical examiners in recreational drug use deaths. However, dextropropoxyphene is still prescribed for the short term relief of opiate withdrawal symptoms, particularly when the aim of treatment is to smooth detoxification to a drug-free state rather than a switch to maintenance treatment.
Other analogs of methadone which are still in clinical use are dipipanone (Diconal) and dextromoramide (Palfium) which are shorter-lasting but considerably more effective as analgesics. In the 1980s and beginning of the 1990s, before pharmaceutical grade IV heroin treatment became available to heroin addicts, as either single drug replacement for street heroin, or to be used alongside prescribed methadone, oral dextromoramide was prescribed to heroin addicts instead, because even when taken orally it still produces a strong, so called "rush", without the need of IV administration and any of the risks involved with it. These drugs have a high potential for abuse and dependence and were notorious for being widely abused and sought after by drug addicts in the 1970s. They are still rarely used for the relief of severe pain in the treatment of terminal cancer or other serious medical conditions. Different nations within the EU have different regulations, and in some nations general practitioners have the legal right to maintain addicts with whatever they deem to be most efficacious in maintaining their health and well being.
- 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 1743125. PMID 15537850.
- Chen LH, Hedegaard H, Warner M. Drug-poisoning deaths involving opioid analgesics: United States, 1999–2011. NCHS data brief, no 166. Hyattsville, MD: National Center for Health Statistics. 2014.
- DEA Office of Diversion Control website: Schedules, Conversion factors.
- "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- Hull JD, Scheinmann F, Turner NJ, (March 2003). "Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations". Tetrahedron: Asymmetry 14 (5): 567–576. doi:10.1016/S0957-4166(03)00019-3.
- US patent 6143933
- 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 12519570.
- 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. Methadone for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003971. 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.
- "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. doi:10.4061/2010/524764. PMC 3021856. 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.
- "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 2396610. 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.
- Brondani, M; Park, PE (NaN). "Methadone and oral health--a brief review.". Journal of dental hygiene : JDH / American Dental Hygienists' Association 85 (2): 92–8. PMID 21619737. Check date values in:
- Graham, CH; Meechan, JG (October 2005). "Dental management of patients taking methadone.". Dental update 32 (8): 477–8, 481–2, 485. PMID 16262036.
- Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 941–5.
- 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.
- "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.
- Code of Federal Regulations, Title 42, Sec 8.
- 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.
- http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm[full citation needed]
- "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.
- "Methadone Research Web Guide". NIDA.
- Bennet C (2011) 'Methadone Maintenance Treatment: Disciplining the "Addict"' Health and History vol. 13 (2) pp. 130-157
- Bergschmidt V (2004) 'Pleasure, Power, and Dangerous Substances: Applying Foucault to the study of "Heroin dependance" in Germany' Anthropology and Medicine Vol. 11 (1) pp. 59-73
- Bennet C (2011) 'Methadone Maintenance Treatment: Disciplining the "Addict"' Health and History vol. 13 (2) pg. 150
- Bergschmidt V (2004) 'Pleasure, Power, and Dangerous Substances: Applying Foucault to the study of "Heroin dependance" in Germany' Anthropology and Medicine Vol. 11 (1) pg. 62
- Foucault M (1980) The History of Sexuality Vol. 1 An Introduction New York: Vintage/Random House
- Butler J (1997) 'Subjection, resistance, resignification: between Freud and Foucault' in The Psychic Life of Power: Theories in Subjection, Standford: Stanford University Press pg. 27
- Michels, Ingo; Stöver, Heino; Gerlach, Ralf (2007). "Substitution treatment for opioid addicts in Germany". Harm Reduction Journal 4: 5. doi:10.1186/1477-7517-4-5. PMC 1797169. PMID 17270059.
- Robertson, J. Roy; Raab, Gillian M.; Bruce, Malcolm; McKenzie, James S.; Storkey, Helen R.; Salter, Amy (2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction 101 (12): 1752–9. doi:10.1111/j.1360-0443.2006.01603.x. PMID 17156174.
- http://www.medscape.com/viewarticle/736718?src=mp&spon=25[full citation needed]
- Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 1362. ISBN 1437727883.
- ONDCP Fact Sheet
- Clinic Locator, United States
- DHHS, Centers for Disease Control and Prevention (CDC)
- TAPERING OFF OF METHADONE MAINTENANCE: EVIDENCE-BASED GUIDELINES
- BEST PRACTICES: Methadone Maintenance Treatment