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Methadone



Methadone
Systematic (IUPAC) name
6-(Dimethylamino)-4,4-diphenylheptan-3-one
Identifiers
CAS number 76-99-3
ATC code N02AC52 N07BC02, R05DA06
PubChem 4095
DrugBank APRD00485
Chemical data
Formula C21H27NO 
Mol. mass 309.445 g/mol
Pharmacokinetic data
Bioavailability 40-80(-92)
Metabolism Hepatic
Half life 24-36 hrs.
Excretion Urine, Test by specific gravity and bilirubin
Therapeutic considerations
Pregnancy cat.

Reduction of oxygen to unborn child due to depression of breathing

Legal status

Class A(UK) Schedule II(US)

Dependence Liability Moderate
Routes oral, intravenous

Methadone is a synthetic opioid, used medically as an analgesic and anti-addictive. It was developed in Germany in 1937.

Although chemically unlike morphine or heroin, methadone also acts on the opioid receptors and thus produces many of the same effects.

Methadone maintenance therapy is the most systematically studied and the most politically polarizing pharmacotherapy for the treatment of drug addiction patients.[citation needed]

Methadone is also used in managing chronic pain due to its long duration of action and very low cost. In late 2004, the cost of a one-month supply of methadone was $20, as compared to an equivalent analgesic amount of Demerol at $120.

Today a number of pharmaceutical companies produce and distribute methadone. However, the major producer remains Mallinckrodt. Mallinckrodt sells bulk methadone to most of the producers of generic preparations and also distributes its own brand name product in the form of tablets, dispersible tablets and oral concentrate under the name Methadose in the United States.

Contents

History

Methadone was developed in Germany in 1937.

On September 11, 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or polamidon and whose structure had no relation to morphine or the opioid alkaloids (Bockmühl and Ehrhart, 1949).

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic (they gave it the trade name Dolophine®, which is now registered to Roxane Laboratories). Since then, it has been best known for its use in treating narcotic addiction. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and it had even been used in some hospitals. 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 more than 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 (as Dolophine) was first manufactured in the USA by Mallinckrodt Pharmaceuticals, a St. Louis-based subsidiary of the Tyco International corporation. Mallinckrodt held the patent up until the early 1990s, and is still the major producer.

Generally, one will only hear "dolophine" used by older addicts who used the product in the 1960s and 1970s. Medical professionals who believe that dolophine is the generic name for methadone, when actually it is the reverse, may also use the old brand name.

In the United States, methadone maintenance treatment emerged from trials in New York City in 1964 in response to the dramatic and continuing increase of heroin abuse and addiction following World War II. The results of the early major studies showed methadone could effectively interrupt illicit opioid use and reduce the associated costs to society, findings which have been consistent with later research and backed up by modern knowledge of the psychological, social and pharmacological mechanisms of illicit opioid addiction.

Origin of Dolophine name

A persistent but untrue urban legend claims that the trade name "Dolophine" was coined in tribute to Adolf Hitler by its German creators, and it is sometimes even claimed that the drug was originally named "adolphine" or "adolophine" or "Dolphamine". The claim is still presented as fact by Church of Scientology literature[1] and was repeated by actor and vocal Scientologist Tom Cruise in a 2005 Entertainment Weekly interview. However, as the magazine pointed out, this is not true: the name "Dolophine" was in fact created after the war by the American branch of Eli Lilly,[2] and the name "Adolphine" (never an actual name of the drug) was created in the United States in the early 1970s.[3] Dolophine actually comes from the German Dolphium. The name derives from the Latin dolor which means "pain" and fīnis which means "end".

Pharmacology

Methadone acts by binding to the NMDA receptor. It is metabolized by the enzymes CYP3A4 and CYP2D6, with great variability between individuals. Its main route of administration is oral. Adverse effects include hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal symptoms. The latter are less severe compared to those of e.g. morphine and heroin, but are on the other hand more prolonged.

Mode of action

Methadone binds to the glutamate NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. 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, ketamine, and ibogaine are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. Methadone is also a full mu-opioid agonist.

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[4][5], ranging from as few as 4 hours to as many as 130 hours [6], or even 190 hours[7]. This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4 and CYP2D6. A longer half life frequently allows for administration only once a day in heroin 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.[6] 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 toxic effects of an overdose can be treated with naloxone. [8]

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)-methadone enantiomer has traditionally been used, as it is responsible for most of the desired opioid effects[6]. This is becoming less common due to the higher production costs.

Methadone is available in pill, sublingual tablet and liquid formulations, with the liquid form the most common as it allows for finer grained dose titration. Methadone is almost as effective when administered orally as by injection. In fact, injection of methadone does not result in a "rush" as with most opioids, 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. This is another aspect of methadone that makes it desirable for use in maintenance treatment, as abuse in the form of injection will not be repeated by a maintenance patient who attempts to inject methadone.

Adverse effects

Adverse effects of methadone include[8]:

  • Hypoventilation
  • Decreased bowel motility - constipation
  • miotic pupils
  • nausea
  • hypotension

When combined with other drugs, however, methadone can cause death:

Mortality

According to the National Center for Health Statistics, as well as a 2006 series in the Charleston (WV) Gazette,[9] medical examiners listed methadone as contributing to 2,992 deaths in 2003, up from 790 in 1999. Approximately 82% of those deaths were listed as accidental- and most deaths involved combinations of methadone with other drugs (especially benzodiazepines).

More information on methadone associated mortality can be found at Substance Abuse and Mental Health Services Administration (SAMHSA - U.S. Dept. of Health and Human Services).

Tolerance and dependence

As with other opioid medications, tolerance and dependence usually develop with repeated doses. Tolerance to the different physiological effects of methadone varies. Tolerance to analgesia usually occurs during the first few weeks of use; whereas with respiratory depression, sedation, and nausea it is seen within approximately 5-7 days. There is no tolerance formed to constipation produced by methadone or other opioids; however, effects may be less severe after time and can often be alleviated through dietary fiber supplements.

Withdrawal symptoms

Withdrawal symptoms of methadone include:[8]

Withdrawal symptoms are generally slightly less severe than those of morphine or heroin at equivalent doses but are significantly more prolonged; methadone withdrawal symptoms can last for several weeks or more. Anecdotal reports, such as those by author and lifelong opiate addict William S. Burroughs in the postscript of his book Naked Lunch, suggest that "cold turkey" barbiturates withdrawal is substantially more difficult and unpleasant than similar withdrawal from opiates, presumably because its duration of withdrawal is almost an order of magnitude greater than short-acting opiate withdrawals, such as those from heroin or morphine. Indeed, there is a trend in the management of opiate addiction towards the reduction of a patient's methadone dosage to a point where they can be switched to buprenorphine or another opiate with an easier withdrawal profile. Ultimately, methadone is all but ideal for maintenance, but is not considered to be a desirable opiate to withdraw from when attempting to become completely opiate-free.

Methadone maintenance treatment

MMT (Methadone Maintenance Treatment) reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity [10]. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV.[10] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. Methadone maintenance has been found to be medically safe and nonsedating.[10] It is also indicated for pregnant women addicted to heroin. [10].

Effect

Methadone maintenance treatment significantly decreases the rate of HIV infection for those patients participating in MMT programs (Firshein, 1998). At proper dosing, methadone usually reduces the appetite for and need to take heroin. Furthermore, higher doses, generally above 120mg, provide cross-tolerance and block the euphoric effects of other opioids such as heroin, greatly reducing the motivation of patients to use them.

Methadone offers patients the freedom from active addiction and use of mind-altering drug use and in turn allows them to seek concurrent psychological, psychiatric and self-help based therapies for both the disease of addiction and any comorbid illnesses they have, freedom they would not have when experiencing severe ongoing withdrawal and/or cravings. In addition, and perhaps most importantly, methadone allows addicts to become productive members of society; freed from the need to obtain money through often illicit means, opiate addicts can return to their normal lives, or develop skills, further their education, and (re)join the workforce.

A proper dose used in methadone maintenance therapy will block or greatly reduce cravings and illicit opioid use while not inducing any euphoric feelings or other subjective sense of being high, and if high enough will actively prevent the patient from experiencing any high if they do use other opioids. Methadone-based treatment is significantly more effective clinically and more cost effective than no-drug treatment modalities for opiate-dependent patients[11].

Dosage

A majority of patients require 80-120 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for opiate addiction.[10] Lower doses are sometimes not as effective or provide the blockade effect as higher dosages.

In the United States clinics typically start patients at a low dose, generally only starting patients on methadone when they are in withdrawal and providing a small test dose, after which the patients are observed for possible adverse effects. Assuming there are no complications, the remaining portion of the first day's dose is then given. After this the doses are titrated until they reach either a clinically sufficient level that prevents withdrawal, cravings and possible continued use of illicit opioids, or until they reach a maximum dose set by clinic policy. For example, a clinic may start addicts at 30mg and raise the dosage 5mg a day until the addict feels they are at a comfortable level of dosage or will stop at 80mg and allowing the patient move up by 5mg or 10mg every 2 or 3 days, free from withdrawal symptoms and intense cravings. Once stabilized patients may require occasional dose adjustments as their clinical or subjective tolerance changes.

The most common and traditional dosing regimens, however, tend to fall far short of providing optimum or even sufficient results for a number of patients. This is due to the ceilings many clinics place on dose levels[12][13].

A 100-mg dose has become accepted as a 'glass ceiling', rarely to be penetrated, and in practice much lower thresholds are maintained even though the optimal dose varies greatly between patients, often quite higher than this and with no inherent threshold in the possible dose, as the toxic dose for patients with very high tolerance can exceed this ten-fold or more. The blood concentrations of patients on an equivalent dose, when adjusted for body weight, can vary as much as 17-fold, or up to 41-fold when influenced by other medications, leading to a vast range of potentially required doses. [14][15]

Duration

While there is much debate over the treatment schedule and duration required, treatment at a methadone maintenance clinic is intended to be for an indefinite duration, lasting as long as the patient requires it. Many factors determine the treatment dose schedule. In general, methadone maintenance is seen as ongoing symptom management rather than a curative treatment. Compared to other narcotics (morphine, hydrocodone, heroin), methadone is much safer (when used as directed) and does not harm any of the body's vital organs (brain, liver, lungs, kidneys) even after long term use (30+ years).

Visits to clinics

Methadone has traditionally been provided to the addict population in a highly regulated methadone clinic, generally associated with an outpatient department of a hospital.

New patients are required to visit the clinic daily so that they may be observed taking their dose by the dispensing nurse, but may be allowed to leave the clinic with increasing supplies of "take home doses" after several months of adherence to the clinic's regulations, including consistent negative drug-screen results. The law stipulates clinics may provide at most one week's worth of methadone, (two weeks in the USA) except for patients unable to visit the clinic without undue hardship due to a medical disability or infrequent exceptions made for necessary travel to areas without clinics, and this level is only reached after a few years of proper results.

Most patients treated at this type of clinic for addiction treatment receive psychological counseling for their addiction, which is also provided by the clinics. Though the laws vary, this is required by law in many states and countries.

Analgesic

In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an analgesic in chronic pain. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than short-acting drugs like morphine or hydrocodone. Another factor in the increased usage is the low cost of methadone. A month's supply will typically have a retail cost of $30-50 in the United States, compared to hundreds of dollars for alternative opioids. Methadone, with its long half-life (and thus long duration of effect) and good oral bioavailability, is a common second-choice drug for pain that does not respond to weaker agonists. A major drawback is that unlike OxyContin (oxycodone continuous release), methadone is not technologically engineered for sustained release of the drug so blood concentrations will fluctuate greatly between dosing. This problem is overcome to a great extent by the practice of dosing methadone two or three three times a day in pain patients. Some physicians also choose methadone for treating chronic pain in patients who are thought to have a propensity for addiction, because it causes less of an intoxicated or euphoric "high". The effect is of morphine-equivalent origin.

On November 29, 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.[16] As with any strong medication which can be fatal in large doses methadone must be taken properly and with due care. Otherwise the accumulation of methadone could potentially reach a level of toxicity if the dose is too high or if the user's metabolism of the drug is slow. In such a situation, a patient who fared fine after the first few doses could reach high levels of the drug in his body without ever taking more than was prescribed. For this reason, it is reasonable to make sure that patients who do not have a tolerance to opiates be prescribed methadone in initially small doses, and that when sent home, patients and their families are made very aware of the symptoms characteristic of opiate overdose. Also, there is some evidence methadone and other opiods may cause cardiac conduction problems (prolonged QTc interval[17]) although there are few documented cases of fatalities resulting from this side-effect with methadone.

Similar drugs

The closest chemical relative of methadone in clinical use is levomethadone, the laevorotary or left-handed stereoisomer of methadone. It is about eight times stronger than the racaemic drug 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.

Related to methadone, the synthetic compound levo-α-acetylmethadol (or LAAM) has an even longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994 it was approved as a treatment of narcotic addiction. Like methadone, LAAM is 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. LAAM is still available at many MMT clinics throughout the US though methadone is preferred by most patients, though it is restricted to existing patients.

Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Subutex® (buprenorphine) and Suboxone® (buprenorphine combined with naloxone). In the UK and other European countries, however, not only buprenorphine and methadone but also diamorphine (heroin) or other opioids may be used for outpatient treatment of opiate addiction, and treatment is generally provided in much less heavily regulated environments than in the United States. A study from Austria indicated that oral morphine provides 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.[18] Other opiates such as dihydrocodeine are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine.[19]

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 analogues of methadone which are still in clinical use are dipipanone (Diconal) and dextromoramide (Palfium) which are shorter lasting than methadone but considerably more effective as analgesics. 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.

Notes

  1. ^ Buttnor, Al. "The Drug Problem: How It CAN be Solved". Freedom Magazine (vol. 4, iss. 1) p. 15. Retrieved April 7, 2006.
  2. ^ www.exchangesupplies.org/publications/methadone_briefing/section1.html. Retrieved on 2007-07-09.
  3. ^ http://www.indro-online.de/discovery.pdf (PDF format)
  4. ^ Kell MJ (1994). "Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting". Journal of addictive diseases : the official journal of the ASAM, American Society of Addiction Medicine 13 (1): 5–26. PMID 8018740.
  5. ^ Eap CB, DeglonJ-J, Boumann P. (1999). "Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance". Heroin Addiction and Related Clinical Problems: The official journal of EUROPAD, European Opiate Addiction Treatment Association 1 (1): 19-34.
  6. ^ a b c Eap CB, Buclin T, Baumann P (2002). "Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence". Clinical pharmacokinetics 41 (14): 1153–93. PMID 12405865.
  7. ^ Manfredonia, John (2005-03-18). Prescribing Methadone for Pain Management in End-of-Life Care. JAOA The Journal of the American Osteopathic Association. Retrieved on 2007-01-29.
  8. ^ a b c Public Health Issue: Methadone Maintenance Therapy RICHARD SADOVSKY, M.D. - Anderson IB, Kearney TE. Use of methadone. West J Med January 2000;172:43-6.
  9. ^ http://www.wvgazette.com/section/Series/The+Killer+Cure. Retrieved on 2007-07-09.
  10. ^ a b c d e Joseph H, Stancliff S, Langrod J (2000). "Methadone maintenance treatment (MMT): a review of historical and clinical issues". Mt. Sinai J. Med. 67 (5-6): 347–64. PMID 11064485.
  11. ^ Connock M, Juarez-Garcia A, Jowett S, et al (2007). "Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation". Health technology assessment (Winchester, England) 11 (9): 1–171, iii–iv. PMID 17313907.
  12. ^ Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL (2005). "Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers". Addiction 100 (10): 1496–509. doi:10.1111/j.1360-0443.2005.01232.x. PMID 16185211.
  13. ^ Latowsky M (2006). "Methadone death, dosage and torsade de pointes: risk-benefit policy implications". Journal of psychoactive drugs 38 (4): 513–9. PMID 17373567.
  14. ^ Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P (2000). "When "Enough" Is Not Enough: New Perspectives on Optimal Methadone Maintenance Dose". Mount Sinai Journal of Medicine 67 (5&6): 404-411.
  15. ^ Faggiano F, Vigna-Taglianti F, Versino E, Lemma P (2003). "Methadone maintenance at different dosages for opioid dependence". Cochrane database of systematic reviews (Online) (3): CD002208. doi:10.1002/14651858.CD002208. PMID 12917925.
  16. ^ 2006 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements. MedWatch. Food and Drug Administration.
  17. ^ Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A (2005). "QTc interval prolongation in patients on long-term methadone maintenance therapy". European addiction research 11 (1): 44–9. doi:10.1159/000081416. PMID 15608471.
  18. ^ Michels II, Stover H, Gerlach R. Substitution treatment for opioid addicts in Germany. Harm Reduction Journal. 2007 February 2;4:5.
  19. ^ Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A. Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial. Addiction. 2006 Dec;101(12):1752-9.
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  This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Methadone". A list of authors is available in Wikipedia.
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