Methadone
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| Pregnancy category |
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| Dependence liability | Moderate |
| Routes of administration | oral, intravenous |
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| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 40-80(-92) |
| Metabolism | Hepatic |
| Elimination half-life | 24-36 hrs. |
| Excretion | Urine, Test by specific gravity and bilirubin |
| Identifiers | |
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| CAS Number | |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.000.907 |
| Chemical and physical data | |
| Formula | C21H27NO |
| Molar mass | 309.445 g/mol g·mol−1 |
Methadone is a synthetic opioid, used medically as an analgesic and in the treatment of narcotic addiction. It was developed in Germany in 1937, and in the USA was first brought to market by the pharmaceutical company Eli Lilly and Company.
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). Although chemically unlike morphine or heroin, methadone also acts on the opioid receptors and thus produces many of the same effects.
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 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. Australians have recently utilised methadone to treat amphetamine addictions in the hope of reducing foetal harm among aboriginals [citation needed].
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. 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.
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. 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". The claim is still presented as fact by Church of Scientology literature[2] and was repeated by actor and vocal Scientologist Tom Cruise in a 2005 Entertainment Weekly interview. However, as the magazine pointed out, this isn't true: the name "Dolophine" was in fact created after the war by the American branch of Eli Lilly,[3] and the name "Adolphine" (never an actual name of the drug) was created in the United States in the early 1970s.[4] Dolophine actually comes from the German Dolphium. The name derives from the Latin dolor which means "pain" and phine which means "end".
Pharmacology
Methadone has a slow metabolism and very high lipid solubility, making it longer lasting than morphine-based drugs. Methadone has a typical half-life of 15 to 60 hours, in rare cases up to 190 hours.[5] permitting the administration only once a day in heroin detoxification and maintenance programs. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day. The most common mode of delivery at a methadone clinic is in an oral solution, usually Methadose is used. Methadone is almost as effective when administered orally as by injection. As with heroin, 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.
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. [1]
Current research shows methadone has a unique affinity for the NMDA (N-methyl-D-aspartic acid) brain receptor. Some researchers propose that NMDA may regulate psychic dependence and tolerance by exhibiting opioid antagonist like activity. Withdrawal symptoms are generally more acutely severe than those of morphine or heroin at equivalent doses, and are significantly more prolonged; methadone withdrawal symptoms can last for several weeks or more, and so individuals maintained on methadone for long periods of time may in fact find it more difficult to give up methadone than people who go directly from heroin use to abstinence.
Clinical use
Opioid addiction
Methadone has traditionally been provided to the addict population in a highly regulated methadone clinic, generally associated with an outpatient department of a hospital. Numerous clinics start addicts at 30mg and raise the dosage 10mg a day until the addict feels they are at a comfortable level of dosage, free from withdrawal symptoms and intense cravings. In the United States, clinics such as these stem from programs set up during the Nixon administration to combat heroin use, first in Washington, D.C., then nationwide. In addition to obtaining a daily methadone dose, some who go to this type of clinic for addiction treatment may attend some type of psychological counseling for their addiction. Some are required to attend drug addiction programs but many are not.
Research suggests that MMT (Methadone Maintenance Treatment) significantly decreases the rate of HIV infection for those patients participating in MMT programs (Firshein, 1998). However, for the addict to remain HIV free, safe-sex must be practiced. At proper dosing, methadone usually reduces the appetite for and need to take heroin. However, most heroin addicts report more difficulty in quitting methadone than heroin. 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. Many factors determine the treatment dose schedule. There are some who follow the philosophy that methadone maintenance treatment is not curative for heroin addiction.
Chronic pain
In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as 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 doesn't respond to weaker agonists. A major drawback is that unlike Oxycontin, methadone is not technologically engineered for sustained release of the drug so blood concentrations will fluctuate greatly between dosing. Some physicians also choose methadone for treating chronic pain in patients who are thought to have a propensity for addiction.
Efficacy
The efficacy of Methadone, whether for heroin addiction or chronic pain, has long been established. Methadone is a strong opioid that induces analgesia which is indistinguishable from morphine's and other opiate agonists. Regarding addiction, a Cochrane review (neutral organization that examines medical treatments) from 2004 noted, "Methadone is an effective maintenance therapy intervention for the treatment of heroin dependence as it retains patients in treatment and decreases heroin use better than treatments that do not utilize opioid replacement therapy. It does not show statistically significant superior effect on criminal activity." In other words, opiate-dependent patients stayed in methadone programs, but reduction in criminal activity was no greater than that seen in patients treated without methadone.
These studies of criminal activity, however, ignore the many homeless and extremely impoverished who are in methadone programs. In studies of people with access to housing and jobs, the cessation of illegal opiate use (and continuance of legal opiate use) which methadone's prescription provides reduces criminality. In methadone users who continue to use other drugs and who have access to housing and jobs, the problem lies in use of non-opiate drugs. Since methadone use is not a substitute for non-opiate use, this is to be expected.
Worldwide, there has been an explosion of deaths related to methadone. Methadone has recently come into favor because of its morphine-equivalent analgesia and the longer half-life of methadone which makes blood levels and thus analgesia more stable in patients. Germany noted that one-half of its drug-related deaths were caused in whole or in part by methadone. In 1996, more than twice as many people died from methadone as died from heroin in England. It should be noted that nearly half of all overdose deaths involving methadone in Indiana and South Carolina were contributed to by the victim's concurrent use of benzodiazepines or other sedative drugs such as alcohol.[citation needed]Relatives of the deceased report that many who died had solely consumed low doses of methadone. Methadone is thought to cause cardiac conduction problems leading to arrest more often than is recorded. Six percent of people carry a gene that makes such a life threatening effect likely(Medsafe).
Abuse
Most methadone abuse is perpetrated by friends and family members of people who receive the drug on a prescription basis for medical conditions. [citation needed] "Street methadone" has a black market value of $0.20 - $1.00 per milligram. [citation needed] As most programs require daily pharmacy attendance, travelling can be difficult if not impossible for methadone patients. Some of the more affluent patients resort to the purchase of a sufficient supply of black market methadone prior to travel, to last for the duration of the trip. However, if not used responsibly, black market methadone can be dangerous. If a person who does not have a tolerance to opiates takes a dose of methadone intended for someone on a maintenance program, they will quickly overdose. I think the main reason so many people die from methadone is because it takes about twice the amount of time for it to effect you verses a different "Pain Killer".And you keep taking more because you dont think what you have allready taken is working
A new population of users has been presenting with methadone addiction - the methamphetamine abusers. They buy street methadone or trade their stimulant drugs for diverted methadone to enable them to settle and get some sleep. The abuse of stimulants by methadone patients to combat lethargy is a major treatment complication today and studies to see whether replacement drug therapy or support for patients who become addicted to stimulants are ongoing.
A major study found that methadone prescribed for chronic pain is also tied to an increasing number of drug overdose deaths in the United States, more than any other prescription narcotic painkiller. The study has been criticised for the Organiser's lack of impartiality. Stewart B Leavitt is employed by a methadone manufacturer which supplies addiction treatment facilities.
According to the National Center for Health Statistics, as well as a 2006 series in the Charleston (WV) Gazette,[6] 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).
Data confirms a correlation between increased methadone distribution through pharmacy channels and the rise in methadone associated mortality. This supports the hypothesis that the growing use of oral methadone, prescribed and dispensed for the outpatient management of chronic pain (vs. opioid addiction treatment), explains the dramatic increases in methadone consumption and the growing availability of the drug for diversion to abuse.
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).
Similar drugs
Related to methadone, the synthetic compound levo-alphacetylmethadol (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.
Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Buprenorphine. 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. [7] Other opiates such as dihydrocodeine are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine. [8]
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
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
- ^ Buttnor, Al. "The Drug Problem: How It CAN be Solved". Freedom Magazine (vol. 4, iss. 1) p. 15. Retrieved Apr. 7, 2006.
- ^ http://www.exchangesupplies.org/publications/methadone_briefing/section1.html
- ^ http://www.indro-online.de/discovery.pdf (PDF format)
- ^ Manfredonia, John (2005-03-18). "Prescribing Methadone for Pain Management in End-of-Life Care". JAOA The Journal of the American Osteopathic Association. Retrieved 2007-01-29.
- ^ http://www.wvgazette.com/section/Series/The+Killer+Cure
- ^ Michels II, Stover H, Gerlach R. Substitution treatment for opioid addicts in Germany. Harm Reduction Journal. 2007 Feb 2;4:5.
- ^ 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.