Methadone's usefulness in treatment of opioid dependence is the result of several factors. It has cross-tolerance with other opioids including heroin and morphine, long duration of effects with the result that oral dosing with methadone will stabilise the condition of the patient by stopping and preventing the opioid withdrawal syndrome, and by at least partially blocking the "rush" resulting from intravenous injection of heroin, morphine, and similar drugs.
Today a number of pharmaceutical companies produce and distribute methadone, with only the racemic hydrochloride being available in the United States as of March 2008 but the tartrate and other salts of the laevorotary form (levomethadone, with trade names like Polamidone, Heptadon etc.), which is more potent and lacks the cardiac effects like lengthened QT interval caused by the dextrorotary form, being available in Europe and elsewhere. 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.
Methadone was developed in Nazi Germany in the late 1930s in anticipation of possible shortages of raw opium during the upcoming war and possible blockades by the enemy, which would result in shortages of morphine and other opiates for both the military and civilian populations. It was tested by medical professionals in the German military in 1939-40 but decided that it was too toxic and too likely to become addictive upon repeated use (habituation) for use in the army and other organisations.
The drug was given the trade name Dolophine from the Latin dolor meaning pain (Cf. Dipidolor for piritramide, Dolantin for pethidine, and the "-dol" ending in so many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf Hitler as explored in greater detail below.
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 no relation to morphine or the opiate 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 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 (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.
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.
The toxic effects of an overdose can be treated with naloxone.
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. Though there seems to be some discrepancy regarding effects felt from one person to the next, "rush" like effects have been occasionally reported by some. At best, most oral and pill preparations of the drug are hardly suitable for intravenous injection and perhaps account for the prevailing attitude against IV use.
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).
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. 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's long half-life and minimal side-effect profile makes it ideal for maintenance, but is not considered to be a desirable opiate to withdraw from when attempting to become completely opiate-free.
In Russia, methadone treatment is illegal. Health officials are not convinced of the treatment's efficacy. Instead, doctors encourage immediate abstinence from drug use, rather than the gradual process that methadone substitution therapy entails. Patients are often given sedatives and painkillers to cope with withdrawal symptoms.
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.
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 patients 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.
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.
In many Western countries, 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 way that MMT is delivered in some countries create barriers to scaling up access to the treatment. For example, in Australia, people who are on MMT are dosed in a designated area in front of other pharmacy customers. This can inhibit people's willingness to access treatment due to a lack of confidentiality and anonymity. In some countries or regions, law stipulates that clinics may provide at most one week's worth of methadone, (up to 30 days 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.
Some people treated for MMT at a specific MMT clinic receive psychological counseling, which is also provided on site. Though the laws vary, this is required by law in many states and countries. In some countries psycho-social support, including counselling, is compulsory, regardless of whether a person needs or wants to engage in that kind of intervention (for example, recent changes in Taiwan).
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. 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 opioids may cause cardiac conduction problems (prolonged QTc interval) although there are few documented cases of fatalities resulting from this side-effect with methadone.
In an effort to turn the tide on reported increases in methadone-related adverse events, the DEA announced in a recent advisory that manufacturers of methadone hydrochloride 40-mg tablets have agreed to restrict their distribution of that particular formulation of the drug.
As of 1. January 2008, manufacturers will ship the methadone hydrochloride 40-mg formulation only to hospitals and facilities that have been authorized for detoxification and maintenance treatment of patients with opioid addiction. In addition, manufacturers of the drug will instruct their wholesale distributors to stop supplying the formulation to any facility that doesn't meet the criteria.
The DEA advisory stresses that the 40-mg formulation of methadone hydrochloride is indicated only for the detoxification and maintenance treatment of opioid-addicted patients and is not FDA-approved for use in pain management.
Federal law does not restrict the prescribing, dispensing or administration of methadone for the treatment of pain, and the 5-mg and 10-mg methadone formulations will continue to be available as a tool family physicians can use to treat patients for pain.
Natural and semi-synthetic opiates with antitussive effects include codeine, ethylmorphine (also known as dionine or codethyline), dihydrocodeine, benzylmorphine, laudanum, dihydroisocodeine, nicocodeine, nicodicodeine, hydrocodone, hydromorphone, acetyldihydrocodeine, thebacon, diamorphine (heroin), acetylmorphone, noscapine and pholcodine and others. Amongst other synthetics are dimemorfan and dextromethorphan in the morphinan group, tipepidine of the thiambutenes, and other drugs of the open-chain (methadone) type with antitussive efficacy include levomethadone, normethadone, and levopropoxyphene.
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 oral methadone but also injectable methadone and pharaceutical 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. A study from Austria indicated that oral morphine (in the form of MS-Contin, also known as Vendal retard, MST-Continus and others) 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. Other opiates such as dihydrocodeine in both extended-release and plain form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine.
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.