Methadone, sold under the brand name Dolophine, among others, is an opioid used to treat pain and as maintenance therapy or to help with tapering in people with opioid dependence. Detoxification using methadone can either be done relatively rapidly in less than a month or gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take five days of use. The effects last about six hours after a single dose. After long term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.
Side effects are similar to those of other opioids. Commonly these include dizziness, sleepiness, vomiting, and sweating. Serious risks include opioid abuse and a decreased effort to breathe. Abnormal heart rhythms may also occur due to a prolonged QT interval. The number of deaths in the United States involving methadone poisoning declined to 3,300 in 2015, from 4,418 in 2011. Risks are greater with higher doses. Methadone is made by chemical synthesis and acts on opioid receptors.
Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl. It was approved for use in the United States in 1947. Methadone is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. Globally in 2013, about 41,400 kilograms were manufactured. It is regulated similarly to other narcotic drugs. It is not particularly expensive in the United States.
Methadone is used 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 less than that of other opioids.
People with long-term pain will sometimes have to perform so-called opioid rotation. Opioid rotation involves switching from one opioid to another, usually at intervals of between a few weeks, or more commonly, several months. Opioid rotation may allow for a lower equivalent dose, and hence fewer side effects may be encountered to achieve the desired effect. Then, over time, tolerance increases with the new opioid, requiring higher doses. This, in turn, increases the possibility of adverse reactions and toxicity. Then it is time to rotate again to another opioid. Such opioid rotation is standard practice for managing people with tolerance development. Usually when doing opioid rotation, one cannot go down to a completely naive dose, because there is cross-tolerance carried over to the new opioid. However, methadone has a lower cross-tolerance when switching to it from other opioids, than other opioids. This means that methadone can start at a comparatively lower dose than other opiates, and the time for the next switch will be longer.
Methadone is approved in the US, and many other parts of the world, for the treatment of opioid addiction. Its use for the treatment of addiction is usually strictly regulated. In the US, outpatient treatment programs must be certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA) in order to prescribe methadone for opioid addiction.
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Street methadone was ranked 4th in dependence, 5th in physical harm, and 5th in social harm.
On 29 November 2006, the U.S. Food and Drug Administration issued a Public Health Advisory about methadone titled “Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat”. The advisory said that “the FDA has received reports of death and life-threatening side effects in patients taking methadone. These deaths and life-threatening side effects have occurred in patients newly starting methadone for pain control and in patients who have switched to methadone after being treated for pain with other strong opioid pain relievers. Methadone can cause slow or shallow breathing and dangerous changes in heartbeat that may not be felt by the patient.” The advisory urged that physicians use caution when prescribing methadone to people who are not used to the drug and that people take the drug exactly as directed.
Adverse effects of methadone include:
Diarrhea or constipation
Perspiration and sweating
Dizziness or fainting
Chronic fatigue, sleepiness and exhaustion
Sleep problems such as drowsiness, trouble falling asleep (Insomnia), and trouble staying asleep
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
Swelling of the hands, arms, feet, and legs
Feeling restless or agitated
Mood changes, euphoria, disorientation
Nervousness or anxiety
Decreased libido, missed menstrual periods, difficulty in reaching orgasm, or impotence
Central sleep apnea
Tearing of the eyes
Mydriasis (dilated pupils)
Photophobia (sensitivity to light)
Hyperventilation syndrome (breathing that is too fast/deep)
Nausea, vomiting, and diarrhea
Tachycardia (fast heartbeat)
Aches and pains, often in the joints or legs
Elevated pain sensitivity
Blood pressure that is too high (hypertension, may cause stroke)
Cognitive symptoms
Susceptibility to cravings
Increased perception of odors (olfaction), real or imagined
Marked decrease or increase in sex drive
Methadone withdrawal symptoms are reported as being significantly more protracted than withdrawal from opioids with shorter half-lives.
Methadone is sometimes administered as an oral liquid. Methadone has been implicated in contributing to significant tooth decay. Methadone causes dry mouth, reducing the protective role of saliva in preventing decay. Other putative mechanisms of methadone-related tooth decay include craving for carbohydrates related to opioids, poor dental care, and general decrease in personal hygiene. These factors, combined with sedation, have been linked to the causation of extensive dental damage.
Most people who have overdosed on methadone may show some of the following symptoms:
Miosis (constricted pupils)
Hypoventilation (breathing that is too slow/shallow)
Drowsiness, sleepiness, disorientation, sedation, unresponsiveness
Skin that is cool, clammy (damp), and pale
Limp muscles, trouble staying awake, nausea
The respiratory depression of an overdose can be treated with naloxone. Naloxone is preferred to the newer, longer acting antagonist naltrexone. Despite methadone’s much longer duration of action compared to either heroin and other shorter-acting agonists, and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half-life, it is more difficult to titrate. If too large a dose of the opioid antagonist is given to a dependent person, 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 person’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 person will initially work to bring the person out of overdose, but once the naloxone wears off, if no further naloxone is administered, the person 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).
40 mg of methadone
Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany’s opium shortage problem. On September 11, 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany) and whose structure had only slight relation to morphine or the opiate alkaloids. (Bockmühl and Ehrhart, 1949[full citation needed]) It was brought to market in 1943 and was widely used by the German army during WWII.
In the 1930s, meperidine went into production in Germany; however, production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research. After the war, all German patents, trade names and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US. The report published by the committee noted that while methadone was potentially addictive, it produced less sedation and respiratory depression than morphine and was thus interesting as a commercial drug.
In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.
From this research came a generally non-controlled—or controlled for having the same precursors and effects of strong pure agonist agents of the open chain type, this one a phenaloxam derivative, levopropoxyphene with optical isomerism and one of which appeared to have no narcotic properties but was an antitussive which did have dissociative effects if misused; the isomer form which is removed from the racemic salts to yield dextromethorphan, or remove the other isomer to purify a dextropropoxyphene, or left in to finish with a racemic salts mixture dimethorphan. The open chain opioids tend to have at least one isomer that is at some level a strong pure mu opioid receptor agent.
Isomethadone, noracymethadol, LAAM, and normethadone were first developed in Germany, United Kingdom, Belgium, Austria, Canada, and the United States in the thirty or so years after the 1937 discovery of pethidine, the first synthetic opioid used in medicine, prolonging and increasing length and depth of satiating any opiate cravings and generating very strong analgesia (the long metabolic half-life and the strong receptor affinity at the mu opioid receptor sites, therefore imparting much of the satiating and anti-addictive effects of methadone) by means of suppressing drug cravings and the discovery in the early 1950s. of methadone’s antitussive properties first tested in dogs in Europe in 1952-1955 with different inert placebos, active placebos like codeine.
It was only in 1947 that the drug was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association. Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected each pharmaceutical company interested in the formula could buy the rights for the commercial production of methadone for just one dollar (MOLL 1990).
Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic under the trade name Dolophine, which is now registered to Roxane Laboratories. Since then, it has been best known for its use in treating opioid dependence. A great deal of anecdotal evidence was available “on the street” that methadone might prove effective in treating heroin withdrawal and is not uncommonly used in hospitals and other de-addiction centers to enhance rates of completed opioid withdrawal. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of people with drug addiction.
Methadone was first manufactured in the US by Eli Lilly, who obtained FDA approval on August 14, 1947, for their Dolophine 5 mg and 10 mg Tablets. Mallinckrodt Pharmaceuticals did not receive approval until December 15, 1947 to manufacture their bulk compounding powder. Mallinckrodt received approval for their branded generic, Methadose, on April 15, 1993 for their 5 mg and 10 mg Methadose Tablets. Mallinckrodt who also makes 5 mg, 10 mg and 40 mg generic tablets in addition to their branded generic Methadose received approval for their plain generic tablets on April 27, 2004.
The trade name Dolophine was created by Eli Lilly after World War II and used in the United States; the claim that Nazi leader Adolf Hitler ordered the manufacture of methadone or that the brand name ‘Dolophine’ was named after him is an urban legend. The pejorative term “adolphine” (never a widely used name for the drug) appeared in the United States in the early 1970s as a reference to the aforementioned urban myth that the trade name Dolophine was a reference to Adolf Hitler.