Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic
opioid agonist used for chronic pain and also for
opioid dependence.
It is used to treat chronic pain, and it is also used to treat addiction to
heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Detoxification using methadone can be accomplished in less than a month, or it may be done gradually over as long as six months.
While a single dose has a rapid effect, maximum effect can take up to five days of use.
The pain-relieving 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
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenate ...
.
[
Side effects are similar to those of other opioids.][ These frequently include dizziness, sleepiness, vomiting, and sweating.][ Serious risks include ]opioid abuse
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. O ...
and respiratory depression
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide ( hypercapn ...
.[ Abnormal heart rhythms may also occur due to a prolonged QT interval.][ The number of deaths in the United States involving methadone poisoning declined from 4,418 in 2011 to 3,300 in 2015. Risks are greater with higher doses. Methadone is made by ]chemical synthesis
As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In mo ...
and acts on opioid receptors
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatosta ...
.[
Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl. It was approved for use as an analgesic in the United States in 1947, and has been used in the treatment of addiction since the 1960s.][ It is on the ]World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
.
Medical uses
Opioid addiction
Methadone is used for the treatment of opioid use disorder
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. O ...
.
It may be used as maintenance therapy or in shorter periods for detoxification to manage opioid withdrawal symptoms. 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
The Substance Abuse and Mental Health Services Administration (SAMHSA; pronounced ) is a branch of the U.S. Department of Health and Human Services. It is charged with improving the quality and availability of treatment and rehabilitative services ...
(SAMHSA) and registered by the Drug Enforcement Administration
The Drug Enforcement Administration (DEA; ) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within th ...
(DEA) in order to prescribe methadone for opioid addiction.
A 2009 Cochrane review found methadone was effective in retaining people in treatment and in the reduction or cessation of heroin use as measured by self-report and urine/hair analysis, and did not affect criminal activity or risk of death.
Treatment of opioid-dependent persons with methadone follows one of two routes: maintenance or detoxification. Methadone maintenance therapy (MMT) usually takes place in outpatient settings. It is usually prescribed as a single daily dose medication for those who wish to abstain from illicit opioid use. Treatment models for MMT differ. It is not uncommon for treatment recipients to be administered methadone in a specialist clinic, where they are observed for around 15–20 minutes post-dosing, to reduce the risk of diversion of medication.
The duration of methadone treatment programs range from a few months to years. Given opioid dependence is characteristically a chronic relapsing/remitting disorder, MMT may be lifelong. The length of time a person remains in treatment depends on a number of factors. While starting doses may be adjusted based on the amount of opioids reportedly used, most clinical guidelines suggest doses start low (e.g. at doses not exceeding 40 mg daily) and are incremented gradually. It has been found that doses of 40 mg per day were sufficient to help control the withdrawal symptoms but not enough to curb the cravings for the drug. Doses of 80 to 100 mg per day have shown higher rates of success in patients and less illicit heroin use during the maintenance therapy. However, higher doses do put a patient more at risk for overdose than a moderately low dose (e.g. 20 mg/day).
Methadone maintenance has been shown to reduce the transmission of bloodborne viruses associated with opioid injection, such as hepatitis B and C, and/or HIV. The principal goals of methadone maintenance are to relieve opioid cravings, suppress the abstinence syndrome, and block the euphoric effects associated with opioids.
Chronic methadone dosing will eventually lead to neuroadaptation, characterised by a syndrome of tolerance and withdrawal (dependence). However, when used correctly in treatment, maintenance therapy has been found to be medically safe, non-sedating, and can provide a slow recovery from opioid addiction. Methadone has been widely used for pregnant women addicted to opioids.
Pain
Methadone is used as an analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
in chronic pain, often in rotation with other opioids. Due to its activity at the NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
, it may be more effective against neuropathic pain
Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli ( allodynia). It may have continuo ...
; for the same reason, tolerance to the analgesic effects may be less than that of other opioids.
Adverse effects
Adverse effects of methadone include:
* Sedation
* Constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel moveme ...
[
* Flushing][
* Perspiration][
* Heat intolerance
* Dizziness][ or fainting][
* Weakness][
* Chronic fatigue, sleepiness][ and exhaustion
* Sleep problems such as drowsiness,][
*]Insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...
*
* Dry mouth
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side e ...
[
* ]Nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
[ and ]vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
[
* Low blood pressure
* ]Headache
Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a resul ...
* 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[
* weight gain][
* Memory loss
* Itching
* Difficulty urinating][
* Swelling of the hands, arms, feet, and legs][
* Mood changes,][ euphoria, disorientation
* ]Blurred vision
Blurred vision is an ocular symptom where vision becomes less precise and there is added difficulty to resolve fine details.
Temporary blurred vision may involve dry eyes, eye infections, alcohol poisoning, hypoglycemia, or low blood pressu ...
[
* Decreased ]libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act ...
,[ difficulty in reaching ]orgasm
Orgasm (from Greek , ; "excitement, swelling") or sexual climax is the sudden discharge of accumulated sexual excitement during the sexual response cycle, resulting in rhythmic, involuntary muscular contractions in the pelvic region charact ...
,[ or impotence][
* Missed menstrual periods,][
* ]Skin rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...
* Central sleep apnea
Withdrawal symptoms
Physical symptoms
* Lightheadedness
* Tearing of the eyes[
* ]Mydriasis
Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs.
Normally, a ...
(dilated pupils)[
* ]Photophobia
Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
(sensitivity to light)
* Hyperventilation syndrome
Hyperventilation syndrome (HVS), also known as chronic hyperventilation syndrome (CHVS), dysfunctional breathing hyperventilation syndrome, cryptotetany, spasmophilia, latent tetany, and central neuronal hyper excitability syndrome (NHS), is a re ...
(breathing that is too fast/deep)
* Runny nose[
* Yawning
* Sneezing][
* ]Nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,[ vomiting,][ and ]diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin ...
[
* ]Fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
[
* ]Sweating
Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals.
Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distri ...
[
* Chills][
* Tremors][
* Akathisia (restlessness)
* ]Tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...
(fast heartbeat)[
* Aches][ and pains, often in the joints or legs
* Elevated pain sensitivity
* Blood pressure that is too high ( hypertension, may cause a stroke)
Cognitive symptoms
* ]Suicidal ideation
Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
* Susceptibility to cravings[
* Depression][
* Spontaneous ]orgasm
Orgasm (from Greek , ; "excitement, swelling") or sexual climax is the sudden discharge of accumulated sexual excitement during the sexual response cycle, resulting in rhythmic, involuntary muscular contractions in the pelvic region charact ...
* Prolonged insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...
* Delirium
Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
* Auditory hallucinations
* Visual hallucinations
* Increased perception of odors ( olfaction), real or imagined
* Marked increase in sex drive
* Agitation
* Anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil
Turmoil may refer to:
* ''Turmoil'' (1984 video game), a 1984 video game released by Bug-Byte
* ''Turmoil'' (2016 video game), a 2016 indie oil tycoon video ...
[
* ]Panic disorder
Panic disorder is a mental and behavioral disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, ...
* Nervousness[
* Paranoia
* Delusions
* ]Apathy
Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic individual has an absence of inter ...
* Anorexia (symptom)
Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
Methadone withdrawal symptoms are reported as being significantly more protracted than withdrawal from opioids with shorter half-lives.
When used for opioid maintenance therapy, Methadone is generally administered as an oral liquid. Methadone has been implicated in contributing to significant tooth decay. Methadone causes dry mouth
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side e ...
, 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.
Black box warning
Methadone has the following US FDA black box warning:
* Risk of addiction and abuse
* Potentially fatal respiratory depression
* Lethal overdose in accidental ingestion
* QT prolongation
* Neonatal opioid withdrawal syndrome in children of pregnant women
* CYP450 drug interactions
* Risks when used with benzodiazepines and other CNS depressants, including alcohol.
* A certified opioid treatment program is required under federal law (42 CFR 8.12) when dispensing methadone for the treatment of opioid addiction or detoxification.
Overdose
Most people who overdose on methadone show some of the following symptoms:
* (constricted pupils)
* Vomiting
* Spasms of the stomach and intestines
* Hypoventilation (breathing that is too slow/shallow)[
* ]Drowsiness
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asle ...
,[ sleepiness, disorientation, sedation, unresponsiveness
* Skin that is cool, clammy (damp), and pale][
*Blue fingernails and lips
* Limp muscles,][ trouble staying awake, nausea
* ]Unconsciousness
Unconsciousness is a state in which a living individual exhibits a complete, or near-complete, inability to maintain an awareness of self and environment or to respond to any human or environmental stimulus. Unconsciousness may occur as the r ...
[ and ]coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
[
The respiratory depression of an overdose can be treated with ]naloxone
Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...
. Naloxone is preferred to the newer, longer-acting antagonist naltrexone
Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found to ...
. 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). Methadone fills the same opioid receptors in the brain as heroin and other prescription painkillers making it a suitable substitute.
Driving
Methadone treatment may impair driving ability. Drug abusers had significantly more involvement in serious crashes than non-abusers in a study by the University of Queensland. In the study of a group of 220 drug abusers, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other people 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 license 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.
Mortality
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 Gazette'' (West Virginia),["The Killer Cure"](_blank)
''The Charleston Gazette'' 2006 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
The Substance Abuse and Mental Health Services Administration (SAMHSA; pronounced ) is a branch of the U.S. Department of Health and Human Services. It is charged with improving the quality and availability of treatment and rehabilitative services ...
, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remains incomplete, National Assessment meeting participants concurred that methadone tablets or Diskets® distributed through channels other than opioid treatment programs most likely are the central factors 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."
Pharmacology
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
, an ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
Func ...
, CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
, and is a substrate
Substrate may refer to:
Physical layers
*Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
** Substrate (locomotion), the surface over which an organism lo ...
, or in this case target, for the P-glycoprotein efflux protein, a protein which helps pump foreign substances out of cells, in the intestine
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...
s and brain
The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...
. The bioavailability and elimination half-life of methadone are subject to substantial interindividual variability. Its main route of administration
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
is oral. Adverse effects include sedation, hypoventilation, constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel moveme ...
and , in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opioids, spanning anywhere from two weeks to several months.
The metabolic half-life of methadone differs from its duration of action. The metabolic half-life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours in opioid-naive people), as opposed to a half-life of 1 to 5 hours for morphine. The length of the half-life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.[
]
Mechanism of action
Levomethadone
Levomethadone, sold under the brand name L-Polamidon among others, is a synthetic opioid analgesic and antitussive which is marketed in Europe and is used for pain management and in opioid maintenance therapy. In addition to being used as a ph ...
(the ''L'' enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity. Dextromethadone
Esmethadone (; developmental code name REL-1017), also known as dextromethadone, is the (''S'')-enantiomer of methadone. It acts as an ''N''-methyl-D-aspartate receptor (NMDAR) antagonist, among other actions. Unlike levomethadone, it has low a ...
(the ''S'' enantiomer) has lower affinity to the μ-opioid receptor than Levomethadone. Both enantiomers bind to the glutamatergic NMDA (''N''-methyl--aspartate) receptor, acting as noncompetitive antagonists. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. NMDA antagonists such as dextromethorphan, ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...
, tiletamine 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 also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.
Metabolism
Methadone has a slow metabolism and very high fat solubility
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves ...
, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
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 cytochrome enzymes CYP3A4, CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
Func ...
and CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
. 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. People 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 people. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day normally dividing daily dosage for administration at 8 hour intervals.
The main metabolic pathway involves ''N''-demethylation by CYP3A4 in the liver and intestine to give 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).[ This inactive product, as well as the inactive 2-ethyl-5-methyl-3,3-
diphenyl-1-pyrroline (EMDP), produced by a second ''N''-demethylation, are detectable in the urine of those taking methadone.
File:Methadone.svg, Methadone
File:EDDP.png, EDDP
File:EDMP.png, EDMP
]
Route of administration
The most common route of administration
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
at a methadone clinic is in a racemic oral solution, though in Germany, only the ''R'' enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
(the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects. The single-isomer form 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 person to drink. Drinkable forms include ready-to-dispense liquid (sold in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., federal district, five ma ...
as Methadose), and Diskets (known on the street as "wafers" or "biscuits") tablets which are dispersible 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. Oral medication is usually preferable because it 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.[Code of Federal Regulations, Title 42, Sec 8.] 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. The formulation sold under the brand name Methadose (flavored liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either.
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 in the tablet formulation to make the use of them by the IV route more difficult.
Chemistry
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-naïve individual. Chronic users often have high methadone and EDDP baseline values.
Conformation
The protonated form of methadone takes on an extended conformation, while the free base is more compact. In particular, it was found that there is an interaction between the tertiary amine and the carbonyl carbon of the ketone function (R3N ••• >C=O) that limits the molecule's conformation freedom, though the distance (291 pm by X-ray) is far too long to represent a true chemical bond. However, it does represent the initial trajectory of attack of an amine on a carbonyl group and was an important piece of experimental evidence for the proposal of the Bürgi–Dunitz angle for carbonyl addition reactions.
History
Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG
Interessengemeinschaft Farbenindustrie AG (), commonly known as IG Farben (German for 'IG Dyestuffs'), was a German chemical and pharmaceutical conglomerate. Formed in 1925 from a merger of six chemical companies—BASF, Bayer, Hoechst, Agfa, ...
at the Farbwerke Hoechst
Hoechst AG () was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999. With the new company's 2004 merger with Sanofi-Synthélabo, it became a subsidiary of ...
who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's opium
Opium (or poppy tears, scientific name: ''Lachryma papaveris'') is dried latex obtained from the seed capsules of the opium poppy '' Papaver somniferum''. Approximately 12 percent of opium is made up of the analgesic alkaloid morphine, which ...
and morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. Ther ...
shortage problem. On 11 September 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 little relation to morphine or other "true opiates” such as diamorphine (Heroin), desomorphine
Desomorphine is a semi-synthetic opioid commercialized by Roche, with powerful, fast-acting effects, such as sedation and analgesia. It was first discovered and patented by a German team working for Knoll in 1920 but was not generally recogni ...
(Permonid), nicomorphine (Vilan), codeine, dihydrocodeine
Dihydrocodeine is a semi-synthetic opioid analgesic prescribed for pain or severe dyspnea, or as an antitussive, either alone or compounded with paracetamol (acetaminophen) (as in co-dydramol) or aspirin. It was developed in Germany in 1908 ...
, oxymorphone
Oxymorphone (sold under the brand names Numorphan and Opana among others) is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes, after oral administration it beg ...
(Opana), hydromorphone
Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by m ...
(Dilaudid), oxycodone
Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...
(OxyContin), hydrocodone
Hydrocodone, also known as dihydrocodeinone, is an opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe en ...
(Dicodid), and other closely related opium alkaloid derivatives and analogues. It was brought to market in 1943 and was widely used by the German army during WWII as a substitute for morphine.[
In the 1930s, ]pethidine
Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Ei ...
(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 itself was potentially addictive, it produced “considerably” less ]euphoria
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and dan ...
, sedation, and respiratory depression than morphine at equianalgesic doses and was thus interesting as a commercial drug. The same report also compared methadone to pethidine. German researchers reported that methadone was capable of producing strong morphine-like physical dependence, which is characterized by opioid withdrawal symptoms which are lesser in severity and intensity compared to morphine, but methadone was associated with a considerably prolonged or protracted withdrawal syndrome when compared to morphine.[ Morphine produced higher rates of self-administration and reinforcing behaviour in both human and animal subjects when compared to both methadone and pethidine. In comparison to equianalgesic doses of pethidine (Demerol), methadone was shown to produce less euphoria, but higher rates of constipation, and roughly equal levels of respiratory depression and sedation.][
In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.]
Isomethadone
Isomethadone (INN, BAN; trade nameLiden; also known as isoamidone) is a synthetic opioid analgesic and antitussive related to methadone that was used formerly as a pharmaceutical drug but is now no longer marketed. Isomethadone was used as bo ...
, noracymethadol, LAAM, and normethadone
Normethadone (International Nonproprietary Name, INN, British Approved Name, BAN; brand names Cophylac, Dacartil, Eucopon, Mepidon, Noramidone, Normedon, and others), also known as desmethylmethadone or phenyldimazone, is a Chemical synthesis, sy ...
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. These synthetic opioids have increased length and depth of satiating any opiate cravings and generate very strong analgesic effects due to their long metabolic half-life and strong receptor affinity at the mu-opioid receptor sites. Therefore, they impart much of the satiating and anti-addictive effects of methadone by means of suppressing drug cravings.
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
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colon ...
as an analgesic under the trade name Dolophine.[ An urban myth later arose that ]Nazi
Nazism ( ; german: Nazismus), the common name in English for National Socialism (german: Nationalsozialismus, ), is the far-right politics, far-right Totalitarianism, totalitarian political ideology and practices associated with Adolf Hit ...
leader Adolf Hitler
Adolf Hitler (; 20 April 188930 April 1945) was an Austrian-born German politician who was dictator of Nazi Germany, Germany from 1933 until Death of Adolf Hitler, his death in 1945. Adolf Hitler's rise to power, He rose to power as the le ...
ordered the manufacture of methadone or that the brand name 'Dolophine' was named after him, probably based on the similarity of “doloph” with “Adolph”. (The pejorative term “adolphine” would appear in the early 1970s.) However, the name “Dolophine” was a contraction of "Dolo” from the Latin word ''dolor'' (pain), and ''finis'', the Latin word for “end”. Therefore, Dolophine literally means “pain end”.
Methadone was studied as a treatment for opioid addiction at the Addiction Research Center of the Narcotics Farm in Lexington, Kentucky in the 1950s, and by Rockefeller University physicians Robert Dole and Marie Nyswander in the 1960s in New York City. By 1976, methadone clinics had opened in cities including Chicago, New York, and New Haven, with some 38,000 patients treated in New York City alone.
Society and culture
Brand names
Brand names include Dolophine, Symoron, Amidone, Methadose, Physeptone, Metadon, Metadol, Metadol-D, Heptanon and Heptadon among others.
Cost
In the US, generic methadone tablets are inexpensive, with retail prices ranging from $0.25 to $2.50 per defined daily dose. Brand-name methadone tablets may cost much more.
Methadone maintenance clinics in the US may be covered by private insurances, Medicaid
Medicaid in the United States is a federal and state program that helps with healthcare
Health care or healthcare is the improvement of health via the prevention, diagnosis, treatment, amelioration or cure of disease, illness, injury, and ...
, or Medicare. Medicare covers methadone under the prescription drug benefit, Medicare Part D, when it is prescribed for pain, but not when it is used for opioid dependence treatment because it cannot be dispensed in a retail pharmacy for this purpose. In California methadone maintenance treatment is covered under the medical benefit. Patients' eligibility for methadone maintenance treatment is most often contingent on them being enrolled in substance abuse counseling. People on methadone maintenance in the US either have to pay cash or if covered by insurance must complete a pre-determined number of hours per month in therapeutic groups or counseling. The United States Department of Veteran's Affairs (VA) Alcohol and Drug Dependence Rehabilitation Program offers methadone services to eligible veterans enrolled in the VA health care system.
Methadone maintenance treatment
Methadone maintenance treatment is the use of the medicine methadone, administered on an ongoing basis, as treatment for dependence on heroin or other opioids. Methadone is an opioid agonist, binding to the same receptors in the brain as heroin ...
(MMT) cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use. A preliminary cost analysis conducted in 2016 by the US Department of Defense determined that methadone treatment, which includes psychosocial and support services, may cost an average of $126.00 per week or $6,552.00 per year. The average cost for one full year of methadone maintenance treatment is approximately $4,700 per patient, whereas one full year of imprisonment costs approximately $24,000 per person.
Controversy
Methadone substitution as a treatment of opioid addiction has been criticized in the social sciences for its role in the social control of addicts. 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 labeled as a "treatment" and so achieves the disciplinary objectives of managing the "undesirables". 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.[Bergschmidt V (2004) 'Pleasure, Power, and Dangerous Substances: Applying Foucault to the study of "Heroin Dependence" in Germany' Anthropology and Medicine Vol. 11 (1) pp. 59–73]
Regulation
United States and Canada
Methadone is a Schedule I Schedule 1 may refer to:
* Schedule I Controlled Substances within the US Controlled Substances Act
* Schedule I Controlled Drugs and Substances within the Canadian Controlled Drugs and Substances Act
* Schedule I Psychotropic Substances within th ...
controlled substance in Canada and Schedule II in the United States, with an ACSCN of 9250 and a 2014 annual aggregate manufacturing quota of 31,875 kilos for sale. Methadone intermediate
Methadone intermediate is a methadone precursor scheduled by UN Single Convention on Narcotic Drugs. It is a Schedule II Narcotic controlled substance in the United States and has an ACSCN of 9254. The 2014 annual manufacturing quota was ...
is also controlled, under ACSCN 9226 also under Schedule II, with a quota of 38,875 kilos. In most countries of the world, methadone is similarly restricted. The salts of methadone in use are the hydrobromide (free base conversion ratio 0.793), hydrochloride (0.894), and HCl monohydrate (0.850). Methadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.
Methadone clinics
In the United States, prescription of methadone requires intensive monitoring and must be obtained in-person from an opioid treatment program—colloquially known as a 'methadone clinic'—when prescribed for opioid use disorder
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. O ...
(OUD). According to federal laws, methadone cannot be prescribed by a doctor and obtained from a pharmacy in order to treat addiction. Because of its long half-life, methadone is almost invariably prescribed to be taken in a single daily dose. At nearly all methadone clinics in the US, patients must visit a clinic to receive and take their dose under the supervision of a nurse. Both patients who are new to methadone treatment and high-risk patients—such as those who are using drugs and alcohol, including cannabis—must visit the clinic daily. However, some clinics close on national holidays and provide doses to patients to take home.
'Take-home' or 'take-away' methadone
After 90 days to six months (depending on the clinic), if patients have met the clinic's criteria, they are typically eligible for take-home doses of methadone. Therefore, they may be allowed to take anywhere from one to six days to visit the clinic once or twice weekly instead of every day. In accordance with DEA and SAMHSA regulations, patients who use other drugs may not eligible for take-home methadone.
In recent years, patients, doctors, nurses, those working in the addiction field, and advocates of many kinds have heavily criticized the extremely tight regulations regarding take-home methadone. Advocates for reforming methadone regulations argue that methadone could be much more effective if it was not necessary for patients to visit clinics daily. Many addicts seeking treatment usually avoid methadone or see it as a last resort, specifically because they do not want to have to go to a clinic every day to receive their medication.
Other countries
In Russia
Russia (, , ), or the Russian Federation, is a transcontinental country spanning Eastern Europe and Northern Asia. It is the largest country in the world, with its internationally recognised territory covering , and encompassing one-eigh ...
, methadone treatment is illegal. In 2008, Chief Sanitary Inspector of Russia Gennadiy Onishchenko
Gennadiy Grigoryevich Onishchenko (russian: Геннадий Григорьевич Онищенко, born 20 November 1950) is a Russian government official who was the Chief Sanitary Inspector of Russia from 1996 to 2013.
Early life
Gennad ...
, claimed that Russian health officials are not convinced of the methadone's efficacy in treating heroin and/or opioid addicts. Instead of replacement therapy and gradual reduction of illicit drug abuse, Russian doctors encourage immediate cessation and withdrawal. Addicts are generally given sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...
s and non-opioid analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
s in order to cope with withdrawal symptoms. Brazilian footballer assistant Robson Oliveira was arrested in 2019 upon arriving in Russia with methadone tablets sold legally in other countries for what was considered drug trafficking
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
under Russian law.
As of 2015 China had the largest methadone maintenance treatment program with over 250,000 people in over 650 clinics in 27 provinces.
References
External links
*
Methadone
Substance Abuse and Mental Health Services Administration, U.S. Department of Health and Human Services
Tapering off of methadone maintenance
*
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