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Methadone

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Not to be confused with Methedrine, Methedrone, Mephedrone, or Methylone.
Methadone
Clinical data
Trade namesDolophine
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa682134
Pregnancy
category
Dependence
liability		Low
Routes of
administration		Oral, intravenous, insufflation, sublingual, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40-90% (oral)
MetabolismHepatic
Elimination half-life36-55 h [3]
ExcretionUrine, Test by specific gravity and bilirubin
Identifiers
  • (RS)-6-(Dimethylamino)-4,4-diphenylheptan-3-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.907 Edit this at Wikidata
Chemical and physical data
FormulaC21H27NO
Molar mass309.445 g/mol g·mol−1
3D model (JSmol)
  • CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c2ccccc2
  • InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3 checkY
  • Key:USSIQXCVUWKGNF-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Methadone (also known as Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon and many other names) is a synthetic opioid. It is used medically as an analgesic and a maintenance anti-addictive and reductive preparation for use by patients with opioid dependency. It was developed in Germany in 1937, mainly because Germany required a reliable internal source of opiates. Because it is an acyclic analog of morphine or heroin, methadone acts on the same opioid receptors as these drugs, and thus has many of the same effects. Methadone is also used in managing severe chronic pain, owing to its long duration of action, extremely powerful effects, and very low cost. Methadone was introduced into the United States in 1947 by Eli Lilly and Company.

Methadone is mainly used in the treatment of opioid dependence. It has cross-tolerance with other opioids including heroin and morphine, offering very similar effects and a longer duration of effect. Oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.

Methadone is approved for different indications in different countries. Common is approval as an analgesic and approval for the treatment of opioid dependence. It is not intended to reduce the use of non-opioid drugs such as methamphetamine, or alcohol.

A number of pharmaceutical companies produce and distribute methadone. The racemic hydrochloride is the only form available in most countries, such as the Netherlands, Belgium, France and in the United States, as of March 2008. The dextrorotary enantiomer of methadone, dextromethadone, is an NMDA antagonist rather than an opiate agonist. Therefore, methadone medications used for opiate addiction sometimes only contain levomethadone, the levorotary enantiomer. Levomethadone is available under the trade names Polamidone and Heptadon, among others. Covidien (formerly Mallinckrodt), is the major racemic methadone producer and sells bulk methadone to producers of generic preparations and distributes its own product in the form of tablets, dispersible tablets and oral concentrate under the brand name Methadose in the United States.[4]

Medical uses

The treatment of opiate addicted persons with Methadone will follow one of two routes.[citation needed] MMT (methadone maintenance therapy) is prescribed to individuals who wish to abstain from illicit drug use but have failed to maintain abstinence from opiates for significant periods. The duration of methadone maintenance can be for months or even years. Methadone reduction programmes are suitable for addicted persons who wish to stop using drugs altogether. The length of the reduction programme will depend on the starting dose and speed of reduction, this varies from clinic to clinic and person to person.[5][6] In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.[5] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. When used correctly, Methadone maintenance has been found to be medically safe and non-sedating.[5] It is also indicated for pregnant women addicted to opiates.[5]

In Russia, methadone treatment is illegal. Health officials there are not convinced of the treatment's efficacy. Instead, doctors encourage immediate cessation of drug use, rather than the gradual process that methadone substitution therapy entails. Patients are often given sedatives and non-opiate analgesics to cope with withdrawal symptoms.[7]

Dosage

Dosing considerations in an outpatient treatment program, where individuals carry a high degree of tolerance to opioids and are closely monitored with witnessed daily dosing, is a separate consideration from the patient with chronic pain requiring analgesia.[citation needed] The intermittent follow up of the pain patient, coupled with the relatively unforgiving nature of the drug (compared with other Long acting opioids), should generate caution in the patient and prescriber alike in an outpatient pain environment. A majority of patients in outpatient treatment programs require 80–125 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for opiate addiction.[5] Lower doses are sometimes not as effective, or do not provide an equivalent blockade effect as higher dosages can. Some patients will be prescribed as much as 325 mg of methadone a day;[8] though a dose as low as 30 mg can prove fatal in an opiate naive individual, or in individuals who lack cross-tolerance to other opioids.[citation needed].Patients prescribed Methadone for pain control, are likely to be given Methadone tablets, that come in the strength of 5 mg in the Uk. The usual dose for pain control is 1 or 2 tablets every 8 hours, which is considerably lower than the dose given in opioid dependency.[citation needed]

In the United States addiction 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.[citation needed] 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 30 mg and raise the dosage 5 mg a day until the patient reports feeling comfortable (e.g. free of withdrawal symptoms). Alternatively, the clinic may stop dosage at 80 mg, then allow the patient to move up by 5 mg or 10 mg every 2 or 3 days, until they are free from withdrawal symptoms and intense cravings. Once stabilized, patients may require periodic dose adjustments as their clinical or subjective tolerance changes.[citation needed]

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.[9][10]

Until recently a 100-mg/d dose was regarded as a 'glass ceiling,' rarely to be penetrated. In practice much lower thresholds were 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 tenfold 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.[11][12]

In the United States, federal law was changed in 2001 to eliminate some restrictions imposed on patients dosed on more than 100 mg per day.[citation needed]

Dosage reduction

After a patient has been on a maintenance programme for a period, they will be offered the opportunity to move over to a Methadone reduction programme. This is normally only started after the patient has been free from illicit drugs for a considerable amount of time and feel able or willing to attempt to go the whole way and to get completely free of substance use. Policies on dose reduction vary from clinic to clinic, from a focus on tapering the patient down to a low dose of Methadone so that they can be detoxified completely, to tapering the dose down to less than 10 mg so that they are able to abstain completely. Many methadone clinics will adjust doses upon personal evaluation of the correct care for the individual patient. A higher methadone dose may be considered preferable by a clinic treating patients addicted to illicit opioids, in order to discourage the use of illegal opioids. This can be due to the large increase in tolerance, a chemical blocking effect caused by methadone above certain doses, or by filling a psychological or physical need provided by illicit opioids.[13][14] A dose should be taken within the same time frame or close to it each day, not doing so will trick the body and not allow the dosage to be as potent as usual.

Visits to clinics

Methadone has traditionally been provided to people who are opiate dependent in a highly regulated methadone clinic, generally associated with an outpatient department of a hospital, though this varies country by country. For example in Australia, methadone maintenance treatment (MMT) is delivered by private pharmacies for a nominal fee to the client (regardless of the fact it is free as it is subsidized by the Federal government). This nominal fee covers the costs of providing the service, such as purchase and maintenance of supplies and equipment like dosing cups and precision measuring devices, supply costs involved in transporting a highly regulated drug from supplier to the pharmacy, extensive record-keeping as per government requirements, and compensation to the pharmacy staff for the time involved in preparing for and dosing a client (none of which are funded by the Federal government).

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" or "carries" after several months of adherence to the clinic's regulations, including consistent negative drug-screen results.[citation needed] The way that MMT is delivered in some countries creates barriers to scaling up access to the treatment. This can inhibit people's willingness to access treatment due to a lack of confidentiality and anonymity. In most well-designed pharmacies in Australia, however, dosing occurs in a discreet location away from other customers, and may even take place in a room specially designed for this purpose. 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 but states may allow as few as three), 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. A lot of patients report that this type of treatment is the only long term treatment option that has ever continued to be effective for them. A lot of mental issues that come from discontinuing the use of all types of opiates do not cease for years or more. The methadone programs, if correctly monitored, can help the patient get back to their life and be able to function without the constant cravings and insomnia reported after quitting opiates. Methadone can provide a method of stable treatment of the symptoms associated with withdrawal and mental anguish, and, with a proper slow taper, can be discontinued after the patient feels he or she is ready, often after a year or more, which gives the addict time to get away from old habits or triggers.[citation needed] However, patients who have been prescribed doses higher than 100 mg/d and have been in MMT for over a year reported withdrawal symptoms while attempting to taper off Methadone. Methadone is sometimes referred to as "liquid handcuffs," due to the fact that some patients cannot taper off Methadone without having withdrawal symptoms. This is an ethical concern for some since some patients may no longer have an opioid dependency, but subsequently have a chemical dependency on Methadone.

In the U.S., MMT patients generally receive psycho-social support (i.e. "counseling"), which is provided on site. Although laws vary, this is required in many states and countries regardless of whether a person needs or wants to engage in that kind of intervention (for example, recent changes in Taiwan). Patients are often required to attend 10 hours or more of therapy per week, having their daily dose withheld (thereby inducing withdrawal) for failure to comply. Methadone maintenance is rarely covered by private insurance and patients are encouraged to enroll in public welfare programs or face upwards of $500 USD per month. Although a supervised dose costs more than a take-home dose the risk of diversion means clinics/prescribers are often reluctant to provide take-home privileges.

In the UK, patients who are going abroad can be prescribed the required amount of medication upon provision of checkable proof of travel. When an individual is leaving the UK with an amount of Methadone that exceeds 500 mg, a Home Office Export License is required which should be arranged by the prescriber. This license allows the individual to export the licensed amount and import any remaining Methadone that has not yet been used. The granting of a license does not guarantee that the Methadone or person will be allowed entrance into the country of travel. Individuals who intend to undertake overseas travel should make contact with the embassy of the intended destination to arrange for the importation of the Methadone. Some countries do not allow the importation of controlled drugs and some countries only allow certain controlled drugs to be imported. Persons going overseas for an extended period of time should arrange for "courtesy dosing" arrangements to be put in place with a clinic at their destination.[15] In the UK, when a prescriber of Methadone uses form FP10 for the daily dispensing of the drug, the name of the allocated pharmacy that the user must go to is included. This is present so that if the prescription is lost in transit between prescriber and dispenser, it can be cancelled and also to allow the prescriber to cancel the prescription if the user has not attended scheduled appointments. Prior to this system being put in place, users could "double dose" if they were able to convince the prescriber to give them a new prescription to replace the one that they had "lost", by taking each prescription to a different pharmacy. Possession of Methadone without a valid prescription is an arrestable offense in the UK, as it is in most jurisdictions.

Cost

In Germany the annual cost per patient is less than 3000 euros, while heroin assisted treatment costs up to 10,000 euros per year.

Methadone clinics in the U.S. charge anywhere from $5–400 per week, which may be covered by private insurance or Medicaid.

MMT cost analysis often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.[16][17]

Analgesic

In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such 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 lesser compared to other opioids. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than shorter-acting drugs like morphine or hydrocodone. Another factor in the increased usage is the low cost of methadone.[18][19][20]

While the cost for pain patients varies based on many factors, leading to few specifics in the literature, one source[21] states that "in some cases monthly costs to patients for oral methadone can be more than 30-fold less than equianalgesic doses of other generic or brand-name opioid analgesics".

A week's supply will typically have a retail cost of $50–$100 in the United States,[citation needed] compared to hundreds of dollars for alternative opioids. Methadone, with its long half-life (and thus long duration of effect) and good oral bioavailability, is a common second-choice drug for pain that does not respond to weaker agonists. A major drawback is that unlike OxyContin (oxycodone continuous release), methadone is not technologically engineered for sustained release of the drug so blood concentrations will fluctuate greatly between dosing. This problem is overcome to a great extent by the practice of dosing methadone two or three times a day in pain patients. Some physicians also choose methadone for treating chronic pain in patients who are thought to have a propensity for addiction, because it causes less of an intoxicated or euphoric "high". The effect is of morphine-equivalent origin. The analgesic effect of Methadone has been known to mask the onset of malignant disease in patients undergoing treatment with Methadone, the disease only becoming apparent when the dose (and pain-killing effect) of Methadone is reduced. 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.[22] As with any strong medication that 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. When taken according to the prescribers instructions, Methadone is relatively safe, as the prescriber will have gradually built the dose up to avoid the danger of overdose. Deaths of persons receiving Methadone are normally attributable to other factors, such as alcohol or additional drug use on top of the prescribed Methadone. Other substances can reduce the metabolism of Methadone and 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 that methadone and other opioids may cause cardiac conduction problems (prolonged QTc interval[23][24]) although there are few documented cases of fatalities resulting from this side effect with methadone. The use of Amitriptyline alongside methadone has been shown to be particularly dangerous.[citation needed]

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 that family physicians can use to treat patients for pain. Despite the FDA directive, many doctors continue to prescribe Methadone as a pain killer, but only to patients which have shown to be responsible in their use of previous pain killers. One reason for use of Methadone is its advantages for opioid rotation.

Patients with long-term pain will sometimes have to perform so-called opioid rotation.[25] What this means is switching from one opioid to another, usually at intervals of between a few weeks, or more commonly, several months. Opioid rotation may allow a lower equivalent dose, and because of this less 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. So then it is time rotate again to another opioid. Such opioid rotation is standard practice for managing patients 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.[26] This means that Methadone can start at a low dose, and the time for the next switch will be longer.

Opioids may have fatigue as a major side effect depending on dosage and dependance, which can lead to the patient being in an almost half-awake state, in medical terms known as sedation. Many patients report that Methadone's sedation effect is often less pronounced than with other opioids and cite this as a major argument for preferring Methadone as an analgesic.[27] Persons receiving Methadone maintenance treatment (MMT) should not suffer from extreme sedation as a result of the treatment due to the fact that a properly prescribed person will have had their dose titrated up to the optimal level to remove the effects of withdrawal, but below a point at which sedation would be evident.

Other uses

Methadone linctus, which is prescribed in 1 mg/2.5ml strength is used where approved as a remedy for violent coughing. It is a potential new therapy for leukemia, especially in patients whose cancer no longer responds to chemotherapy and radiation.[28]

Adverse effects

Adverse effects of methadone include:[29][30][31][32][33]

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-naive individual. Chronic users often have high methadone and EDDP baseline values.[34]

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,[35] as well as a 2006 series in the Charleston (West Virginia) Gazette,[36] 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, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor in methadone-associated mortality."[37]

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."[38]

Driving

Methadone treatment may impair driving ability.[39] Drug abuse patients had significantly more involvement in serious crashes than non-abuse patients in a study by Queensland University. In the study of a group of 220 drug abuse patients, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other patients randomly selected having no involvement in fatal crashes.[40] However, there have been multiple studies verifying the ability of methadone maintenance patients to drive.[41] 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 licence will be issued for 12 months at a time and even then, only following a favourable assessment from their own doctor.[15] 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.

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).[42]

Withdrawal symptoms

Physical symptoms[citation needed]

Cognitive symptoms[citation needed]

Withdrawal symptoms are significantly more prolonged but also less intense than withdrawal from opiates with shorter half-lives.

When detoxing at a recommended rate (typically 1-2 mgs per week), withdrawal is either minimal or nonexistent, as the patient's body has time to adjust to each reduction in dose. However, like methadone, buprenorphine produces similar cognitive dehabilitation in multiple areas of mental function in both memory and timed choice task tests, which may persist after cessation of substitution treatment.

Pharmacology

Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6 and is a substrate for the P-Glycoprotein efflux protein in intestine and brain. The bioavailability and elimination half-life of methadone is subject to substantial inter-individual variability. Its main route of administration is oral. Adverse effects include hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opiates, spanning anywhere from two weeks to several months. It can also be found in urine samples six to ten weeks after the last dose.[citation needed][dubious – discuss] It was generally thought it left the system 2–3 days after last use but this is not the case,[citation needed][dubious – discuss] many factors contribute to how long it will stay in the system. It depends on an individual's body weight, metabolism, history of use/abuse and many more factors. In studies done on Methadone users going through detox, individuals experienced different withdrawal symptoms and withdrawal periods even though they received their last dose at the same time.[citation needed][dubious – discuss] When they gave blood and urine samples the methadone showed up in some individuals samples as much as four weeks after it was not evident in other individuals samples.[citation needed]

Mechanism of action

Ball-and-stick model of methadone

Levomethadone is a full µ-opioid agonist.[citation needed] dextromethadone does not affect opioid receptor but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) 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. The dextrorotary form (d-methadone) acts as an NMDA antagonist and is devoid of opioid activity: it has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[43]

Metabolism

Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100,[44][45] ranging from as few as 4 hours to as many as 130 hours,[46] or even 190 hours.[47] This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. 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. Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.[46] This can also allow lower total doses in some such patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.[citation needed]

The toxic effects of an overdose can be treated with naloxone.[29] 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 opioid antagonist is given to a dependent patient, 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 patient'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 patient will initially work to bring the patient out of overdose, but once the Naloxone wears off, if no further Naloxone is administered, the patient can go right back into overdose (based upon time and dosage of the Methadone ingested).

Route of administration

The most common route of administration at a methadone clinic is in a racemic oral solution, though in Germany, only the R enantiomer (the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects.[46] This 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 patient to drink. Drinkable forms include ready-to-dispense liquid, and "Disket" which is a tablet designed to disperse itself 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. In fact, injection of methadone does not result in a "rush" as with some other strong opioids such as morphine or hydromorphone, 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. Injecting Methadone pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects. Methadone pills often contain talc[48][49] 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.[50][51][52] Methadose/Methadone should not be injected either.[53] While it has been done in extremely diluted concentrations, instances of cardiac arrest have been reported as well as damaged veins from sugar and other ingredients (Sugar-Free syrups also should not be injected). Oral medication 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.[54]

Patient 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 into the tablets formulation to make the use of them by the IV route more difficult.[55]

History

40mg of Methadone

Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst (it is synthesised from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's opium shortage problem.[56] The reason for its swift abandonment as an alternative to morphine was due to the adverse effects it had on German soldiers during early trials. In contrast to morphine, which was used to alleviate pain in the injured but also to boost the esteem, stamina, and drive of German soldiers in combat, methadone had effects that have been described as such; "Dolophine (Methadone) had many adverse effects on the soldiers to whom it was given, leading to apathy, lethargy, and decreased willingness to engage in combat".

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).

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.

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 (COUNCIL...1947). 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 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 (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[citation needed], and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.

Methadone was first manufactured in the USA 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.[57]

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 trade name Dolophine was created by Eli Lilly. The pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s.[58][59] An urban legend claims Dolophine was named for Adolf Hitler.

Similar drugs

See also: Heroin-assisted Treatment and Buprenorphine

There are two methadone isomers that form the racemic mixture which is more common as it is cheaper to produce. The laevorotary isomer, which is isolated by several recrystalisations from racemic methadone, is more expensive to produce than the racemate. It is more potent at the opioid receptor than the racemic mixture and is marketed especially in continental Europe as an analgesic under the trade names Levo-Polamidone, Polamidone, Heptanone, Heptadone, Heptadon and others. It is used as the hydrochloride salt almost exclusively with some uncommon pharmaceuticals and research subjects consisting of the tartrate. The dextrorotary isomer d-methadone is not commercially available. It is devoid of opioid activity and it acts as an NMDA antagonist. It has been shown to be analgesic in experimental models of chronic pain. Clinical trials of d-methadone, to test its analgesic efficacy against neuropathic pain are in progress.

The closest chemical relative of methadone in clinical use is levo-α-acetylmethadol or LAAM. It has a longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994, it was approved as a narcotic addiction treatment. In the Netherlands, like methadone and all other strong opioids, LAAM is a List I drug of the Opium Law, and 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.

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 Netherlands, Switzerland, the UK and a few other European countries, however, not only buprenorphine and oral methadone but also injectable methadone and pharmaceutical 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. In the United Kingdom, diamorphine is used extremely selectively and is not available on prescription to addicts; except in specialist trials which involved no more than 300 participants. A study from Austria indicated that slow release oral morphine (in the form of MS-Contin), under trade names Substitol-Retard and Compensan, provide 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.[60] Since the late 1990s in Austria, slow release oral morphine has been used alongside methadone and buprenorphine for Opioid Substitution Therapy (OST) and more recently it has been approved in Slovenia and Bulgaria, and it has gained approval in other EU nations including the United Kingdom, although its use is not yet as widespread. The more attractive side-effect profile of morphine compared to buprenorphine or methadone has led to the adoption of morphine as an option for OST treatment, and currently in Vienna over 60 percent of substitution therapy utilizes slow release oral morphine. Illicit diversion has been a problem, but to the many proponents of the utilization of morphine for OST, the benefits far outweigh the costs, taking into account the much higher percentage of addicts who are "held" or, from another perspective, satisfied by this treatment option, as opposed to methadone and buprenorphine treated addicts, who are more likely to forgo their treatment and revert to using heroin etc., in many cases by selling their methadone or buprenorphine prescriptions to afford their opiate of choice. Driving impairment tests done in the Netherlands that have shown morphine to have the least negative effects on cognitive ability on a number of mental tasks also suggest morphines use in OST may allow for better psychological functioning and engagement in society. Other opiates such as dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.[61]

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 but considerably more effective as analgesics. In the 1980s and beginning of the 1990s, before pharmaceutical grade IV heroin treatment became available to heroin addicts, as either single drug replacement for street heroin, or to be used alongside prescribed methadone, oral dextromoramide was prescribed to heroin addicts instead, because even when taken orally it still produces a strong, so called "rush", without the need of IV administration and any of the risks involved with it. 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. Different nations within the EU have different regulations, and in some nations general practitioners have the legal right to maintain addicts with whatever they deem to be most efficacious in maintaining their health and well being.

Notes

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Additional references

  • Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 1362. ISBN 1437727883. {{cite book}}: Invalid |ref=harv (help)

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