Methadone drug

Methadone

Methadone – © Fred Shakeshaft

Methadone, sold under the brand names Dolophine among others, is an opioid used to treat pain and as maintenance therapy or to help with detoxification in people with opioid dependence.^[3] Detoxification using methadone can either be done relatively rapidly in less than a month or gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take five days of use. The effects last about six hours after a single dose and a day and a half after long-term use in people with normal liver function. Methadone is be taken by mouth and rarely by injection into a muscle or vein.^[3]

Side effects are similar to those of other opioids. Commonly these include dizziness, sleepiness, vomiting, and sweating. Serious risks include opioid abuse or a decreased effort to breathe. Heart arrhythmia may also occur including prolonged QT.^[3] The number of deaths in the United States involving methadone poisoning was 4,418 in 2011, which was 26% of total deaths from opioid poisoning.^[4] Risks are greater with higher doses.^[5] Methadone is made by chemical synthesis and acts onopioid receptors.^[3]

Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl.^[6][7] It was approved for use in the United States in 1947.^[3]Methadone is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.^[8] Globally in 2013, about 41,400 kilograms were manufactured.^[9] It is regulated similarly to other narcotic drugs.^[10] In the United States it is not very expensive.^[11]

Medical uses[edit]

Methadone maintenance[edit]

Methadone is indicated for the maintenance treatment of opioid dependency (i.e. opioid use disorder per the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM)). A 2009 Cochrane review found that methadone was effective in retaining people in treatment and in the suppression of heroin use as measured by self-report and urine/hair analysis but did not affect criminal activity or risk of death.^[12]

The treatment of opiate-dependent 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 ranges from a few months to lifetime maintenance. Methadone reduction programs are suitable for addicted persons who wish to stop using drugs altogether. The length of the reduction program will depend on the starting dose and speed of reduction, this varies from clinic to clinic and from person to person.^[13][14] 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.^[13] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates, however methadone abuse can cause the very opposite of what its original intention is. When used correctly, methadone maintenance has been found to be medically safe and non-sedating, and provide a slow recovery from opiate addiction^[13] It is also indicated for pregnant women addicted to opiates.^[13]

In Russia, methadone treatment is illegal. Gennadiy Onishchenko, Chief Sanitary Inspector, claimed in 2008 that health officials 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.^[15]

Pain[edit]

In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an analgesic in chronic pain. Methadone is a very effective pain medication. 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.^[16][17]

On 29 November 2006, the U.S. Food and Drug Administration issued a Public Health Advisory about methadone titled "Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat". The advisory 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.^[18]

Patients with long-term pain will sometimes have to perform so-called opioid rotation.^[19] 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 hence fewer side effects may be encountered to achieve the desired effect. Then, over time, tolerance increases with the new opioid, requiring higher doses. This in turn increases the possibility of adverse reactions and toxicity. So then it is time to 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.^[20] This means that methadone can start at a comparatively lower dose than other opiates, and the time for the next switch will be longer.

Opioid detoxification[edit]

Methadone is also approved in the US for detoxification treatment of opioid addiction; however, its use in this regard must follow strict federal regulations. Outpatient treatment programs must be certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA) in order to prescribe methadone for opioid detoxification.

Adverse effects[edit]

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Street methadone was ranked 4th in dependence, 5th in physical harm, and 5th in social harm.^[21]

Adverse effects of methadone include:^{[citation needed]}

·         Sedation

·         Diarrhea^[22] or constipation^[22][23]

·         Flushing^[23]

·         Perspiration^[23] and sweating^[23]

·         Heat intolerance

·         Dizziness^[22][24][25] or fainting^[22][24][25]

·         Weakness^[23]

·         Chronic fatigue, sleepiness^[23] and exhaustion

·         Sleep problems such as drowsiness,^[22] trouble falling asleep (Insomnia),^[23][24] and trouble staying asleep^[23]

·         Constricted pupils

·         Dry mouth^[22][23]

·         Nausea^[22][23] and vomiting^[22][23]

·         Low blood pressure

·         Hallucinations^[22][24] or confusion^[22][24]

·         Headache^[23]

·         Heart problems such as chest pain^[22][24] or fast/pounding heartbeat^[22][24][25]

·         Abnormal heart rhythms^[25][26]

·         Respiratory problems such as trouble breathing,^[22][24] slow or shallow breathing (hypoventilation),^[22][24] light-headedness,^[22][24][25] or fainting^[22][24]

·         Loss of appetite,^[22][23] and in extreme cases Anorexia

·         Weight gain^[23]

·         Memory loss

·         Stomach pains^[23]

·         Itching

·         Difficulty urinating^[23]

·         Swelling of the hands, arms, feet, and legs^[23]

·         Feeling restless^[22] or agitated

·         Mood changes^[23] Euphoria, disorientation

·         Nervousness^[22] or anxiety^[22][24]

·         Blurred vision^[23]

·         Decreased libido,^[22][23] missed menstrual periods,^[23] difficulty in reaching orgasm,^[22] and impotence^[22][23]

·         Skin rash

·         Seizures

·         Central sleep apnea

Withdrawal symptoms[edit]

Physical symptoms^{[citation needed]}

·         Lightheadedness^[27]

·         Tearing of the eyes^[27][28]

·         Mydriasis (dilated pupils)^[27]

·         Photophobia (sensitivity to light)

·         Hyperventilation syndrome (breathing that is too fast/deep)

·         Runny nose^[28]

·         Yawning

·         Sneezing^[28]

·         Nausea,^[27][28] vomiting,^[27][28] and diarrhea^[27]

·         Fever^[28]

·         Sweating^[27]

·         Chills^[28]

·         Tremors^[27][28]

·         Akathisia (restlessness)

·         Tachycardia (fast heartbeat)^[28]

·         Aches^[27] and pains, often in the joints and/or legs

·         Elevated pain sensitivity

·         Blood pressure that is too high (hypertension, may cause stroke)

Cognitive symptoms^{[citation needed]}

·         Suicidal ideation

·         Susceptibility to cravings^[27]

·         Depression^[27]

·         Spontaneous orgasm

·         Prolonged insomnia

·         Delirium

·         Auditory hallucinations

·         Visual hallucinations

·         Increased perception of odors (olfaction), real or imagined

·         Marked decrease or increase in sex drive

·         Agitation

·         Anxiety^[27]

·         Panic disorder

·         Nervousness^[27]

·         Paranoia

·         Delusions

·         Apathy

·         Anorexia (symptom)

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 mg per week), withdrawal is either minimal or nonexistent, as the patient's body has time to adjust to each reduction in dose.

Methadone is sometimes administered in an oral form of sugary syrup. This preparation has been proposed to cause significant tooth decay. Methadone causes dry mouth, reducing the protective role of saliva in preventing decay. It known that most opiates increase craving for carbohydrates. General decrease in personal hygiene due to these factors combined with sedation have been noted to cause extensive damage to the teeth.^[29][30]

Overdose[edit]

Most people who have overdosed on methadone may show some of the following symptoms:

·         Miosis (constricted pupils)^[31]

·         Hypoventilation (breathing that is too slow/shallow)^[31]

·         Drowsiness^[31] Sleepiness, disorientation, sedation, unresponsiveness

·         Skin that is cool, clammy, and pale^[31]

·         Limp muscles,^[31] trouble staying awake, nausea.

·         Unconsciousness^[31] and coma^[31]

·         Excessive vomiting

The respiratory depression of an overdose can be treated with naloxone.^[28] 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).

History[edit]

40mg of Methadone

Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's opium shortage problem.^[61][62] On September 11, 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany) and whose structure had only slight relation to morphine or the opiate alkaloids. Bockmühl and Ehrhart, 1949^{[full citation needed]} It brought to market in 1943 and was widely used by the German army during WWII.^[61]

In the 1930s, meperidine went into production in Germany; however, production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research.^[63] 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.^[61] The report published by the committee noted that while methadone was potentially addictive, it produced less sedation and respiratory depression than morphine and was thus interesting as a commercial drug.^[61]

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 commercial production of methadone for just one dollar (MOLL 1990).

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic under the trade name Dolophine,^[61] which is now registered to Roxane Laboratories. Since then, it has been best known for its use in treating opioid dependence. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and is not uncommonly used in hospitals and other de-addiction centers to enhance rates of completed opioid withdrawal. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful,^{[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.^[64]

The trade name Dolophine was created by Eli Lilly after World War II and used in the United States; the claim that Nazi leader Adolf Hitler ordered the manufacture of methadone and/or that the brand name Dolophine was bestowed in honor of Hitler is an urban legend. ^{[clarification needed][65]} The pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s as a reference to the aforementioned urban myth that the trade name Dolophine was a reference to Adolf Hitler.^[66][67]