methadone methadone 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 for the rest of the patient’s life. while a single dose has a rapid effect, maximum effect can take up to five days of use. 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. methadoneskeletal formulaball-and-stick model based on the crystal structureclinical datatrade namesdolophine, methadose, othersahfs/drugs.commonographmedlineplusa682134license data us dailymed: methadone pregnancycategory au: c addictionliabilityhighroutes ofadministrationby mouth, intravenous, insufflation, sublingual, rectalatc coden02ac52 (who) n07bc02 (who) qn02ac90 (who)legal statuslegal status au: s8 (controlled drug) br: class a1 (narcotic drugs) ca: schedule i de: anlage iii (special prescription form required) uk: class a us: schedule ii pharmacokinetic databioavailability15-20% subcutaneous 100% intravenous 41–99% (by mouth)protein binding85–90%metabolismliver (cyp3a4, cyp2b6 and cyp2d6-mediated)onset of actionrapidelimination half-life15 to 55 hoursduration of actionsingle dose: 4–8 hprolonged use: • withdrawal prevention: 1–2 days • pain relief: 8–12 hoursexcretionurine, faecesidentifiers iupac name (rs)-6-(dimethylamino)-4,4-diphenylheptan-3-one cas number76-99-3 ypubchem cid4095iuphar/bps5458drugbankdb00333 ychemspider3953 yuniiuc6vbe7v1zkeggd08195 ychebichebi:6807 nchemblchembl651 ycomptox dashboard (epa)dtxsid7023273 echa infocard100.000.907 chemical and physical dataformulac21h27nomolar mass309.453 g·mol−13d model (jsmol)interactive imagechiralityracemic mixture smiles ccc(c(c1=cc=cc=c1)(c2=cc=cc=c2)cc(n(c)c)c)=o inchi 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 ykey:ussiqxcvuwkgnf-uhfffaoysa-n y ny (what is this?) (verify) side effects are similar to those of other opioids. these frequently include dizziness, sleepiness, vomiting, and sweating. serious risks include opioid abuse and respiratory depression. 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 and acts on opioid receptors. methadone was developed in germany around 1937 to 1939 by gustav ehrhart and max bockmühl. it was approved for use 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. medical uses opioid addiction methadone is used for the treatment of opioid use disorder. 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 (samhsa) and registered by the drug enforcement administration (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 specialized 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 ranges 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 in chronic pain, often in rotation with other opioids. due to its activity at the nmda receptor, it may be more effective against neuropathic pain; for the same reason, tolerance to the analgesic effects may be less than that of other opioids. adverse effects 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. adverse effects of methadone include: sedation constipation flushing perspiration heat intolerance dizziness or fainting weakness chronic fatigue, sleepiness and exhaustion sleep problems such as drowsiness, insomnia constricted pupils dry mouth nausea and vomiting low blood pressure headache 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 decreased libido, difficulty in reaching orgasm, or impotence missed menstrual periods, skin rash central sleep apnea withdrawal symptoms physical symptoms lightheadedness tearing of the eyes mydriasis (dilated pupils) photophobia (sensitivity to light) hyperventilation syndrome (breathing that is too fast/deep) runny nose yawning sneezing nausea, vomiting, and diarrhea fever sweating chills tremors akathisia (restlessness) tachycardia (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 susceptibility to cravings depression spontaneous orgasm prolonged insomnia delirium auditory hallucinations visual hallucinations increased perception of odors (olfaction), real or imagined marked increase in sex drive agitation anxiety panic disorder nervousness paranoia delusions apathy anorexia (symptom) 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, 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: miosis (constricted pupils) vomiting spasms of the stomach and intestines hypoventilation (breathing that is too slow/shallow) drowsiness, sleepiness, disorientation, sedation, unresponsiveness skin that is cool, clammy (damp), and pale blue fingernails and lips limp muscles, trouble staying awake, nausea unconsciousness and coma the respiratory depression of an overdose can be treated with naloxone. naloxone is preferred to the newer, longer-acting antagonist naltrexone. despite methadone's much longer duration of action compared to either heroin and other shorter-acting agonists and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. as naltrexone has a longer half-life, it is more difficult to titrate. if too large a dose of the opioid antagonist is given to a dependent person, it will result in withdrawal symptoms (possibly severe). when using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short-lived. doses of naltrexone take longer to be eliminated from the person's system. a common problem in treating methadone overdoses is that, given the short action of naloxone (versus the extremely longer-acting methadone), a dosage of naloxone given to a methadone-overdosed person will initially work to bring the person out of overdose, but once the naloxone wears off, if no further naloxone is administered, the person can go right back into overdose (based upon time and dosage of the methadone ingested). tolerance and dependence as with other opioid medications, tolerance and dependence usually develop with repeated doses. there is some clinical evidence that tolerance to analgesia is less with methadone compared to other opioids; this may be due to its activity at the nmda receptor. tolerance to the different physiological effects of methadone varies; tolerance to analgesic properties may or may not develop quickly, but tolerance to euphoria usually develops rapidly, whereas tolerance to constipation, sedation, and respiratory depression develops slowly (if ever). 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), 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 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 receptor binding affinities of isomers of methadone compound affinities (ki, in nm) ratios mor dor kor