Methadone (oral): Difference between revisions

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{{drugbox
{{DrugProjectFormSinglePage
| IUPAC_name = 6-(Dimethylamino)-4,4-diphenylheptan-3-one
|authorTag={{chetan}}
| image = Methadone.svg
|genericName=Methadone
| width =  
|aOrAn=an
| CAS_number = 76-99-3a
|drugClass=analgesic opioid
| ATC_prefix = N02
|indicationType=treatment
| ATC_suffix = AC52
|indication=drug detoxification - opioid abuse, opioid abuse, maintenance therapy, pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time, pain (moderate to severe), not responsive to non-narcotic analgesics.
| ATC_supplemental = {{ATC|N07|BC02}}, {{ATC|R05|DA06}}
|hasBlackBoxWarning=Yes
| PubChem = 4095
|adverseReactions=cardiovascular: [[hypotension]], endocrine metabolic: [[diaphoresis]],  [[gastrointestinal]]: [[constipation]], [[nausea]], [[vomiting]], [[neurologic]]: [[asthenia]], [[dizziness]], [[lightheadedness]], [[sedated]]
| smiles = CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c2ccccc2
|blackBoxWarningTitle=<b><span style="color:#FF0000;">Conditions For Distribution And Use Of Methadone Products</span></b>
| DrugBank = APRD00485
|blackBoxWarningBody={{clr}}
| C=21 | H=27 | N=1 | O=1
* Methadone products when used for the treatment of narcotic addiction in detoxification or maintenance programs, shall be dispensed only by approved hospital pharmacies, approved community pharmacies and by maintenance programs approved by the food and drug administration and the designated state authority.
| molecular_weight = 309.445 g/mol
* Approved maintenance programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the federal methadone regulations (21 CFR 291.505).
| bioavailability = 40-80(-92)
*Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval and injunction precluding operation of the program.
| protein_bound =
|fdaLIADAdult=* Pharmacokinetic properties and high inter patient variability in absorption, metabolism, and relative analgesic potency of methadone necessitates a cautious an individualized approach to prescribing; careful dose initiation and titration are necessary.
| metabolism = [[Hepatic]]
* Do not abruptly discontinue.
| elimination_half-life = 24-36 hrs.
* Conversion from oral methadone to parenteral methadone; initially use a 2:1 dose ratio (eg, 10 milligrams oral methadone to 5 milligrams parenteral methadone.
| pregnancy_category = Reduction of oxygen to unborn child due to depression of breathing
* Conversion from other opioids to methadone; conversion ratios may overestimate dose of methadone; use cautiously.
| legal_AU =
* Drug detoxification - Opioid abuse: initial, 20 to 30 mg orally administered when there are no signs of sedation or intoxication, and patient shows signs of withdrawal; Max initial dose 30 mg.
| legal_CA =
* Drug detoxification - Opioid abuse: maintenance, additional 5 to 10 mg can be given 2 to 4 hours later if needed; adjust dose cautiously over the first week based upon control of withdrawal 2 to 4 hours post dose; usual total daily dose is 40 mg/day.
| legal_UK = Class A
* Drug detoxification - Opioid abuse: short-term detoxification, titrate to about 40 mg/day in divided doses; keep on stable dose for 2 to 3 days then decrease in 1 to 2 day intervals according to response.
| legal_US = Schedule II
* Drug detoxification - Opioid abuse: maintenance treatment, titrate to a dose that prevents opioid withdrawal for 24 hours; generally 80 to 120 mg/day.
| legal_status =
* Drug detoxification - Opioid abuse: (unable to take oral medication) parenteral methadone may be used.
| routes_of_administration = oral, intravenous
* Opioid abuse, maintenance therapy: maintenance doses must be individualized; methadone doses should be titrated to a dose where symptoms are prevented for 24 hours; usual maintenance doses range from 80 to 120 mg/day.
| excretion = Urine, Test by specific gravity and bilirubin
* Opioid abuse, maintenance therapy: (unable to take oral medication) parenteral methadone may be used.
| dependency_liability = Moderate
* Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: (opioid naive) initial, no more than 2.5 mg to 10 mg orally every 8 to 12 hours.
}}
* Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: (titration and maintenance) titrate slowly to effect; dose adjustment every 1 to 2 days; immediate-release rescue medication may be needed during titration.
{{SI}}
* Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: (discontinuation) do not discontinue abruptly; gradual downward titration every 2 to 4 days.
{{CMG}} <br>
* Pain (moderate to severe), not responsive to non-narcotic analgesics: (opioid naive) initial, 2.5 mg to 10 mg IV/IM/SubQ every 8 to 12 hours; titrate slowly based on individual response (manufacturer dosing).
<small>'''''Street Names/Slangs: Amidone, Dollies, Dolls, Done, Jungle juice, Junk, Maria, Meth, Methadose, Metho, Pastora, Phizzies, Phy, Wafer'''''</small>
* Pain (moderate to severe), not responsive to non-narcotic analgesics: opioid naive patients: (initial) 2.5 mg ORAL/IV/IM/SubQ every 8 hour (guideline dosing).
|offLabelAdultGuideSupport=* Neuropathic pain.
|offLabelAdultNoGuideSupport=* There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Methadone in adult patients.
|fdaLIADPed=* Safety and efficacy not established in pediatric patients younger than 18 years of age.
* Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: 0.1 to 0.2 mg/kg Orally every 6 hour as needed; Max 10 mg/dose.
* Pain (Moderate to Severe), Not responsive to non-narcotic analgesics: 0.1 to 0.2 mg/kg Orally every 6 hours as needed; MAX 10 mg/dose.
|offLabelPedGuideSupport=* There is limited information about <i>Off-Label Guideline-Supported Use</i> of Methadone in pediatric patients.
|offLabelPedNoGuideSupport=* There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Methadone in pediatric patients.
|contraindications=* [[Hypersensitivity]] to methadone.
|warnings=* Methadone hydrochloride powder is for oral administration only and is used in the preparation of a liquid by dissolving the powder in an appropriate vehicle. This preparation must not be injected. It is recommended that the methadone hydrochloride liquid preparation, if dispensed, be packaged in child-resistant containers and kept out of the reach of children to prevent accidental ingestion.
* Methadone hydrochloride, a narcotic, is a Schedule II controlled substance under the Federal Controlled Substances Act. Appropriate security measures should be taken to safeguard stocks of methadone against diversion.
|clinicalTrials=* Heroin Withdrawal:
:* During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore show typical withdrawal symptoms, which should be differentiated from methadone-induced side-effects. They may exhibit some or all of the following symptoms associated with acute withdrawal from [[heroin]] or other [[opiates]]: [[lacrimation]], [[rhinorrhea]], [[sneezing]], [[yawning]], excessive [[perspiration]], [[gooseflesh]], fever, chilliness alternating with flushing, restlessness, irritability, “sleepy yen,” [[weakness]], [[anxiety]], depression, [[dilated pupils]], [[tremors]], [[tachycardia]], [[abdominal cramps]], body aches, involuntary [[twitching]] and kicking movements, [[anorexia]], [[nausea]], [[vomiting]], [[diarrhea]], [[intestinal spasms]], and [[weight loss]].


==Overview==
* Initial Administration:
'''Methadone''' ('''Dolophine, Amidone, Methadose, Physeptone, Heptadon''' and many others) is a synthetic [[opioid]], used medically as an [[analgesic]], [[antitussive]] and a maintenance [[anti-addictive]] for use in patients on opioids. It was developed in [[Germany]] in 1937. Although chemically unlike [[morphine]] or [[heroin]], methadone also acts on the [[opioid receptor]]s and thus produces many of the same effects. Methadone is also used in managing [[chronic pain]] due to its long duration of action and very low cost. In late 2004, the cost of a one-month supply of methadone was $20, as compared to an equivalent [[analgesic]] amount of [[Demerol]] ([[pethidine]]) at $120, up to $500 and more for Palladone ([[hydromorphone]]), MS-Contin ([[morphine]]) and Duragesic ([[fentanyl]]) as well as the Opana series of extended-release [[oxymorphone]].
:* Initially, the dosage of methadone should be carefully titrated to the individual. Induction too rapid for the patient’s sensitivity is more likely to produce the following effects.
:* The major hazards of methadone, as of other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory depression. [[respiratory arrest]], [[shock]], and [[cardiac arrest]] have occurred.
:* The most frequently observed adverse reactions include [[lightheadedness]], [[dizziness]], [[sedation]], [[nausea]], [[vomiting]], and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Some adverse reactions may be alleviated in the ambulatory patient if he lies down.


Methadone's usefulness in treatment of opioid dependence is the result of its cross-tolerance with other opioids including [[heroin]], [[morphine]], etc. and long duration of effects with the result that oral dosing with methadone will stabilise the condition of the patient by stopping and preventing the opioid [[withdrawal]] syndrome and getting patients off the needle by at least partially blocking the "rush" resulting from intravenous injection of heroin, morphine, and similar drugs.
* Other adverse reactions include the following:
:* Central Nervous System – [[euphoria]], [[dysphoria]], weakness, headache, insomnia, agitation, [[disorientation]], and visual disturbances.
:* Gastro-Intestinal – Dry mouth, anorexia, [[constipation]], and [[biliary tract spasm]].
:* Cardiovascular – Flushing of the face, [[bradycardia]], [[palpitation]], [[faintness]], and syncope.
:* Genito-Urinary – Urinary retention or hesitancy, antidiuretic effect, and reduced libido and/or potency.
:* Allergic – [[pruritus]], [[urticaria]], other skin rashes, edema, and, rarely, hemorrhagic [[urticaria]].


Today a number of pharmaceutical companies produce and distribute methadone, with only the racemic hydrochloride being available in the United States as of March 2008 but the tartrate and other salts of the laevorotary form ([[levomethadone]], with trade names like Polamidone, Heptadon etc.), which is more potent and lacks the cardiac effects like lengthened QT interval caused by the dextrorotary form, being available in Europe and elsewhere. The major producer remains [[Mallinckrodt]]. Mallinckrodt sells bulk methadone to most of the producers of generic preparations and also distributes its own brand name product in the form of tablets, dispersible tablets and oral concentrate under the name ''Methadose'' in the United States.  
* Maintenance on a Stabilized Dose:
:* During prolonged administration of methadone, as in a methadone maintenance treatment program, there is a gradual, yet progressive, disappearance of side-effects over a period of several weeks. However, constipation and sweating often persist.
|drugInteractions=* Interaction with [[Pentazocine]]:
:* Patients who are addicted to heroin or who are on the methadone maintenance program may experience withdrawal symptoms when given pentazocine.


==History==
* Interaction with [[Rifampin]]:
Methadone was developed in [[Germany]] in the late 1930s in anticipation of possible shortages of raw opium during the upcoming war and possible blockades by the enemy, which would result in shortages of morphine and other opiates for both the military and civilian populations.  It was tested by medical professionals in the German military in 1939-40 but decided that it was too toxic and perhaps too likely to impart a morbid seek orientation for the drug in its users upon repeated use (habituation) for use in the army and other organisations.
:* The concurrent administration of [[rifampin]] may possibly reduce the blood concentration of methadone to a degree sufficient to produce withdrawal symptoms. The mechanism by which rifampin may decrease blood concentrations of methadone is not fully understood, although enhanced microsomal drug-metabolized enzymes may influence drug disposition.


The drug was given the trade name Dolophine from the Latin ''dolor'' meaning pain (Cf. Dipidolor for [[piritramide]], Dolantin for [[pethidine]], and the "-dol" ending in so many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf [[Hitler]] as explored in greater detail below.
* Acute Abdominal Conditions:
:* The administration of methadone or other narcotics may obscure the diagnosis or clinical course patients with acute abdominal conditions.


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 no relation to morphine or the opiate alkaloids (Bockmühl and Ehrhart, 1949).
* Interaction with Monoamine Oxidase (MAO) Inhibitors:
:* Therapeutic doses of meperidine have precipitated severe reactions patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents with fourteen days. Similar reactions thus far have not been reported with methadone; but if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient’s condition and vital signs are under careful observation.
|useInPregnancyFDA=* Caution shall be taken in the maintenance treatment of pregnant patients. Dosage levels shall be kept as low as possible if continued methadone treatment is deemed necessary. It is the responsibility of the program sponsor to assure that each female patient be fully informed concerning the possible risks to a pregnant woman or her unborn child from the use of methadone.
|overdose=* Symptoms:
:* Serious overdosage of methadone is characterized by [[respiratory depression]] (a decrease in respiratory rate and/or [[tidal volume]], [[Cheyne-Stokes respiration]], [[cyanosis]]), extreme [[somnolence]] progressing to [[stupor]] or [[coma]], maximally constricted [[pupils]], [[skeletal-muscle flaccidity]], [[cold and clammy skin]], and, sometimes, [[bradycardia]] and [[hypotension]]. In severe overdosage, particularly by the intravenous route, [[apnea]], [[circulatory collapse]], [[cardiac arrest]], and death may occur.


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 more than a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.
* Treatment:
:* Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant person, especially a child, takes a large dose of methadone, effective narcotic antagonists are available to counter-act the potentially lethal respiratory depression. The physician must remember, however, that methadone is a long-acting depressant (thirty-six to forty-eight hours), whereas the antagonists act for much shorter periods (one to three hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the diagnosis is correct and respiratory depression is due only to overdosage of methadone, the use of respiratory stimulants is not indicated.


Methadone (as Dolophine) was first manufactured in the USA by [[Mallinckrodt]] Pharmaceuticals, a [[St. Louis, Missouri|St. Louis]]-based subsidiary of the [[Tyco International]] corporation. Mallinckrodt held the patent up until the early 1990s, and is still the major producer.
:* An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists, naloxone hydrochloride, nalorphine hydrochloride, or levallorphan tartrate are the drugs of choice to reverse signs of intoxication. These agents should be given repeatedly until the patient's status remains satisfactory. The hazard that the narcotic antagonist will further depress respiration is less likely with the use of naloxone.


In the United States, methadone maintenance treatment emerged from trials in New York City in 1964 in response to the dramatic and continuing increase of heroin abuse and addiction following World War II.
:* Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated.


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.
Note: In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. the severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. the use of a narcotic antagonist in such a person should be avoided if possible. if it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 420419989
| IUPAC_name = (''RS'')-6-(Dimethylamino)-4,4-diphenylheptan-3-one
| image = Methadone wiki1.png
| width = 180px
| image2 = Methadonewiki2.gif
| width2 = 280px
| imagename = 1 : 1 Mixture ([[racemate]])
| drug_name = Methadone


===Origin of Dolophine name===
<!--Clinical data-->
A persistent but untrue [[urban legend]] claims that the trade name "Dolophine" was coined in tribute to [[Adolf Hitler]] by its German creators, and it is sometimes even claimed that the drug was originally named "adolphine" or "adolophine" or "Dolphamine". The claim is still presented as fact by [[Church of Scientology]] literature<ref>Buttnor, Al. "[http://www.freedommag.org/english/canada/vol004i1/page13.htm The Drug Problem: How It CAN be Solved]". ''[[Freedom Magazine]]'' (vol. 4, iss. 1) p. 15. Retrieved April 7, 2006.</ref> and was repeated by actor and vocal Scientologist [[Tom Cruise]] in a 2005 ''[[Entertainment Weekly]]'' interview.<ref>[http://www.ew.com/ew/article/0,,1069956_4,00.html Tom Responds], Entertainment Weekly, May 11, 2005</ref>  However, as the magazine pointed out, this is not true: the name "Dolophine" was in fact created after the war by the American branch of Eli Lilly,<ref>{{cite web|url=http://web.archive.org/web/20030928123648/http://www.exchangesupplies.org/publications/methadone_briefing/section1.html|title=www.exchangesupplies.org/publications/methadone_briefing/section1.html<!--INSERT TITLE-->|accessdate=2007-07-09}}</ref> and the pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s.<ref>http://www.indro-online.de/discovery.pdf ([[PDF]] format)</ref> ''Dolophine'' actually comes from the German ''Dolphium''. The name derives from the [[Latin]] ''dolor'' which means "pain".
| tradename = Dolophine
| Drugs.com = {{drugs.com|CDI|methadone}}
| MedlinePlus = a682134
| pregnancy_AU = C
| pregnancy_US = C
| legal_AU = Schedule 8
| legal_US = Schedule II
| legal_UK = Class A
| dependency_liability = <!--need a reliable [[WP:MEDRS]]-compliant source to include this information-->
| routes_of_administration = Oral, intravenous, insufflation, sublingual, rectal


==Pharmacology==
<!--Pharmacokinetic data-->
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the [[NMDA]] ionotropic glutamate receptor. It is metabolized by the enzymes [[CYP3A4]] and [[CYP2D6]], with great variability between individuals. Its main [[route of administration]] is oral. Adverse effects include [[hypoventilation]], [[constipation]] and [[miosis]], in addition to tolerance, dependence and withdrawal symptoms. The withdrawal can be much more severe than other opiates spanning anywhere from two weeks to six months.
| bioavailability = 41-99% (oral)<ref name = acta08>{{cite journal|last=Fredheim|first=OM|coauthors=Moksnes, K; Borchgrevink, PC; Kaasa, S; Dale, O|title=Clinical pharmacology of methadone for pain.|journal=Acta Anaesthesiologica Scandinavica|date=August 2008|volume=52|issue=7|pages=879–89|doi=10.1111/j.1399-6576.2008.01597.x|pmid=18331375}}</ref>
===Mode of action===
| protein_binding = 85-90%<ref name = acta08/>
Methadone is a full mu-opioid agonist. Methadone also 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 [[central nervous system|CNS]]. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as [[dextromethorphan]], [[ketamine]], 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.
| metabolism = [[Hepatic]] ([[CYP3A4]], [[CYP2B6]] and [[CYP2D6]]-mediated)<ref name = acta08/><ref name = PMJ04>{{cite journal|last=Brown|first=R|coauthors=Kraus, C; Fleming, M; Reddy, S|title=Methadone: applied pharmacology and use as adjunctive treatment in chronic pain.|journal=Postgraduate Medical Journal|date=November 2004|volume=80|issue=949|pages=654–9|doi=10.1136/pgmj.2004.022988|pmid=15537850|url=http://pmj.bmj.com/content/80/949/654.full.pdf|format=PDF|pmc=1743125}}</ref>
| elimination_half-life = 7-65 hours<ref name = PMJ04/>
| excretion = Urine, faeces<ref name = PMJ04/>


===Metabolism===
<!--Identifiers-->
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,<ref name="Kell">{{cite journal |author=Kell MJ |title=Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting |journal=Journal of addictive diseases : the official journal of the ASAM, American Society of Addiction Medicine |volume=13 |issue=1 |pages=5–26 |year=1994 |pmid=8018740 |doi=}}</ref><ref name=EUROPAD>{{cite journal |author=Eap CB, DeglonJ-J, Boumann P. |title=Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance|journal=Heroin Addiction and Related Clinical Problems: The official journal of EUROPAD, European Opiate Addiction Treatment Association|volume=1 |issue=1 |pages=19-34 |year=1999}}</ref> ranging from as few as 4 hours to as many as 130 hours,<ref name="EapI">{{cite journal |author=Eap CB, Buclin T, Baumann P |title=Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence |journal=Clinical pharmacokinetics |volume=41 |issue=14 |pages=1153–93 |year=2002 |pmid=12405865 |doi=}}</ref> or even 190 hours.<ref>{{cite web | last=Manfredonia | first=John |url=http://www.jaoa.org/cgi/content/full/105/3_suppl/18S | title=Prescribing Methadone for Pain Management in End-of-Life Care | publisher=JAOA The Journal of the American Osteopathic Association | date=2005-03-18|accessdate=2007-01-29 }}</ref> This variability is apparently due to genetic variability in the production of the associated enzymes [[CYP3A4]] and [[CYP2D6]]. A longer half life frequently allows for administration only once a day in heroin [[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.<ref name="EapI"/> 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(Quote Needed).
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 76-99-3
| ATC_prefix = N02
| ATC_suffix = AC52
| ATC_supplemental = {{ATC|N07|BC02}}
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 6807
| PubChem = 4095
| IUPHAR_ligand = 1605
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00333
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3953
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = UC6VBE7V1Z
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08195
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 651


The toxic effects of an overdose can be treated with [[naloxone]].<ref name=sadovsky> [http://www.aafp.org/afp/20000715/tips/1.html Public Health Issue: Methadone Maintenance Therapy] RICHARD SADOVSKY, M.D. - Anderson IB, Kearney TE. Use of methadone. West J Med January 2000;172:43-6. </ref>
<!--Chemical data-->
 
| C=21 | H=27 | N=1 | O=1
===Route of administration===
| molecular_weight = 309.445 g/mol
The most common [[route of administration]] at a methadone clinic is in a [[racemic]] oral solution, though in Germany, only the (R)-methadone [[enantiomer]] has traditionally been used, as it is responsible for most of the desired opioid effects.<ref name="EapI"/> This is becoming less common due to the higher production costs.
| smiles = CCC(C(C1=CC=CC=C1)(C2=CC=CC=C2)CC(N(C)C)C)=O
 
| InChI = 1/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
Methadone is available in pill, [[sublingual]] tablet and liquid formulations, with the liquid form the most common as it allows for finer grained dose titration. Methadone is almost as effective when administered orally as by injection. In fact, injection of methadone does not result in a "rush" as with most opioids, because its extraordinarily high [[pharmacokinetics|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. Though there seems to be some discrepancy regarding effects felt from one person to the next, "rush" like effects have been occasionally reported by some. At best, most oral and pill preparations of the drug are hardly suitable for intravenous injection and perhaps account for the prevailing attitude against IV use.
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
 
| StdInChI = 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
===Adverse effects===
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
Adverse effects of methadone include<ref name=sadovsky/><ref>
| StdInChIKey = USSIQXCVUWKGNF-UHFFFAOYSA-N
{{cite web |url=http://www.rxlist.com/cgi/generic/methdone.htm
}}
|title=Dolophine Drug Description
|mechAction=* Methadone hydrochloride is a synthetic narcotic analgesic with multiple actions quantitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation, detoxification or maintenance in narcotic addiction. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.
|publisher=RxList}}
* When administered orally, methadone is approximately one-half as potent as when given parenterally. Oral administration results in a delay of the onset, a lowering of the peak, and an increase in the duration of analgesic effect.
</ref><ref> {{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682134.html |title=Methadone
|structure=* Methadone Hydrochloride is a white powder. It is chemically named 6-dimethylamino-4, 4-diphenyl-3-heptanone hydrochloride.
|publisher=MedlinePlus}}</ref><ref>
|howSupplied=* Methadone Hydrochloride is supplied in containers of 50 gm., 100 gm., 500 gm., and 1 kilogram.
{{cite web
* Preserve in tight, light-resistant containers. Store at controlled room temperature (15° to 30°C.) (59° to 86°F.)
|url=http://www.drugs.com/methadone.html
MALLINCKRODT
|title=Methadone
MALLINCKRODT INC.
|publisher=Drugs.com}}
St. Louis, Missouri 63134
</ref><ref>
July 1998                                                     
{{cite web |url=http://www.medicinenet.com/methadone-dispersible_tablet/article.htm |title=Methadone
1274111                                         
|publisher=MedicineNet
Printed in U.S.A.
}}</ref>
|alcohol=* Alcohol-Methadone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
*[[Hypoventilation]]
}}
*Decreased bowel motility - [[constipation]]
{{PillImage
*[[miotic]] pupils
|fileName=Pill_Image.jpeg
*nausea
|drugName=Methadone
*hypotension
|NDC=0406-1510-56
*hallucination
|drugAuthor=Mallinckrodt, Inc.
*headache
|ingredients=Lactose monohydrate, magnesium stearate, cellulose, microcrystalline, silicon dioxide
*vomiting
|pillImprint=57;55;M
*Cardiac arrhythmia
|dosageValue=5
*[[anorexia (symptom)]]
|dosageUnit=mg
*weight gain
|pillColor=White
*stomach pain
|pillShape=Rectangular
*[[xerostomia]]
|pillSize=9.00
*[[perspiration]]
|pillScore=2
*flushing
}}
*itching
{{LabelImage
*difficulty urinating
|fileName=Methadone label.png
*swelling of the hands, arms, feet, and legs
}}
*mood changes
*blurred vision
*insomnia
*impotence
*skin rash
*seizures
 
When combined with other drugs, however, methadone can cause death:
 
====Mortality====
According to the National Center for Health Statistics,<ref> {{cite web |url=http://www.cdc.gov/nchs/products/pubs/pubd/hestats/methadone1999-04/methadone1999-04.htm |title=Increases in Methadone-Related Deaths:1999-2004}} </ref> as well as a 2006 series in the Charleston (WV) Gazette,<ref name="http://www.wvgazette.com/section/Series/The+Killer+Cure">{{cite web|url=http://www.wvgazette.com/section/Series/The+Killer+Cure|title=http://www.wvgazette.com/section/Series/The+Killer+Cure|accessdate=2007-07-09}}</ref> medical examiners listed methadone as contributing to 3,849 deaths in 2004, up from 790 in 1999. Approximately 82% of those deaths were listed as accidental- and most deaths involved combinations of methadone with other drugs (especially [[benzodiazepines]]).
 
More information on methadone associated mortality can be found at Substance Abuse and Mental Health Services Administration (SAMHSA - U.S. Dept. of Health and Human Services).
 
===Tolerance and dependence===
As with other opioid medications, tolerance and dependence usually develop with repeated doses. Tolerance to the different physiological effects of methadone varies. Tolerance to analgesia usually occurs during the first few weeks of use; whereas with respiratory depression, sedation, and nausea it is seen within approximately 5-7 days. There is no tolerance formed to constipation produced by methadone or other opioids; however, effects may be less severe after time and can often be alleviated through dietary fiber supplements.
 
===Withdrawal symptoms=== <!--Methadone withdrawal symptoms redirects here-->
Withdrawal symptoms of methadone include:<ref name=sadovsky/>
 
== Physiological Effects ==
 
*  Increased [[lacrimation]]
*  [[rhinorrhea]]
*  sneezing
*  [[nausea]]
*  vomiting
*  [[diarrhea]]
*  [[fever]]
*  chills
*  [[tremor]]
*  [[tachycardia]]
*  aches and pains, often in the joints
*  elevated pain sensitivity
*  elevated blood pressure
 
== Cognitive Effects ==
 
* [[suicidal ideation]]
* [[Depression (mood)|depression]]
* [[adrenal exhaustion]]
* [[adrenal fatigue]]
*  spontaneous [[orgasm]]
*  prolonged [[insomnia]] leading up to [[delirium]]
* [[auditory hallucinations]]
* [[visual hallucinations]]
*  enhance [[olfactory]] sense
*  decreased sexual drive
* [[agitation]]
* [[panic disorder]]
*  anxiety
* [[paranoia]]
* [[delusion]]
 
Withdrawal symptoms are generally slightly less severe than those of morphine or heroin at equivalent doses but are significantly more prolonged; methadone withdrawal symptoms can last for several weeks or more. Anecdotal reports, such as those by author and lifelong opiate addict [[William S. Burroughs]] in the postscript of his book [[Naked Lunch]], suggest that "cold turkey" barbiturates withdrawal is substantially more difficult and unpleasant than similar withdrawal from opiates, presumably because its duration of withdrawal is almost an order of magnitude greater than short-acting opiate withdrawals, such as those from heroin or morphine. Indeed, there is a trend in the management of opiate addiction towards the reduction of a patient's methadone dosage to a point where they can be switched to [[buprenorphine]] or another opiate with an easier withdrawal profile. Ultimately, methadone is all but ideal for maintenance, but is not considered to be a desirable opiate to withdraw from when attempting to become completely opiate-free.
 
==Methadone maintenance treatment==
MMT (Methadone Maintenance Treatment) reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity<ref name="JosephStancliffLangrod"/>. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV.<ref name="JosephStancliffLangrod"/> The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. Methadone maintenance has been found to be medically safe and [[non-sedating]].<ref name="JosephStancliffLangrod"/> It is also indicated for pregnant women addicted to heroin.<ref name="JosephStancliffLangrod"> {{cite journal |author=Joseph H, Stancliff S, Langrod J |title=Methadone maintenance treatment (MMT): a review of historical and clinical issues |journal=Mt. Sinai J. Med. |volume=67 |issue=5-6 |pages=347–64 |year=2000 |pmid=11064485 |doi=}}</ref>
 
===Effect===
Methadone maintenance treatment significantly decreases the rate of [[HIV]] infection for those patients participating in MMT programs (Firshein, 1998). At proper dosing, methadone usually reduces the appetite for and need to take heroin. Furthermore doses ≥40mg and above provide cross-tolerance and block the euphoric effects of other opioids such as [[heroin]], [[fentanyl]], [[hydrocodone]], [[oxycodone]], [[hydromorphone]], and [[morphine]] or [[codeine]] syrup, thus greatly reducing the motivation of patients to use them.
 
Methadone offers patients the freedom from active addiction and use of mind-altering drug use and in turn allows them to seek concurrent psychological, psychiatric and self-help based therapies for both the disease of addiction and any comorbid illnesses they have, freedom they would not have when experiencing severe ongoing withdrawal and/or cravings. In addition, and perhaps most importantly, methadone allows addicts to become productive members of society; freed from the need to obtain money through often illicit means, opiate addicts can return to their normal lives, or develop skills, further their education, and (re)join the workforce.
 
A proper dose used in methadone maintenance therapy will block or greatly reduce cravings and illicit opioid use while not inducing any euphoric feelings or other subjective sense of being high, and if high enough will actively prevent the patient from experiencing any high if they do use other opioids.
Methadone-based treatment is significantly more effective clinically and more cost effective than no-drug treatment modalities for opiate-dependent patients.<ref name="Connock">{{cite journal |author=Connock M, Juarez-Garcia A, Jowett S, ''et al'' |title=Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation |journal=Health technology assessment (Winchester, England) |volume=11 |issue=9 |pages=1–171, iii–iv |year=2007 |pmid=17313907 |doi=}}</ref>
 
===Dosage===
A majority of patients require 80-120 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.<ref name="JosephStancliffLangrod"/> Lower doses are sometimes not as effective or provide the blockade effect as higher dosages.
 
In the United States 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. 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 addicts at 30mg and raise the dosage 5mg a day until the addict feels they are at a comfortable level of dosage or will stop at 80mg and allowing the patient move up by 5mg or 10mg every 2 or 3 days, free from withdrawal symptoms and intense cravings. Once stabilized patients may require occasional dose adjustments as their clinical or subjective tolerance changes.
 
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.<ref name="DonnyBrasser">{{cite journal |author=Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL |title=Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers |journal=[[Addiction (journal)|Addiction]] |volume=100 |issue=10 |pages=1496–509 |year=2005 |pmid=16185211 |doi=10.1111/j.1360-0443.2005.01232.x}}</ref><ref name="pmid17373567">{{cite journal |author=Latowsky M |title=Methadone death, dosage and torsade de pointes: risk-benefit policy implications |journal=Journal of psychoactive drugs |volume=38 |issue=4 |pages=513–9 |year=2006 |pmid=17373567 |doi=}}</ref>
 
A 100-mg dose has become accepted as a 'glass ceiling', rarely to be penetrated, and in practice much lower thresholds are 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 ten-fold 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.<ref name=Eap>{{cite journal |author=Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P |title=When "Enough" Is Not Enough: New Perspectives on Optimal Methadone Maintenance Dose|journal= Mount Sinai Journal of Medicine |volume=67 |issue=5&6 |pages=404-411 |year=2000}}</ref><ref name="Faggiano">{{cite journal |author=Faggiano F, Vigna-Taglianti F, Versino E, Lemma P |title=Methadone maintenance at different dosages for opioid dependence |journal=Cochrane database of systematic reviews (Online) |volume= |issue=3 |pages=CD002208 |year=2003 |pmid=12917925 |doi=10.1002/14651858.CD002208}}</ref>
 
===Duration===
While there is much debate over the treatment schedule and duration required, treatment at a methadone maintenance clinic is intended to be for an indefinite duration, lasting as long as the patient requires it. Many factors determine the treatment dose schedule. In general, methadone maintenance is seen as ongoing symptom management rather than a curative treatment. Compared to other narcotics (morphine, hydrocodone, heroin), methadone is much safer (when used as directed) and does not harm any of the body's vital organs (brain, liver, lungs, kidneys) even after long term use (30+ years).
 
===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 maitenance treatment (MMT) is delivered by private pharmacies for a nominal fee to the client (regardless of the fact it is free as it is subsidised 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" after several months of adherence to the clinic's regulations, including consistent negative drug-screen results. The way that MMT is delivered in some countries create barriers to scaling up access to the treatment. For example, in Australia, people who are on MMT are dosed in designated area in front of other pharmacy customers. This can inhibit people's willingness to access treatment due to a lack of confidentiality and anonymity. 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) 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.
 
Some people treated for MMT at a specific MMT clinic receive psychological counseling, which is also provided on site. Though the laws vary, this is required by law in many states and countries. In some countries psycho-social support, including counselling, is compulsory, regardless of whether a person needs or wants to engage in that kind of intervention (for example, recent changes in Taiwan).
 
==Analgesic==
In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an [[analgesic]] in chronic pain. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than short-acting drugs like morphine or [[hydrocodone]]. Another factor in the increased usage is the low cost of methadone. A month's supply will typically have a retail cost of $30-50 in the United States, 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 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.
 
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.<ref>{{cite web | url = http://www.fda.gov/medwatch/safety/2006/safety06.htm#Methadone | title = 2006 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements | work = MedWatch | publisher = [[Food and Drug Administration]]}}</ref>
As with any strong medication which 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. 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 methadone and other opioids may cause cardiac conduction problems (prolonged [[QTc]] interval<ref name="Maremmani">{{cite journal |author=Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A |title=QTc interval prolongation in patients on long-term methadone maintenance therapy |journal=European addiction research |volume=11 |issue=1 |pages=44–9 |year=2005 |pmid=15608471 |doi=10.1159/000081416}}</ref>) although there are few documented cases of fatalities resulting from this side-effect with methadone.
 
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 family physicians can use to treat patients for pain.
 
==Antitussive==
Methadone linctus, which is about one-third the concentration of the liquid methadone used for opioid maintenance, is used where available and approved for such use as a cough syrup for violent coughing. Narcotic cough suppressants are very useful against dry, unproductive coughing, especially that which persists after an illness has otherwise resolved and/or is a manifestation of recurring bronchitis, causes pain in the chest, and/or prevents the patient from sleeping. These drugs work directly on the coughing centre in the brain, and several branches of the opioid family contain effective cough suppressants.
 
Natural and semi-synthetic opiates with antitussive effects include [[codeine]], [[ethylmorphine]] (also known as dionine or codethyline), [[dihydrocodeine]], [[benzylmorphine]], [[laudanum]], [[dihydroisocodeine]], [[nicocodeine]], [[nicodicodeine]], [[hydrocodone]], [[hydromorphone]], [[acetyldihydrocodeine]], [[thebacon]], [[diamorphine]] ([[heroin]]), [[acetylmorphone]], [[noscapine]] and [[pholcodine]] and others. Amongst other synthetics are [[dimemorfan]] and [[dextromethorphan]] in the [[morphinan]] group, [[tipepidine]] of the [[thiambuetenes]], and other drugs of the open-chain (methadone) type with antitussive efficacy include levomethadone, [[normethadone]], and [[levopropoxyphene]].
 
==Similar drugs==
The closest chemical relative of methadone in clinical use is [[levomethadone]], the laevorotary or left-handed stereoisomer of methadone.  It is about eight times stronger than the racemic drug 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.
 
Related to methadone, the synthetic compound [[LAAM|levo-α-acetylmethadol]] (or LAAM) has an even longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994 it was approved as a treatment of narcotic addiction. Like methadone, LAAM is 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. LAAM is still available at many MMT clinics throughout the US though methadone is preferred by most patients, though it is restricted to existing patients.
 
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 [[United Kingdom|UK]] and other European countries, however, not only buprenorphine and oral methadone but also injectable methadone and pharaceutical [[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. A study from Austria indicated that oral morphine (in the form of MS-Contin, also known as Vendal retard, MST-Continus and others) provides 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.<ref> Michels II, Stover H, Gerlach R. Substitution treatment for opioid addicts in Germany. Harm Reduction Journal. 2007 February 2;4:5. </ref> Other opiates such as [[dihydrocodeine]] in both extended-release and plain form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine.<ref> Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A. Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial. Addiction. 2006 Dec;101(12):1752-9. </ref>
 
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&nbsp;mg approximately equivalent to about 600&nbsp;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&nbsp;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 than methadone but considerably more effective as analgesics. 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.
 
==References==
{{reflist|2}}
 
{{Opioids}}
{{Analgesics}}
{{Drugs used in addictive disorders}}
{{Cough and cold preparations}}
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Latest revision as of 18:36, 15 May 2015

Methadone (oral)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

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Black Box Warning

Conditions For Distribution And Use Of Methadone Products
See full prescribing information for complete Boxed Warning.
  • Methadone products when used for the treatment of narcotic addiction in detoxification or maintenance programs, shall be dispensed only by approved hospital pharmacies, approved community pharmacies and by maintenance programs approved by the food and drug administration and the designated state authority.
  • Approved maintenance programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the federal methadone regulations (21 CFR 291.505).
  • Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval and injunction precluding operation of the program.

Overview

Methadone (oral) is an analgesic opioid that is FDA approved for the treatment of drug detoxification - opioid abuse, opioid abuse, maintenance therapy, pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time, pain (moderate to severe), not responsive to non-narcotic analgesics.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: hypotension, endocrine metabolic: diaphoresis, gastrointestinal: constipation, nausea, vomiting, neurologic: asthenia, dizziness, lightheadedness, sedated.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • Pharmacokinetic properties and high inter patient variability in absorption, metabolism, and relative analgesic potency of methadone necessitates a cautious an individualized approach to prescribing; careful dose initiation and titration are necessary.
  • Do not abruptly discontinue.
  • Conversion from oral methadone to parenteral methadone; initially use a 2:1 dose ratio (eg, 10 milligrams oral methadone to 5 milligrams parenteral methadone.
  • Conversion from other opioids to methadone; conversion ratios may overestimate dose of methadone; use cautiously.
  • Drug detoxification - Opioid abuse: initial, 20 to 30 mg orally administered when there are no signs of sedation or intoxication, and patient shows signs of withdrawal; Max initial dose 30 mg.
  • Drug detoxification - Opioid abuse: maintenance, additional 5 to 10 mg can be given 2 to 4 hours later if needed; adjust dose cautiously over the first week based upon control of withdrawal 2 to 4 hours post dose; usual total daily dose is 40 mg/day.
  • Drug detoxification - Opioid abuse: short-term detoxification, titrate to about 40 mg/day in divided doses; keep on stable dose for 2 to 3 days then decrease in 1 to 2 day intervals according to response.
  • Drug detoxification - Opioid abuse: maintenance treatment, titrate to a dose that prevents opioid withdrawal for 24 hours; generally 80 to 120 mg/day.
  • Drug detoxification - Opioid abuse: (unable to take oral medication) parenteral methadone may be used.
  • Opioid abuse, maintenance therapy: maintenance doses must be individualized; methadone doses should be titrated to a dose where symptoms are prevented for 24 hours; usual maintenance doses range from 80 to 120 mg/day.
  • Opioid abuse, maintenance therapy: (unable to take oral medication) parenteral methadone may be used.
  • Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: (opioid naive) initial, no more than 2.5 mg to 10 mg orally every 8 to 12 hours.
  • Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: (titration and maintenance) titrate slowly to effect; dose adjustment every 1 to 2 days; immediate-release rescue medication may be needed during titration.
  • Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: (discontinuation) do not discontinue abruptly; gradual downward titration every 2 to 4 days.
  • Pain (moderate to severe), not responsive to non-narcotic analgesics: (opioid naive) initial, 2.5 mg to 10 mg IV/IM/SubQ every 8 to 12 hours; titrate slowly based on individual response (manufacturer dosing).
  • Pain (moderate to severe), not responsive to non-narcotic analgesics: opioid naive patients: (initial) 2.5 mg ORAL/IV/IM/SubQ every 8 hour (guideline dosing).

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

  • Neuropathic pain.

Non–Guideline-Supported Use

  • There is limited information about Off-Label Non–Guideline-Supported Use of Methadone in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Safety and efficacy not established in pediatric patients younger than 18 years of age.
  • Pain, chronic (moderate to severe), in patients requiring a continuous around-the-clock opioid analgesic for an extended period of time: 0.1 to 0.2 mg/kg Orally every 6 hour as needed; Max 10 mg/dose.
  • Pain (Moderate to Severe), Not responsive to non-narcotic analgesics: 0.1 to 0.2 mg/kg Orally every 6 hours as needed; MAX 10 mg/dose.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

  • There is limited information about Off-Label Guideline-Supported Use of Methadone in pediatric patients.

Non–Guideline-Supported Use

  • There is limited information about Off-Label Non–Guideline-Supported Use of Methadone in pediatric patients.

Contraindications

Warnings

Conditions For Distribution And Use Of Methadone Products
See full prescribing information for complete Boxed Warning.
  • Methadone products when used for the treatment of narcotic addiction in detoxification or maintenance programs, shall be dispensed only by approved hospital pharmacies, approved community pharmacies and by maintenance programs approved by the food and drug administration and the designated state authority.
  • Approved maintenance programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the federal methadone regulations (21 CFR 291.505).
  • Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval and injunction precluding operation of the program.
  • Methadone hydrochloride powder is for oral administration only and is used in the preparation of a liquid by dissolving the powder in an appropriate vehicle. This preparation must not be injected. It is recommended that the methadone hydrochloride liquid preparation, if dispensed, be packaged in child-resistant containers and kept out of the reach of children to prevent accidental ingestion.
  • Methadone hydrochloride, a narcotic, is a Schedule II controlled substance under the Federal Controlled Substances Act. Appropriate security measures should be taken to safeguard stocks of methadone against diversion.

Adverse Reactions

Clinical Trials Experience

  • Heroin Withdrawal:
  • Initial Administration:
  • Initially, the dosage of methadone should be carefully titrated to the individual. Induction too rapid for the patient’s sensitivity is more likely to produce the following effects.
  • The major hazards of methadone, as of other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory depression. respiratory arrest, shock, and cardiac arrest have occurred.
  • The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Some adverse reactions may be alleviated in the ambulatory patient if he lies down.
  • Other adverse reactions include the following:
  • Maintenance on a Stabilized Dose:
  • During prolonged administration of methadone, as in a methadone maintenance treatment program, there is a gradual, yet progressive, disappearance of side-effects over a period of several weeks. However, constipation and sweating often persist.

Postmarketing Experience

There is limited information regarding Methadone (oral) Postmarketing Experience in the drug label.

Drug Interactions

  • Patients who are addicted to heroin or who are on the methadone maintenance program may experience withdrawal symptoms when given pentazocine.
  • The concurrent administration of rifampin may possibly reduce the blood concentration of methadone to a degree sufficient to produce withdrawal symptoms. The mechanism by which rifampin may decrease blood concentrations of methadone is not fully understood, although enhanced microsomal drug-metabolized enzymes may influence drug disposition.
  • Acute Abdominal Conditions:
  • The administration of methadone or other narcotics may obscure the diagnosis or clinical course patients with acute abdominal conditions.
  • Interaction with Monoamine Oxidase (MAO) Inhibitors:
  • Therapeutic doses of meperidine have precipitated severe reactions patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents with fourteen days. Similar reactions thus far have not been reported with methadone; but if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient’s condition and vital signs are under careful observation.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Caution shall be taken in the maintenance treatment of pregnant patients. Dosage levels shall be kept as low as possible if continued methadone treatment is deemed necessary. It is the responsibility of the program sponsor to assure that each female patient be fully informed concerning the possible risks to a pregnant woman or her unborn child from the use of methadone.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methadone (oral) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Methadone (oral) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Methadone (oral) in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Methadone (oral) in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Methadone (oral) in geriatric settings.

Gender

There is no FDA guidance on the use of Methadone (oral) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Methadone (oral) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Methadone (oral) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Methadone (oral) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Methadone (oral) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Methadone (oral) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Methadone (oral) Administration in the drug label.

Monitoring

There is limited information regarding Methadone (oral) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Methadone (oral) and IV administrations.

Overdosage

  • Symptoms:
  • Treatment:
  • Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant person, especially a child, takes a large dose of methadone, effective narcotic antagonists are available to counter-act the potentially lethal respiratory depression. The physician must remember, however, that methadone is a long-acting depressant (thirty-six to forty-eight hours), whereas the antagonists act for much shorter periods (one to three hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the diagnosis is correct and respiratory depression is due only to overdosage of methadone, the use of respiratory stimulants is not indicated.
  • An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists, naloxone hydrochloride, nalorphine hydrochloride, or levallorphan tartrate are the drugs of choice to reverse signs of intoxication. These agents should be given repeatedly until the patient's status remains satisfactory. The hazard that the narcotic antagonist will further depress respiration is less likely with the use of naloxone.
  • Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated.

Note: In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. the severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. the use of a narcotic antagonist in such a person should be avoided if possible. if it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Pharmacology

Template:Px
Template:Px
1 : 1 Mixture (racemate)Methadone
Systematic (IUPAC) name
(RS)-6-(Dimethylamino)-4,4-diphenylheptan-3-one
Identifiers
CAS number 76-99-3
ATC code N02AC52 N07BC02 (WHO)
PubChem 4095
DrugBank DB00333
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 309.445 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 41-99% (oral)[1]
Metabolism Hepatic (CYP3A4, CYP2B6 and CYP2D6-mediated)[1][2]
Half life 7-65 hours[2]
Excretion Urine, faeces[2]
Therapeutic considerations
Pregnancy cat.

C(AU) C(US)

Legal status

Controlled (S8)(AU) Class A(UK) Schedule II(US)

Routes Oral, intravenous, insufflation, sublingual, rectal

Mechanism of Action

  • Methadone hydrochloride is a synthetic narcotic analgesic with multiple actions quantitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation, detoxification or maintenance in narcotic addiction. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.
  • When administered orally, methadone is approximately one-half as potent as when given parenterally. Oral administration results in a delay of the onset, a lowering of the peak, and an increase in the duration of analgesic effect.

Structure

  • Methadone Hydrochloride is a white powder. It is chemically named 6-dimethylamino-4, 4-diphenyl-3-heptanone hydrochloride.

Pharmacodynamics

There is limited information regarding Methadone (oral) Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Methadone (oral) Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Methadone (oral) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Methadone (oral) Clinical Studies in the drug label.

How Supplied

  • Methadone Hydrochloride is supplied in containers of 50 gm., 100 gm., 500 gm., and 1 kilogram.
  • Preserve in tight, light-resistant containers. Store at controlled room temperature (15° to 30°C.) (59° to 86°F.)

MALLINCKRODT MALLINCKRODT INC. St. Louis, Missouri 63134 July 1998 1274111 Printed in U.S.A.

Storage

There is limited information regarding Methadone (oral) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Methadone (oral) Patient Counseling Information in the drug label.

Precautions with Alcohol

  • Alcohol-Methadone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Methadone (oral) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Methadone (oral) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ 1.0 1.1 Fredheim, OM (August 2008). "Clinical pharmacology of methadone for pain". Acta Anaesthesiologica Scandinavica. 52 (7): 879–89. doi:10.1111/j.1399-6576.2008.01597.x. PMID 18331375. Unknown parameter |coauthors= ignored (help)
  2. ↑ 2.0 2.1 2.2 Brown, R (November 2004). "Methadone: applied pharmacology and use as adjunctive treatment in chronic pain" (PDF). Postgraduate Medical Journal. 80 (949): 654–9. doi:10.1136/pgmj.2004.022988. PMC 1743125. PMID 15537850. Unknown parameter |coauthors= ignored (help)

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