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"Phy" redirects here. For other uses, see Phy (disambiguation).
This article is about the synthetic opioid. For the Rise Against song, see The Black Market (Rise Against album).
Not to be confused with Methedrine, Methedrone, Mephedrone, or Methylone.
Systematic (IUPAC) name
Clinical data
Trade names Dolophine
AHFS/ Consumer Drug Information
MedlinePlus a682134
  • AU: C
  • US: C (Risk not ruled out)
Legal status
Routes of
Oral, intravenous, insufflation, sublingual, rectal
Pharmacokinetic data
Bioavailability 41-99% (oral)[1]
Protein binding 85-90%[1]
Metabolism Hepatic (CYP3A4, CYP2B6 and CYP2D6-mediated)[1][2]
Biological half-life 7-65 hours[2]
Excretion Urine, faeces[2]
CAS Number 76-99-3 YesY
ATC code N02AC52 N07BC02
PubChem CID: 4095
DrugBank DB00333 YesY
ChemSpider 3953 YesY
KEGG D08195 YesY
Chemical data
Formula C21H27NO
Molecular mass 309.445 g/mol
 N (what is this?)  (verify)

Methadone, also known as Dolophine among other brand names, is a synthetic opioid. It is used medically as a pain medication and a maintenance therapy in people with opioid dependence. Methadone is also used in managing severe chronic pain owing to its long duration of action and strong analgesic effect.

Side effects are similar to that of other opioids. The number of drug-poisoning deaths in the United States involving methadone increased from 784 in 1999 to 5,518 in 2007 but declined to 4,418 in 2011.[3]

Methadone is a synthetic acyclic analog of morphine and heroin and acts on the same opioid receptors.

Methadone was developed in Germany in 1937 by Gustav Ehrhart and Max Bockmühl. Methadone was introduced into the United States in 1947 by Eli Lilly and Company. It is regulated similarly to morphine in most countries. In the United States, it is a Schedule II controlled substance. Globally in 2013 41,400 kilograms were manufactured.[4] Methadone is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[5]

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). 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.[6] Methadone helps opioid dependent individuals be more social and productive in life, and helps them hold down jobs, and maintain relationships. Methadone has many positive effects.

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 can be for months or even years. 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.[7][8] 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.[7] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. When used correctly, methadone maintenance has been found to be medically safe and non-sedating.[7] It is also indicated for pregnant women addicted to opiates.[7]

In Russia, methadone treatment is illegal. Health officials there are not convinced of the treatment's efficacy. Instead, doctors encourage immediate cessation of drug use, rather than the gradual process that methadone substitution therapy entails. Patients are often given sedatives and non-opiate analgesics to cope with withdrawal symptoms.[9]


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.[10][11]

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.[12]

Patients with long-term pain will sometimes have to perform so-called opioid rotation.[13] 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 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.[14] 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]

At dosage levels[edit]

Adverse effects of methadone include:[citation needed]


Methadone (6-dimethylamino-4,4-diphenyl-3-heptanone, Amidone) is a synthetic opioid developed during World War II by the german chemists Bockmühl and Erhart working for the Hoechst Laboratories of IG Farben8,10.

The pure levo-methadone isomer is 1.5-2.4 times stronger than the racemic mixture, but this small difference usually does not warrant isomer separation. The separation is unusually easy to perform though, as treatment of racemic methadone base with d-(+)-tartaric acid in an acetone/water mixture precipitates almost solely the dextro-methadone levo-tartrate, and the more potent levo-methadone can easily be retrieved from the mother liquor in a high state of optical purity11.

The reaction scheme for the synthesis of Methadone begins with the alkylation of the anion of diphenylacetonitrile (produced by reacting a strong base with diphenylacetonitrile) with 1-dimethylamino-2-chloropropane, which produces a mixture of two isomeric nitriles, one high-melting (commonly referred to as methadone nitrile), 2,2-Diphenyl-4-dimethylaminovaleronitrile (mp 91-92°C) and one low-melting (isomethadone nitrile, 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile (mp 69-70°C). The high-melting nitrile, upon reaction with ethyl magnesium bromide and subsequent hydrolysis gives methadone, while the low-melting nitrile reacts with ethyl magnesium bromide to give a stable ketimine (3-imino-4,4-diphenyl-5-methyl-6-dimethylaminohexane), which only with difficulty can be hydrolyzed to isomethadone13 (which is also an active opioid and a controlled substance), but the effects are much less interesting than those of Methadone itself).

The reason for the formation of two isomeric nitriles in the reaction is that 1-dimethylamino-2-chloropropane (or 1-chloro-2-dimethylamino-propane, which also may be used in the synthesis) cyclizes to an aziridinium salt (1,1,2-trimethylaziridinium chloride)1,5 under the employed reaction conditions:

Depending on from which side the diphenylacetonitrile anion attacks and performs the ring-opening reaction of the aziridinium salt, the different nitriles are formed. If the anion attacks from the left, methadone nitrile is formed, and isomethadone nitrile if it happens from the right.

The right side of the aziridinium salt is slighty more sterically hindered than the left, so it is possible to form the desired nitrile in a slight excess over the undesired one (the ratio is always 50:50 in most published syntheses (using more or less expensive sodium amide3, lithium amide13, or potassium tert-butoxide6) but two chemists using sodium hydroxide as the base managed to increase the yield of the desired isomer, and they are Cusic12 (a 6:4 isomer ratio, using a melt-phase reaction of the reactants with sodium hydroxide in the absence of any solvent), and Barnett5 (a 3:2 isomer ratio, using a dipolar aprotic solvent such as DMF or DMSO as a solvent. These two methods are decribed in this document.

There has been devised other syntheses which only produces the desired methadone nitrile14, but they are cumbersome, low-yielding and much more expensive than this reaction, so it is definitely worthwhile to discard the 1/3 unwanted nitrile produced using this method.

The Precursors

The precursors needed for the synthesis of Methadone are easily bought or synthesized from scratch. The basic building blocks are diphenylacetonitrile and 1-dimethylamino-2-chloropropane. Diphenylacetonitrile is commercially available, but it can be made from benzene and benzyl cyanide as described below. The 1-dimethylamino-2-chloropropane can be found only at a few of the largest chemical supply houses in the world, so it is best made from 1-dimethylamino-2-propanol as described below, and if this too is unavailable, it can be synthezized easily by the Eschweiler-Clarke methylation15 of the very basic building block 1-amino-2-propanol, using formaldehyde and formic acid. 1-dimethylamino-2-propanol can also be had by the alkylation of dimethylamine with propylene oxide. Finally, the ethyl magnesium bromide Grignard reagent used in the final step is made in situ from ethyl bromide and magnesium turnings. All in all, it is a very accessible synthesis to be an opiate, even if it requires several steps in case the final precursors are not available to the chemist who wants to pursue the synthesis. 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile

The only obstacle that might be encountered in the preparation of the nitrile is the isolation of only the desired isomer. A review of the literature shows that the desired high-melting nitrile is much less soluble in hexane, petroleum ether and diethyl ether than the other low-melting nitrile. So when recrystallizing the nitrile mixture (preferably from hexane/petroleum ether), it is always the high-melting nitrile that crystallizes first. It is important that the nitrile mixture is first freed from the reaction solvent and the basic catalyst by an acid/base extraction, followed by drying of the extraction solvent. Cheney13 concentrates a 700ml solution of mixed nitriles in diethyl ether prepared from 278g diphenylacetonitrile, and only the high-melting nitrile crystallizes, the low-melting isomer is left as an oil, which they isolate as its hydrochloride salt (mp 222-225°C). Schulz6 triturate the nitrile mixture from 19.3g diphenylacetonitrile under 35ml hexane, and cool the mixture in an ice-bath, and filter off the high-melting nitrile and recrystallize it from boiling petroleum ether to obtain the product as long needles, mp 90-91°C, and evaporation of the hexane filtrate from the trituration gave the low-melting nitrile as an oil. Schulz3 also states that the high-melting nitrile is quite insoluble in cold hexane, and therefore the amount of this solvent used in the trituration (done ice-cold) of the nitrile mixture is not critical. They also purify the high-melting nitrile by recrystallization from boiling hexane. Experimental

Method 15

A suspension of 1.36g (0.034 mol) of finely ground sodium hydroxide was prepared in 10 ml of dried DMF. A solution containing 6.0g (0.031 mol) of diphenylacetonitrile in 8 ml of DMF was added thereto at room temperature. After stirring the mixture for 15 minutes, 4.1g (0.034 mol) of 1-dimethylamino-2-chloropropane were added. The reaction mixture was heated with stirring to about 50°C for about 1.5 hours and was then cooled. The cooled reaction mixture was diluted with an equal volume of water and the resulting suspension, containing a mixture of 2,2-diphenyl-4-dimethylaminovaleronitrile and 2,2-diphenyl-3-methyl-4-dimethylamino- butyronitrile formed in the above reaction, was extracted with two 350 ml portions of benzene. The benzene extracts were combined, washed with water and with saturated sodium chloride solution and then dried. Removal of the solvent yielded about 7.83g of the crude reaction product which was shown by vapor phase chromatography to contain 58.4% 2,2-diphenyl-4-dimethylaminovaleronitrile, 29.3% of 2,2-diphenyl-3- methyl-4-dimethylaminobutyronitrile, and 10.8% of starting material diphenylacetonitrile. The methadone intermediate isomers were thus present in a ratio of 66.5:33.5. Recrystallization of the crude reaction product from hexane yielded purified 2,2-diphenyl-4-dimethylaminovaleronitrile.

The above reaction was also carried out employing DMSO in place of DMF as a solvent. The crude product analyzed for 60.6% of the desired valeronitrile isomer, 31.2% of the undesired methyl butyronitrile isomer, and 3.4% of unreacted diphenylacetonitrile (isomer ratio 66:34).

Method 25

A solution of 19.3 g. (0.1 mol.) of diphenylacetonitrile in 60 ml dimethylformamide was added with stirring to a slurry of 8g (0.2 mol) finely ground sodium hydroxide in 40 ml dimethylformamide under nitrogen. The dark red color of the nitrile anion was observed immediately. The mixture was heated to 75°C ±5°C and 14.85g (0.12 mol) 1-dimethylamino-2-chloropropane were added at a rate such that the reaction temperature was maintained in the range 75-80°C with external cooling when necessary. The reaction mixture was stirred at 75°C. under nitrogen for 1 hour, cooled and diluted with 250ml water. The aqueous mixture was extracted with 400 ml. of benzene in three portions. The extracts were combined and the combined extracts were washed with water and with saturated sodium chloride solution, and were then dried over anhydrous sodium sulfate. Removal of the benzene at reduced pressure afforded 26.7g of the crude mixture of isomeric nitriles, shown by VPC analysis to contain 64.8% 2,2-diphenyl-4-dimethylaminovaleronitrile, 34% 2,2-diphenyl-3-methyl- 4-dimethylaminobutyronitrile, and 0.35% unreacted diphenylacetonitrile, the remainder of the material consisting of unidentifed volatile impurities. The reaction was thus 99.6%. The ratio of isomeric nitriles was therefore, 65.6:34.4 in favor of the desired valeronitrile methadone intermediate. The crude product thus obtained was allowed to crystallize from hexane, affording 12.6g (45% of theory based on diphenylacetonitrile) of 2,2-diphenyl-4-dimethylaminovaleronitrile, mp 90-91°C. having a purity of 99%.

Method 312

60g (1.5 moles) of flake sodium hydroxide, 77.2g (0.4 moles) diphenylacetonitrile and 79g (0.5 moles) of 1-dimethylamino-2-choropropane hydrochloride were mixed in an erlenmeyer flask and heated with occasional stirring for 6-7 hours on a steam bath [or an oil bath with the temp at 100°C]. The reaction mixture was then extracted with ether and the ether in turn extracted ith dilute hydrochloric acid [~5% HCl(aq)]. The acid solution was made strongly alkaline with 25% sodium hydroxide solution, and the liberated base extracted with ether. The ether solution was dried over anhydrous potassium carbonate, filtered and the ether distilled off. The residue was vacuum distilled to give 89g of product, boiling at 173-174°C at 1 mmHg. It was then recrystallized from petroleum ether to give 49g (45.7%) of 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile, mp 89-90°C. Methadone

Method 1 - Hydrolysis with 13 eqv. HCl after solvent removal5

A 500ml distillation apparatus, equipped with a dropping funnel, condenser, stirrer, and drying tubes, was charged with a solution of ethyl magnesium bromide (prepared from 8.21g of magnesium and 35.57g of ethyl bromide) in 130ml of dry ether. A solution of 42g of 2,2-Diphenyl-3-methyl- 4-dimethylaminobutyronitrile in 80ml of hot anhydrous xylene was added over a period of 15 min. Solvent was distilled from the reaction vessel until the temperature of the reaction mixture rose to 70-80°C, and the mixture heated under reflux for an additional 4.25 h. The condenser was then arranged for distillation, and a solution consisting of 65ml of concentrated (37.5%) hydrochloric acid and 65ml of water was added to the hot reaction mixture over a period of 10 min, all of the remaining solvent distilling during this addition. The hot suspension was drawn off and the vessel rinsed with 20ml of 18% HCl. The crude crystalline Methadone hydrochloride, which crystallized upon cooling the combined acid solutions, was collected, dissolved in 240ml of boiling water containing 2g of activated charcoal, the solution heated to boiling, filtered while hot, and the charcoal residue washed with 10ml boiling water. A solution of 6.5g of sodium hydroxide in 10ml water was added to the combined filtrates. The Methadone freebase, which solidified on cooling, was collected, dissolved in 100ml boiling methanol, the solution filtered to remove a small amount of suspended solid, heated to boiling, and diluted with water until it became slightly turbid. After cooling and stirring the solution, the fine white crystals of Methadone base were collected, washed with 4 ml of methanol, and dried in vacuo. The dried Methadone thus obtained weighed 42.86g, melted at 76-78°C (91.9% yield).

Method 2 - Hydrolysis without prior solvent removal5

A solution of 50.8g of 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile in 40ml of hot anhydrous xylene (~65°C) was added to a stirred solution of ethyl magnesium bromide (prepared from 8.8 grams of magnesium and 44 grams of ethyl bromide) in 60ml of anhydrous ethyl ether, and the mixture thereafter heated under reflux for 3 h. The condenser was arranged for distillation, and 280 ml of 10% HCl was added to the mixture, and the organic solvent distilled from the reaction mixture by the heat of the ensuing vigorous reaction. The residue was then transferred to a beaker and 100 ml of benzene added, whereupon three layers formed. Upon standing, the Methadone hydrochloride, which crystallized from the oily middle layer, was collected, dried, dissolved in water, the aqueous solution made alkaline with sodium hydroxide, and then cooled. The Methadone separated as a solid and was crystallized from methanol, giving 48.8g (85.7% yield) of Methadone freebase, mp 77-79°C.

Method 3 - Hydrolysis with 2N H2SO414

When the toluene solution of the Grignard complex from ethylmagnesium iodide and 2,2-Diphenyl-3-methyl- 4-dimethylaminobutyronitrile was heated with an added excess of 2N (1M) sulfuric acid on a boiling water-bath for 30 minutes, Methadone sulfate crystallized out on cooling. It was filtered off and suspended in water, and excess 25% sodium hydroxide solution was added to liberate the free base, which was extracted with ether. After drying of the etheral solution over MgSO4, Methadone hydrochloride was precipitated by neutralization with ethanolic hydrogen chloride, and obtained pure in 91% yield (mp 232-233°C). Precursors 1-Dimethylamino-2-chloropropane5,6

Both 1-dimethylamino-2-propanol (bp 124°C) and 2-dimethylamino-1-propanol (bp 145°C) can be chlorinated by thionyl chloride in chloroform, to form the respective hydrochlorides of the corresponding alkyl chlorides, with mp 185-186°C and mp 104°C. The hydrochloride salt of the latter is soluble in chloroform, so it is not suitable for separation from the chloroform mother liquor by simple filtration, like the hydrochloride of the former. However, if the salts are made into the freebase and distilled, both rearrange into 1-dimethylamino- 2-chloropropane (bp 60-63°C/100mmHg) through the cyclic intermediate aziridinium salt (1,1,2-trimethyl- aziridinium chloride, see the introducory part above for its structure), as does the salts upon melting (mp 191-191.5°C).2,6 Experimental

A solution containing 3.77g of 1-dimethylamino-2-propanol and 10ml of chloroform was cooled with stirring to about 0°C. A solution of 5.72g freshly distilled thionyl chloride (SOCl2) in 2ml chloroform was added thereto. The reaction mixture was allowed to come to ambient temperature over 30 minutes, and was then boiled under reflux for another 30 minutes (HCl and SO2 gas is being evolved, use good ventilation). The precipitated material redissolved on heating. 1-dimethylamino-2-chloropropane hydrochloride began to precipitate from the boiling solution. The reaction mixture was cooled, diluted with ether and filtered. The preciptate weighed 5.5g (95% yield). Recrystallization gave pure 1-dimethylamino-2-chloropropane hydrochloride, mp 192-193°C.

2.2g 1-dimethylamino-2-chloropropane hydrochloride was dissolved in an equal amount of water and 1.5ml 20% NaOH was added and thorougly shaken. The freebase 1-dimethylamino-2-chloropropane, being insoluble in the aqueous alkaline solution, separated and was extracted with 2x5ml diethyl ether, and the combined etheral layers were dried over MgSO4, and the ether evaporated to give an oily residue consisting of 0.8g 1-dimethylamino-2-chloropropane.

If purer 1-dimethylamino-2-chloropropane freebase is desired, the hydrochloride salt can be turned into the freebase and distilled, by Schultz' method6:

   30g of 1-dimethylamino-2-chloropropane hydrochloride was dissolved in 40-50ml water and made strongly basic with 20% sodium hydroxide solution. The chloroamine layer was separated, dried over solid potassium hydroxide and vacuum distilled under a weak vacuum, bp 62-63°C/100-110mmHg. Yield 19g (82%).


This is an adaption of the Friedel-Crafts method for synthesizing diphenyl- acetonitrile, which minimizes the exposure to the intermediate alpha-bromo-alpha-phenylacetonitrile, which is a powerful lacrymator used in WWI, and also gives diphenylacetonitrile in an overall yield of 80% based on reacted benzyl cyanide.

Diphenylacetonitrile from Benzyl Cyanide7

In a five-liter, three-necked flask equipped with a dropping funnel whose stem extends below the surface of the liquid, a mercury-sealed stirrer and a reflux condenser protected by a calcium chloride tube is placed 441g (3.76 moles, 290 ml) of benzyl cyanide. Stirring is started and the cyanide is heated to 105-110°C by means of an oil-bath. Now 608g (3.80 moles, 195 ml) of bromine is added in the course of 60-90 minutes. Throughout this period the temperature is maintained within the range indicated above. The hydrogen bromide evolved may be absorbed in a water-trap. After addition is complete, two liters of dry benzene is added and the mixture is heated under reflux for about one hour, until virtually all the hydrogen bromide has escaped. The dropping funnel is now instantly replaced by a solid rubber stopper (Note 1).

The reaction mixture is cooled to 20°C. Stirring is continued and 507 g. (3.81 moles) of powdered anhydrous aluminum chloride is added in portions in the course of about one hour with the usual precautions (Note 2). The temperature in this period is maintained at 20-25°C. When the addition of catalyst is complete, the temperature of the mixture is slowly raised. In about fifteen minutes, when the temperature has reached 35-40°C, vigorous evolution of hydrogen bromide commences. Upon abatement of the reaction, the mixture is heated under reflux for 60-90 minutes and then cooled to room temperature.

It is poured slowly and with stirring into a mixture of 1800 g. of ice and 760 ml. of 1:1 hydrochloric acid. The layers are separated. The aqueous portion is extracted twice with 800-ml. portions of benzene. The combined benzene extracts are-washed successively with one liter of water, one liter of 5% sodium carbonate and one liter of water. The washings are discarded; the benzene solution is dried over 250g. of anhydrous sodium sulfate. The benzene is distilled at atmospheric pressure and the residue is distilled under reduced pressure using a steam-heated condenser; bp 160-170°C/5 mmHg. The crude product is recrystallized from methanol (0.5 mL/g); yield (in two crops) 585g (80% based on benzyl cyanide) ; mp 73-74°C. Notes

   The equipment may be originally assembled so that one of the side-necks of the flask carries a two-necked adapter. Then no detachment need be made, and all possibility of exposure to alpha-bromo-alpha-phenylacetonitrile can be eliminated.
   It is convenient to weigh the aluminum chloride into an Erlenmeyer flask and to attach the latter by a rubber sleeve to the available neck of the flask.

Diphenylacetonitrile from Mandelonitrile16

In a 2-liter; four-necked flask, equipped with a condenser, stirrer, thermometer, and addition funnel, were placed anhydrous benzene (4.5 liters) and technical anhydrous aluminum chloride (7 pounds). Operations were conducted in a well ventilated hood since hydrogen chloride and hydrogen cyanide were evolved. The flask and contents were cooled by means of an ice bath. Mandelonitrile (1330 g) was added gradually during a period of 31/2 hours to the stirred reaction mixture, which was maintained at a temperature of 10-20°C. After the addition of the mandelonitrile, the reaction, mixture was heated slowly to a temperature of 75°C and maintained at this temperature, for one hour. After cooling the reaction mixture, water was added cautiously through the addition funnel. Cooling was continued to control the exothermic reaction while a total of 3 liters of water was added. Then excess benzene was removed by steam distillation. The product was present as an oil which solidified on cooling and was filtered from the aqueous part and washed with water. The crude product (1680g, 87% yield) was dissolved in hot methanol (5 L.) and decolorized with activated carbon. The alcoholic solution was chilled and the product which crystallized was filtered. A second recrystallization from methanol (1.6 L) yielded 1464 g. (76% yield) of dry purified diphenylacetonitrile, melting point 73-75°C. References

   E. Schultz, Reaction of Aminoalkylhalides and Diphenylacetonitrile, JACS 69, 188 (1947)
   W. Brode, Rearrangement of the 1,2-dimethylaminochloropropanes, JACS 69, 724 (1947)
   E. Schultz, The Structure of Amidone, JACS 69, 2454-2459 (1947)
   N. Easton, Synthesis and Confirmation of the Amidone Structure, JACS 69, 2941-2942 (1947)
   C. Barnett, Modification of Methadone Synthesis Process Step, US Pat. 4,048,211
   E. Schulz, Rearrangements of 1,2-dimethylaminochloropropanes, JACS 70, 48 (1948)
   D. Ginsburg, Diphenylacetonitrile, JACS 71, 2254 (1949)
   M. Bockmuhl, Über eine neue Klasse von analgetisch wirkenden Verbindungen Ann. Chem. 561, 52 (1948)
   W. B. Reid, Process for Preparing 4,4-Diphenyl-6-dimethylamino-heptanone-3, US Pat. 2,601,323
   Casy & Parfitt, Opioid Analgesics - Chemistry and Receptors, p 303-332, Plenum Press (1986)
   A. A. Larsen, JACS 70, 4 194 (1948)
   J. W. Cusic, An Improvement on the Process for Making Amidone, JACS 71, 3546 (1949)
   L. C. Cheney, Ketimines and Acylketimines Related to Amidone, JACS 71, 53 (1949)
   A. L. Morrison, Synthesis of Compounds Related to Amidone, JCS 1478 (1950)
   Clarke, JACS 55, 4571 (1933)
   A. H. Homeyer and J. S. Splitter, Preparation of certain diarylacetonitriles, US Pat 2,443,246

Withdrawal symptoms[edit]

Physical symptoms[citation needed]

Cognitive symptoms[citation needed]

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

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

Oral symptoms[edit]

Methadone is sometimes administered in a sugary syrup which is swallowed. This preparation has been proposed to cause significant tooth decay. Methadone causes dry mouth, reducing the protective role of saliva in preventing decay as well as with most Opiates an increase in craving for sugary foods and Carbohydrates and a general decrease in personal hygiene due to several factors such as sedation combine to cause extensive damage to the teeth in persons taking methadone.[22][23]

Symptoms of overdose[edit]

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

The respiratory depression of an overdose can be treated with naloxone.[21] 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).

Tolerance and dependence[edit]

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).[25]


Methadone treatment may impair driving ability.[26] Drug abuse patients had significantly more involvement in serious crashes than non-abuse patients in a study by the University of Queensland. In the study of a group of 220 drug abuse patients, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other patients randomly selected having no involvement in fatal crashes.[27] However, there have been multiple studies verifying the ability of methadone maintenance patients to drive.[28] In the UK, persons who are prescribed oral Methadone can continue to drive after they have satisfactorily completed an independent medical examination which will include a urine screen for drugs. The licence will be issued for 12 months at a time and even then, only following a favourable assessment from their own doctor.[29] 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.


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,[30] as well as a 2006 series in the Charleston (West Virginia) Gazette,[31] medical examiners listed methadone as contributing to 3,849 deaths in 2004. That number was up from 790 in 1999. Approximately 82 percent of those deaths were listed as accidental, and most deaths involved combinations of methadone with other drugs (especially benzodiazepines).

Although deaths from methadone are on the rise, methadone-associated deaths are not being caused primarily by methadone intended for methadone treatment programs, according to a panel of experts convened by the Substance Abuse and Mental Health Services Administration, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor in methadone-associated mortality."[32]

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."[33]

Detection in biological fluids[edit]

Methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naive individual. Chronic users often have high methadone and EDDP baseline values.[34]


Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6 and is a substrate for the P-Glycoprotein efflux protein in intestine and brain. The bioavailability and elimination half-life of methadone is subject to substantial inter-individual variability. Its main route of administration is oral. Adverse effects include sedation, hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opiates, spanning anywhere from two weeks to several months. Many factors contribute to its metabolism and excretion rate including the individual's body weight, history of use/abuse, metabolic dysfunctions, renal system dysfunction, among others.

Mechanism of action[edit]

Levomethadone is a full µ-opioid agonist.[citation needed] Dextromethadone does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA antagonism. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (d-methadone) acts as an NMDA antagonist and is devoid of opioid activity: it has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[35]


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,[36][37] ranging from as few as 4 hours to as many as 130 hours,[38] or even 190 hours.[39] This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half-life frequently allows for administration only once a day in Opioid detoxification and maintenance programs. Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.[38] This can also allow lower total doses in some such patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.[citation needed]

Route of administration[edit]

The most common route of administration at a methadone clinic is in a racemic oral solution, though in Germany, only the R enantiomer (the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects.[38] This is becoming less common due to the higher production costs.

Methadone is available in traditional pill, sublingual tablet, and two different formulations designed for the patient to drink. Drinkable forms include ready-to-dispense liquid, and "Disket" which is a tablet designed to disperse itself in water for oral administration, used in a similar fashion to Alka-Seltzer. The liquid form is the most common as it allows for smaller dose changes. Methadone is almost as effective when administered orally as by injection. In fact, injection of methadone does not result in a "rush" as with some other strong opioids such as morphine or hydromorphone, because its extraordinarily high volume of distribution causes it to diffuse into other tissues in the body, particularly fatty tissue; the peak concentration in the blood is achieved at roughly the same time, whether the drug is injected or ingested.[citation needed] Injecting Methadone pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects. Methadone pills often contain talc[40][41] that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots. These particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as pulmonary hypertension, an irreversible and progressive disease.[42][43][44] Methadose/Methadone should not be injected either.[45] While it has been done in extremely diluted concentrations, instances of cardiac arrest have been reported as well as damaged veins from sugar and other ingredients (Sugar-Free syrups also should not be injected). Oral medication offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs.[46]

Patient information leaflets included in packs of UK methadone tablets state that the tablets are for oral use only and that use by any other route can cause serious harm. In addition to this warning, additives have now been included into the tablets formulation to make the use of them by the IV route more difficult.[47]


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.[48][49] 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.[48]

In the 1930s Pethidine (Demerol) went into production in Germany, however methadone called Hosch 10820 was not carried forward because of side effects discovered in the early research.[50] It is a myth that Hitler ordered the manufacture of methadone or that it was named after Hitler (Dolophine is an American tradename). In fact there is no evidence that methadone was ever used in Germany because morphine supplies were cut off.[51]

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.[48] 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.[48]

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,[48] 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.[52]

The trade name Dolophine was created by Eli Lilly. The pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s.[53][54] An urban legend claims Dolophine was named for Adolf Hitler.

Society and culture[edit]

Brand names[edit]

Brand names include Dolophine, Symoron, Amidone, Methadose, Physeptone, and Heptadon among others.


In Germany the annual cost per patient is less than 3000 euros, while heroin assisted treatment costs up to 10,000 euros per year. Methadone clinics in the U.S. charge anywhere from $5–400 per week, which may be covered by private insurance or Medicaid. MMT cost analysis often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.[55][56]


Methadone substitution as a treatment of opiate addiction has been widely criticised in the social sciences for its role in social control of addicts.[57] It is suggested that methadone does not function as much to curb addiction as to redirect it and maintain dependency on authorised channels. Several authors apply a Foucauldian analysis to the widespread prescription of the drug and use in institutions such as prisons, hospitals and rehabilitation centres.[58] Such critique centers on the notion that substance addiction is reframed with a disease model. Thus methadone, which mimics the effects of opioids and renders the addict compliant, is labelled as a “treatment” and so obscures the disciplinary objectives of “managing undesirables”.[57]

Similar drugs[edit]

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

The closest chemical relative of methadone in clinical use is levo-α-acetylmethadol or LAAM. It has a longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994, it was approved as a narcotic addiction treatment. In the Netherlands, like methadone and all other strong opioids, LAAM is a List I drug of the Opium Law, and in Schedule II of the United States Controlled Substances Act. LAAM has since been removed from the US and European markets due to reports of rare cardiac side effects.

Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Subutex (buprenorphine) and Suboxone (buprenorphine combined with naloxone). With the Drug Addiction Treatment Act of 2000, qualified physicians in the U.S. were allowed to prescribe buprenorphine and other Schedule III drugs on an outpatient basis.

In the Netherlands, Switzerland, the UK and a few other European countries, not only buprenorphine and oral methadone but also injectable methadone and pharmaceutical diamorphine (heroin) or other opioids may be used for outpatient maintenance treatment of opiate addiction, and treatment is generally provided in much less heavily regulated environments than in the United States. In the United Kingdom, diamorphine is used extremely selectively and is not available on prescription to addicts; except in specialist trials which involved no more than 300 participants. A study from Austria indicated that slow release oral morphine (in the form of MS-Contin), under trade names Substitol-Retard and Compensan, provide better results than oral methadone, and studies of heroin maintenance have indicated that a low background dose of methadone combined with heroin maintenance may significantly improve outcomes for less-responsive patients.[59] Since the late 1990s in Austria, slow release oral morphine has been used alongside methadone and buprenorphine for Opioid Substitution Therapy (OST) and more recently it has been approved in Slovenia and Bulgaria, and it has gained approval in other EU nations including the United Kingdom, although its use is not yet as widespread. The more attractive side-effect profile of morphine compared to buprenorphine or methadone has led to the adoption of morphine as an option for OST treatment, and currently in Vienna over 60 percent of substitution therapy utilizes slow release oral morphine. Illicit diversion has been a problem, but to the many proponents of the utilization of morphine for OST, the benefits far outweigh the costs, taking into account the much higher percentage of addicts who are "held" or, from another perspective, satisfied by this treatment option, as opposed to methadone and buprenorphine treated addicts, who are more likely to forgo their treatment and revert to using heroin etc., in many cases by selling their methadone or buprenorphine prescriptions to afford their opiate of choice. Driving impairment tests done in the Netherlands that have shown morphine to have the least negative effects on cognitive ability on a number of mental tasks also suggest morphines use in OST may allow for better psychological functioning and engagement in society. Other opiates such as dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.[60]

Another close relative of methadone is dextropropoxyphene, first marketed in 1957 under the trade name of Darvon. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II of the United States Controlled Substances Act, while preparations containing it are in Schedule IV. More than 100 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. Since dextropropoxyphene produces relatively modest pain relief compared to other opioids but still produces severe respiratory depression at high doses, it is particularly dangerous when abused, as drug users may take dangerously high doses in an attempt to achieve narcotic effects. This narcotic is among the top 10 drugs reported by medical examiners in recreational drug use deaths. However, dextropropoxyphene is still prescribed for the short term relief of opiate withdrawal symptoms, particularly when the aim of treatment is to smooth detoxification to a drug-free state rather than a switch to maintenance treatment.

This drug has been taken off the market in Europe and the U.S. due to concerns of fatal overdoses and abnormal heart rhythms.[61] An estimated 10 million patients have used these products.

Other analogs of methadone which are still in clinical use are dipipanone (Diconal) and dextromoramide (Palfium) which are shorter-lasting but considerably more effective as analgesics. In the 1980s and beginning of the 1990s, before pharmaceutical grade IV heroin treatment became available to heroin addicts, as either single drug replacement for street heroin, or to be used alongside prescribed methadone, oral dextromoramide was prescribed to heroin addicts instead, because even when taken orally it still produces a strong, so called "rush", without the need of IV administration and any of the risks involved with it. These drugs have a high potential for abuse and dependence and were notorious for being widely abused and sought after by drug addicts in the 1970s. They are still rarely used for the relief of severe pain in the treatment of terminal cancer or other serious medical conditions. Different nations within the EU have different regulations, and in some nations general practitioners have the legal right to maintain addicts with whatever they deem to be most efficacious in maintaining their health and well being.[citation needed]


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Additional resources[edit]

  • Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 1362. ISBN 1437727883. 
  • Fraser, Suzanne; valentine, kylie (2008). Substance and Substitution: Methadone subjects in liberal societies (1st ed.). Basingstoke: Palgrave Macmillan. p. 216. ISBN 9780230019980. 

External links[edit]