Introduction to Methadone

Methadone is a synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. It has actions and uses similar to those of morphine. It also has a depressant action on the cough center and may be given to control intractable cough associated with terminal lung cancer. Methadone is also used as part of the treatment of dependence on opioid drugs, although prolonged use of methadone itself may result in dependence[1].

Using Methadone

Ways of administration

Methadone can be orally ingested in either tablet form (More often given to patients with sever pain) or as a liquid which is most often prescribed to opiate/opioid addicts. It is given in a liquid form to opiate addicts due to the fact that the methadone dosage for opiate addicts is highly individualized down to the milligram, and it's lower cost. Methadone can also be injected, and is often done in hospital settings when oral administration is difficult for the patient. Otherwise the injectable form of methadone is very rarely given out. Injecting methadone that should be ingested orally is very dangerous as it can lead to collapsed veins and infections.

Effects of Methadone

Methadone has analgesic effects which help those with chronic pain. As with most opiates/opioids it can induce nausea. Other side effects include shallow breathing, increased sweating, dizziness, drowsiness, lightheadedness and itchiness. When used recreationally methadone can have slight euphoric effects, drowsiness and what users would describe as nodding out.

Combinations with Methadone

Combinations that are to be avoided when taking methadone.

Depressants

Central nervous system depressants such as other opiates, benzodiazepines, dissociatives and alcohol. When these substances are mixed this can induce severe respiratory depression and ultimately death.

MAOI's

Methodone in combination with other serotonergics has been implicated in serotonin toxicity[2].

SSRI's

Methodone in combination with other serotonergics has been implicated in serotonin toxicity[2].

Stimulants

Cocaine, MDMA and amphetamines with methadone can also be dangerous as this can induce fatal respiratory depression. Serotonin toxicity has also been implied[2].

Different Uses for Methadone

For the treatment of dry cough, drug withdrawal syndrome, opioid type drug dependence, and pain.

Pharmacology of Methadone

Methadone is a synthetic opioid analgesic with multiple actions quantitatively similar to those at morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. However, Methadone is more active and more toxic than morphine. Methadone is indicated for relief of severe pain, for detoxification treatment of narcotic addiction, and for temporary maintenance treatment of narcotic addiction. The principal actions of therapeutic value are analgesia and sedation and detoxification or temporary 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.

Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA receptor, an ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6 and is a substrate for the P-glycoprotein efflux protein in the intestines and brain. The bioavailability and elimination half-life of methadone are subject to substantial interindividual variability.

LD₅₀ (mg/kg) [3] :
- Hydrochloride
Rat : 95 orally
- l-form hydrochloride
Rat : 44 subcutaneously

Chemistry of Methadone

Column 1	Column 2
Systematic(IUPAC) name:	(RS)-6-(dimethylamino)-4,4-diphenylheptan-3-one
Synonyms:	1,1-diphenyl-1-(2-dimethylaminopropyl)-2-butanone, 4,4-diphenyl-6-dimethylamino-3-heptanone; AN-148, Hoechst 10820, Depridol, Dolophine, Fentadone, Heptadon, Ketalgin, Mephenon, Methadose, Physeptone (hydrochloride); Levomethadone hydrochloride, L-Polamidon (l-form hydrochloride)
Molecular Formula:	C21H27NO, C21H27NO.HCl (hydrochloride)
Molar mass:	309.45 g/mol, 245.91 g/mol (hydrochloride)
CAS Registry Number:	76-99-3, 1095-90-5 (hydrochloride), 5967-73-7 (l-form hydrochloride)
Melting Point:	78°C, 235°C (hydrochloride), 241°C (l-form hydrochloride)
Boiling Point:	no data
Flash Point:	no data
Solubility:	48.5 mg/L (water, 25°C) (ref?) Hydrochloride 0.12 g/mL (water), 0.08 g/mL (alcohol), 0.024 g/mL (isopropanol); freely soluble in chloroform; practically insoluble in ether, glycerol
Additionnal data:	pH of 1% aqueous solution 4.5-5.6
Notes:	Freebase precipitates at pH > 6. Hydrochloride aspect : patelets; crystallized from alcohol + ether

[2]

The dangers of Methadone

FDA Public Health Advisory: Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat

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.

Producing Methadone

Methadone is easily synthetized starting from diphenylacetonitrile according to the following scheme [4] :

Forms of Methadone

Methadone comes in numerous forms such as tablets, orally ingested liquid and injectable liquid vials.

Legal status of Methadone

Methadone is a controlled substance 21 CFR 1308.12

United Nations

Methadone is a controlled substance 21 CFR 1308.12

USA

Methadone is a prescription-only medicine and is a class A controlled drug (Schedule 2).

EU

In the UK methadone is a class A controlled substance if not accompanied by a doctor's prescription.

Other Countries

History of Methadone

Methadone was first synthesized in 1939 at the pharmaceutical laboratories of the I.G. Farbenkonzern, a subsidiary of the Farbwerke Hoechst, Frankfurt am Main, Germany. It was the product of a long and continuous research chain in the area of synthetic antipyretics and analgetics that had already been initiated in the early 1880s (e.g. Antipyrin® 1884, Pyramidon® 1897, and Novalgin® 1921). At the end of the 1920s the Hoechst scientists had focused their research on the development of medications with both painkilling and spasmolytic properties [5][6] and a first major progress in research was made in 1937 when the Hoechst chemists Eisleb and Schaumann discovered Pethidin/pethidine (1-methyl-4-phenyl-4-carbaethoxypiperidin), an effective opioid analgesic drug which was launched in Germany in 1939 under the trade name Dolantin® [1]. In the course of ongoing research on synthetic opioids the Hoechst scientists Bockmühl and Ehrhart discovered a number of basically substituted diphenylmethanes acting both analgesically and spasmolytically. One of these compounds was 2-dimethylamino-4,4-diphenylheptanon-(5), which they numbered Va 10820 [1][1]. Va 10820 was to become known as methadone no sooner than 1947.

Due to the huge number of compounds discovered in 1939 Ehrhart started pharmacological tests with Va 10820 only in early 1942 (after a lot of other compounds had already been tested). Clinical tests still followed in the autumn of the same year[1]. Compound Va 10820 was also provided to the military, the German Wehrmacht, for additional testing under the code name Amidon [7]. To date, there is no evidence that Amidon was handed over to the Wehrmacht in appreciable quantities. Since at Hoechst the production level of Amidon was very low, the top priority of opioid production lay with Pethidin, only an insignificant quantity could have been handed over to the military. All known sources clearly indicate, that after the first clinical tests had been completed, Amidon was not used during World War II - most likely, both the Hoechst scientists and the Wehrmacht doctors used inadequate doses in the experiments causing undesirable side effects: There is no evidence that Amidon had been used as a painkiller in casualty clearing stations or military hospitals. Further, the drug had not been approved for commercial production. Thus, the civic medical sector had also been excluded from being supplied with Amidon.

For the reasons given above, it is dishonest to state that “methadone” had widely been used during the war as a painkiller and a substitute for morphine under the trade name Dolophin (Dolophine), allegedly derived from Hitler’s first name Adolf. Also, stating that Amidon had been called Adolfin (Adolphine) among soldiers and civilian people is entirely unfounded. In fact, the name Adolphine was created in the US in the early 1970s:

“The invention of the term ‘Adolphine’ by New York City street linguists in the 1970s was an apparent attempt to discredit methadone treatment by those unsympathetic to it, using the Hitler association”[8][9].

The discovery of Pethidin (pethidine), Amidon and several other synthetic opioid analgesics must not be seen isolated from Hitler’s attempt to achieve in Germany a state of economic and industrial independence of other countries (autarchy), as pronounced in 1936 when Hitler introduced his war-preparatory Four-Year-Plan[10][11]. As a consequence of the re-organization and re-structuring of the German trade and industry there was also a stepping up of efforts to become independent on the import of opium needed for the production of morphine.

Of course, the discovery of medications cannot be ordered by politicians or military forces. Acting together were both intensified research activities within the scope of the Four-Year-Plan as well as decades of research in the field of analgesics. The more financial support and manpower, the more intensive research is possible and the more chances are there to make discoveries.

After the war, all German patents, trade names and research records were requisitioned and expropriated by the allied forces. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US.

It was only in 1947 that Amidon was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association (COUNCIL...1947). Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected each pharmaceutical company interested in the formula could purchase the rights for commercial production of methadone for just one dollar [5]. Commercial production was first introduced in 1947 by the US company Eli-Lilly. Only then methadone was given the trade name Dolophine, derived from the Latin dolor (pain) and finis (end). Many companies in other countries soon followed and methadone was given many trade names, some of which still exist.

As a consequence of post-war events (e.g. the I.G. Farbenindustrie was broken up by the allies) the newly founded Hoechst AG could only in January 1949 launch methadone on the German pharmaceutical market under the protected trade name “Polamidon”. The patent approval of Polamidon was given on February 2, 1953. It took four years to have the patent problems clarified with the relevant US authorities.

More Methadone Sections

Methadone Forum
Methadone Images
Methadone Studies
Opiate Recovery Journals

References

1. ^Martindale, The Extra Pharmacopoeia, 30th ed, p1082-3
2. ^ a b cDrugs Forum Wiki: Serotonin Toxicity
3. ^ a b c dMerck Index, fifteenth edition (2013)
4. ^ a bSynthesis of Essential Drugs[/I], 1st edition, Ruben Vardanyan & Victor Hruby, Elsevier
5. ^ a bMOLL 1990
6. ^HOECHST AG 1992
7. ^PRESTON 1996
8. ^BYRNE 1995, 20;
9. ^KLEBER 2002
10. ^KÜHNL 1977
11. ^PIEPER 2002