Monday, October 22, 2018

Methadone History


Methadone is a narcotic analgesic that was first discovered by German scientists in the 1930s while they were searching for a painkiller that was less addictive than morphine. It is a synthetic opioid that is made from the poppy plant like both heroin and morphine are and, therefore, has similar actions to both drugs.4 It was discovered by forming different compounds from opium to find a chemical with similar actions to morphine without the addictiveness. It wasn’t until World War 2 that methadone was mass produced by the Germans due to a shortage of morphine and other analgesics. After the end of World War 2, the US obtained the rights of methadone in war requisitions and began to produce it as a painkiller. It was used exclusively as a painkiller until the 1960s when its effectiveness of treating heroin addiction was realized. It is effective as a treatment because it mimics the effects of morphine or other opioid agents such as heroin. However, methadone has a gradual and mild onset of action which helps to prevent the user from experiencing euphoric effects or getting a high.4
Methadone exerts its principal pharmacological effect on the central nervous system and the smooth muscle in the intestines. It is an agonist at specific receptor binding sites in the CNS especially the mu-receptor, an opiate receptor specific to the pain modulating regions of the CNS.1 This simply means that methadone binds to the mu-receptor in the CNS and promotes a painkilling response similar to that of morphine or heroin. Methadone also produces respiratory depression through a direct effect on the respiratory centers in the brain stem.
Studies in the 1970s showed that methadone started to exhibit opiate-like side effects when administered multiple times a day which suggested an accumulation of methadone in the system.3 This meant that while morphine and heroin had half lives of 4-6 hours, methadone had a half-life of 24-36 hours which means that the effects of methadone were prolonged and able to treat heroin addiction by suppressing withdrawal symptoms. Additionally, when given in small enough doses, methadone can treat addiction while not giving the user a high or  for euphoric effect. Methadone is dispensed primarily in oral forms and a single dosage should not exceed 80-100 mg.
The main side effect of methadone is that, if taken in too large of a dose, can have the same euphoric effect as heroin. Other adverse effects of methadone include drowsiness, nausea, vomiting, insomnia, edema of the lower extremities, and constipation. All of these effects are also a result in taking too large of a dose and diminish as tolerance increases. The main drug that has replaced methadone in the past years as a treatment for heroin addiction is Buprenorphine. Buprenorphine is a semi-synthetic Schedule 5 narcotic analgesic. It has replaced methadone in the treatment of opioid dependency because it produces far less respiratory distress which is through to be safer in the event of an overdose.2 It also does not produce significant levels of physical dependence or withdrawal symptoms. Finally, there is strong evidence that it has a lower risk for preterm birth, greater birth weight, and larger head circumference when taken while pregnant compared to methadone.5
The patent for methadone was confiscated by the United States from Germany under war reparations after the end of World War 2. The first company that began to produce methadone in the US was Eli Lilly and Company in 1947 under the brand name Dolophine. Dolophine was approved by the FDA in 1947 and today is being manufactured by West-Ward Pharmaceutics, or Hikma, while other generic formulations are produced by a multitude of companies. Even though many companies produce a knock-off version of methadone, Hikma is the company that has the RLD that the bioavailability is measured against.

The initial drug was approved by the FDA in 1947 while there have been many supplements and modifications made to the original drug that have been approved since then, the most recent being a labeling insert change made in 2018. This shows that the drug is still being used even though it was discovered so long ago. The average cost of a 5 mg tablet can range anywhere from 0.25 to 2.50 USD depending on if it came from a generic or name-brand source. There has been one warning letter sent to Hikma from the FDA explaining that Hikma was not following GMP and corrective actions needed to be taken. There have been no recalls on dolophine and no new patents filed since 1947.

References:
1.) Methadone. (n.d.). Retrieved from             https://pubchem.ncbi.nlm.nih.gov/compound/methadone#section=Top

2.) Methadone | CESAR. (n.d.). Retrieved from               http://www.cesar.umd.edu/cesar/drugs/methadone.asp#5

3.) Rettig, R. A., & Yarmolinsky, A. (1995). Federal regulation of methadone treatment. Washington, D.C.: National Academy Press.

4.) Simpson, C. (1997). Methadone. New York: Rosen Publ.

5.) Zedler, B. K., Mann, A. L., Kim, M. M., Amick, H. R., Joyce, A. R., Murrelle, E. L., & Jones, H. E. (2016). Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: A systematic review and meta-analysis of safety in the mother, fetus and child. Addiction,111(12), 2115-2128. doi:10.1111/add.13462

6.) https://patentscope.wipo.int/search/en/result.jsf
7.) https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
8.) https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm420960.htm

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