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
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
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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