By: Foster Desmond
Discovered in 1966 by Reckitt and Coleman in England, Buprenorphine is the
most predominant drug used to treat opiate addiction. John Lewis was a chemist at
Reckitt and Coleman when the compound was discovered and he was also a
doctoral student of Robert Robinson, the discoverer of morphine. Reckitt and
Coleman sent Buprenorphine to the ARC, addiction research center, in Lexington,
Kentucky throughout the 1970’s to help treat opioid addicts in the Lexington area as
well as provide data on the effectiveness of the compound in addiction therapy. It
took over 20 years for the FDA to approve Buprenorphine as a therapy for addiction
because of many issues that arose in the approval process. One of these issues was
that pharmaceutical companies were hesitant to associate with addiction
medications (Campbell & Levell).
Buprenorphine is synthetic derivatives of opiates and therefore is an opioid.
The creators of the drug, Reckitt and Coleman, developed it by making the structure
of morphine more complex so that the desired effects of morphine would remain in
the new drug without carrying any of the side effects (Campbell & Levell).
Buprenorphine’s mechanism of action is a mix of agonist and antagonist
characteristics depending on the opioid receptor. This drug has a high binding
affinity for the mu opiate receptor, which displays a partial agonist affect, and it
weakly binds to the kappa receptor, which displays an antagonist affect (Whelan &
Remski).
Buprenorphine is FDA approved to treat Opiate dependence as well as pain
management. Both of these approved uses have certain dosage forms that should be
used dependent on the indication. For opiate dependence a patient can use the
Extended-release Injection, Subdermal Implant, or the Sublingual Tablet dosage
form (Lexi-comp).
The adverse drug event, ADE, profile is characterized by the different dosage
forms. I chose to focus on the ADEs of the sublingual tablet due to my experience of
this dosage form being the predominant form. The ADEs that affect the most
patients are central nervous system events and these are headache, affecting 29% of
the patients, and insomnia, affecting 21% of patients. These ADEs are followed by
diaphoresis, Nausea, vomiting, abdominal pain, constipation, and infection. These
events are all fairly common with the lowest incidence affecting 8% of patients
(Lexi-comp).
Buprenorphine is the newer counterpart of methadone. Buprenorphine is
considered a better alterative to methadone for opioid replacement therapy. This is
based on buprenorphine’s unique mechanism of action, which was talked about
above. Methadone, on the other hand, is a full agonist and therefore causes an abuse
potential. Methadone is also dose dependent and therefore increased the overdose
risk. Methadone also led to a potentially severe withdraw. Buprenorphine on the
other hand, being only a partial agonist, provided a lower abuse potential and a
limited overdose risk because the effects felt from buprenorphine are not dose
depended and instead can reach a maximum limiting a patients feeling of needing
more (Campbell & Levell).
For the future of this drug I feel as if the addictive potential will be removed
completely in development of a new drug. I find this to be the future because of the
way in which buprenorphine was so much less addictive than methadone.
There are many manufacturers of buprenorphine, Actavis, Hi-Tech, Hikma, Mylan, Rhodes, Sun, and Teva all produce sublingual buprenorphine as a standalone without Naloxone (BTOD). It is most likely that this is not an exhaustive list of manufacturers since this was only taken from one source and did not include Reckitt Benckiser, who is the manufacturer of Subutex, the brand formulation. One of the most predominant, and apparently the first, generic producer of buprenorphine is Mylan.
Mylan is an American based generic pharmaceutical industry who is publicly traded under Dutch law. Mylan went public on February 23, 1973 and North America makes up for 42% of their third party sale. Mylan has a revenue of 11.87 billion US dollars in 2017 and a operating income of 830.1 million dollars in 2015. Mylan began producing buprenorphine shortly after this ANDA was approved by the FSA in 2015.
A patent for buprenorphine was file with the US patent office on Mar. 18 of 1969 by Reckitt & Sons. Buprenorphine has not had many recalls, at least not that were found. The most recent recall was by Par pharmaceuticals and this was a voluntary recall for the injectable form.
One preclinical trial using buprenorphine evaluated the use of cocaine in monkeys when given buprenorphine and how buprenorphine decreased the use of cocaine use (Nancy et al.). This preclinical trial showed the effectiveness of buprenorphine in opioid use disorder. The antagonistic affects of buprenorphine contribute to the safety profile of the drug since it has no benefit of taking more and potentiating an overdose.
One clinical trial currently ongoing evaluates a new dosing regimen in treating Neonatal abstinence syndrome. The clinical trial has already proven its safety in new born children is now undergoing pharmacokinetic profiling to fine tune the dosing regimen. This study is being completed at Thomas Jefferson University (Kraft).
Reckitt Benckiser had there NDA for Subutex, which is buprenorphine HCl, as well as Suboxone, which is Buprenorphine HCL and Naloxone HCl Dihydrate, approved by the FDA on October 8th, 2002. These were approved under application numbers 020732 and 020733 respectively. There are many generic competitors for buprenorphine since it was approved over 16 years ago (FDA).
References
Nancy K. Mello, Jack H. Mendelson, Scott E. Lukas, David R. Gastfriend, Siew Koon Teoh & B. Leonard Holman (1993) Buprenorphine Treatment of Opiate and Cocaine Abuse: Clinical and Preclinical Studies, Harvard Review of Psychiatry, 1:3, 168-183, DOI: 10.3109/10673229309017075
Kraft, W. (2018 August 1). Buprenorphine Pharmacometric Open Label Research Study of Drug Exposure (B-PHORE). Retrieved from https://clinicaltrials.gov/ct2/show/NCT03608696 ?term=Buprenorphine&rank=1
BTOD. Buprenorphine-containing transmucosal products for opioid dependence. Retrieved from https://www.btodrems.com/SitePages/MedicationGuides.aspx. Retrieved on October 29, 2018
FDA. Drug Aproval Package. Received from https://www.accessdata.fda.gov/drugsatfda_docs/ nda/2002/20-732_20-733_Subutex.cfm. Retrieved on November 2nd 2018.
buprenorphine as an addiction therapeutic. Annuals of the New York Academy
of Sciences, issue: Addiction Reviews, 124-139. doi: 10.1111/j.1749-
6632.2011.06352.x
Lexi-comp, Inc. Lexicomp. Computer Software. Apple App Store. Vers. 4.0.5. Lexi-
Comp, 2016. Web. 07. Sept. 2018.
Whelan, P. J., & Remski, K. (2012). Buprenorphine vs methadone treatment: A
review of evidence in both developed and developing worlds. Journal of
Neurosciences in Rural Practice, 3(1), 45–50. http://doi.org/10.4103/0976-
3147.91934
WOW what a great blog
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