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Pregabalins Impact on Opioid Consumption. a Comparison with Gabapentin Using the Norwegian Prescription Database

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Pregabalins Impact on Opioid Consumption. a Comparison with Gabapentin Using the Norwegian Prescription Database Pregabalins impact on opioid consumption. A comparison with gabapentin using the Norwegian Prescription Database. By Naresh Sugandiran Kull: H10 Veileder: Jørgen Gustav Bramness Biveileder: Svetlana Skurtveit Faculty of medicine UNIVERSITY OF OSLO 01/10/2015 ABSTRACT Introduction Pregabalin's analgesic effect is disputed and the drug might have an abuse or addiction potential. We wanted to study what impact an initiation of pregabalin had on opioid consumption. We used gabapentin, another ligand for the α2δ subunit of presynaptic voltage- gated Ca2+ channels, as the comparator drug. Materials and Methods We extracted our data from the Norwegian Prescription Database (NorPD). NorPD covers the entire nation of Norway and all pharmacies in the country are obliged to submit data on dispensed prescriptions to the health authorities. We studied prescriptions for all patients who had been dispensed at least one prescription of either pregabalin or gabapentin in 2010. We focused on the incident users of these drugs. To study the impact on opioid use we compared the opioid consumption, measured in DDD and number of prescription, before and after. Results There was an increase in mean opioid consumption by 8 DDD amongst those who belonged to lowest consumption quartile of pregabalin. While the increase in opioid consumption measured by mean DDD was 251 DDD for those who belonged to highest consumption quartile of pregabalin. The same numbers amongst gabapentin users were 12 DDD and 25 DDD Conclusions There was a higher increase in opioid use amongst high users of these drugs compared to low users of these drugs. The increase in opioid use was much higher among high users of pregabalin compared to high users of gabapentin. These findings suggests: 1. pregabalin might only have limited analgesic effect 2. pregabalin use in high doses might have an opioid-driving effect 1 Innhold 2 Acknowledgements ...................................................................................... 4 3 Background .................................................................................................. 5 3.1 Pharmacoepidemiology ........................................................................................................... 5 3.1.1 Abuse and pharmacoepidemiology ................................................................................. 6 3.2 History ..................................................................................................................................... 6 3.3 Neuropathic pain ..................................................................................................................... 8 3.3.1 Treatment of neuropathic pain ....................................................................................... 8 3.4 Pregabalins analgesic effect .................................................................................................... 9 3.5 Pregabalin and abuse ............................................................................................................ 10 3.5.1 Online reports ................................................................................................................ 10 3.5.2 Case reports and series ................................................................................................. 10 3.5.3 Other studies ................................................................................................................. 11 3.5.4 Experiences from Adverse Drug Reactions databases .................................................. 11 3.5.5 Off-label use .................................................................................................................. 12 3.5.6 The debate on pregabalins abuse potential .................................................................. 13 3.6 Existing pharmacoepidemiological studies ........................................................................... 13 4 Aim of the study ......................................................................................... 15 5 Materials and Methods .............................................................................. 16 5.1.1 Prescription database .................................................................................................... 16 5.1.2 The drugs ....................................................................................................................... 16 5.1.3 Study population ........................................................................................................... 16 5.1.4 Pharmacoepidemiological parameters ......................................................................... 17 5.1.5 Flowchart ....................................................................................................................... 18 6 Results ....................................................................................................... 19 7 Discussion .................................................................................................. 20 7.1 Discussion of the main findings ............................................................................................. 20 7.2 Strengths and weakness ........................................................................................................ 22 7.3 Conclusions ............................................................................................................................ 23 8 Abbrevations .............................................................................................. 24 9 References ................................................................................................. 25 2 Acknowledgements I would like to use this opportunity to thank my supervisor Professor Dr.med Jørgen Bramness. His feedback has been essential in my work with this paper. Professor Bramness has been a source of inspiration. He has undoubtfully contributed to my increased knowledge in the field of pharmacoepidemiolgy and in addiction medicine. I would also thank my co-supervisor Svetlana Skurtveit, for giving me valuable inputs during the statistical analysis and in interpreting them. Last, but not least I have to thank my wife, Usha, for always encouraging me and believing in me. 3 Background 3.1 Pharmacoepidemiology What is pharmacoepidemiology and why is it important? Brian L. Strom, an acknowledged voice in scientific community and professor emeritus in epidemiology, answer to first question is; «Pharmacoepidemiology is the study of the use of and effects of drugs in large numbers of people»(1) To answer the second question, we have to shed some lights on the current drug approval process in the US and Europe. The current drug approval process allows to prove a drug's efficacy, but it has had its limitations. At a minimum, the approval process demands that a drug should be tested on at least 500 patients in phase-3-studies. This lower limit will only reveal adverse reactions that occur in six or more patients out of per 1000 exposed to the drug. This information is not enough and gives us one of the many answers to our question number two; Pharmacoepidemiology and post-marketing studies gives us the possibility to detect uncommon effects(1). Pharmacoepidemiology and post-marketing studies are important because of two main reasons. 1)It can supplement the information from premarketing trials: - Giving a higher precision, i.e., to determine the incidence of a certain adverse drug reactions. - Giving a clearer picture of how the drugs work in comparison with another drug for the same indication - It can give us information about how the drug works with population that wasn't included in premarketing trials such as patients with comorbid conditions, elderly, pregnant women and children 2) It can give us new type of information which we can't get from premarketing trials such as - Uncommon and delayed effects - Patterns of drug utilization, i.e., prescribing patterns, etc 3.1.1 Abuse and pharmacoepidemiology Drug abuse and drug dependence are difficult to study in pre-marketing studies. There are a lot of reasons for that. Firstly pre-marketing trials are time-limited and happen in controlled settings. Secondly they usually exclude patients with comorbid conditions. A third reason is that some information will never be obtainable before a drug is marketed, such as how a drug is utilized in the community. Drug utilization study can reveal phenomenons like doctors shopping which could indicate drug seeking behavior. Therefore are pharmacoepidemiological studies important. 3.2 History Figure 1. A timeline of important events in the «history» of pregabalin. Pregabalin was discovered by Richard Bruce Silverman and his team in the late 80s. A license agreement was signed with Warner-Lambert and Northwestern University, where Silverman worked in 1990. Phase II/III trials started in 1999 and lasted for four years. During phase II/III trials, Pfizer obtained the rights to develop pregabalin from Warner Lambert. In 2003, Pfizer filed «the new drug application» with Food and Drug Administration(FDA). In 2004, pregabalin was approved by FDA and EU(2). In both US and Europe, it was approved for treating epilepsy. It was also approved for treating peripheral and central neuropathies in Europe while only for diabetic neuropathic pain(DNP) and PostHerpetic Neuralgia(PHN) in The US. Pregabalin area of use was extended by EU in 2006 for General Anxiety Disorder while FDA approved its use for fibromyalgia in The US in 2007. In 2005, the
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