Pregabalin

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Pregabalin
Pregabalin.svg
Pregabalin ball-and-stick.png
Systematic (IUPAC) name
(S)-3-(aminomethyl)-5-methylhexanoic acid
Clinical data
Trade names Lyrica, Nervalin
AHFS/Drugs.com monograph
MedlinePlus a605045
Licence data US Daily Med:link
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
Bioavailability ≥90%
Protein binding Nil
Metabolism Negligible
Half-life 5–6.5 hours
Excretion Renal
Identifiers
CAS number 148553-50-8 YesY
ATC code N03AX16
PubChem CID 5486971
DrugBank DB00230
ChemSpider 4589156 YesY
UNII 55JG375S6M YesY
KEGG D02716 YesY
ChEBI CHEBI:64356 N
ChEMBL CHEMBL1059 YesY
Synonyms PD-144,723
Chemical data
Formula C8H17NO2 
Mol. mass 159.23 g.mol-1
 N (what is this?)  (verify)

Pregabalin (INN) /prɨˈɡæbəlɨn/ is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults.[1] It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union and Russia.[1] It is effective at treating some causes of chronic pain such as fibromyalgia but not others. It is considered to have a low potential for abuse, and a limited dependence liability if misused, but is classified as a Schedule V drug in the U.S.[2] It was designed as a more potent successor to gabapentin.

Pregabalin is marketed by Pfizer under the trade name Lyrica. Pfizer described in an SEC filing that the drug could be used to treat epilepsy, postherpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia. Lyrica was promoted for other uses which had not been approved by medical regulators up until 2009. For this practice, with 3 other drugs, Pfizer was fined a record amount of $2.3 billion by the Department of Justice.[3] Lyrica sales reached a record $3.063 billion in 2010.[4]

Medical uses[edit]

Neuropathic pain[edit]

A package of 150 mg pregabalin (Finland)

The European Federation of Neurological Societies recommends pregabalin as a first line agent for the treatment of pain associated with diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain.[5] Other first line agents, including gabapentin and tricyclic antidepressants, are given equal weight as first line agents, and unlike pregabalin, are available as inexpensive generics.[6] It is not recommended for certain other types of neuropathic pain such as pain associated with trigeminal neuralgia or HIV infection[7] and its use in cancer-associated neuropathic pain is controversial.[7] There is no evidence for its use in the prevention of migraines and gabapentin has been found not to be useful.[8] It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial.[9][10]

Pregabalin is generally not regarded as efficacious in the treatment of acute pain.[11] In clinical trials examining the utility of pregabalin for the treatment of acute post-surgical pain, no effect on overall pain levels was observed but patients required less morphine and suffered fewer opioid-related side effects.[9]

Anxiety disorders[edit]

The World Federation of Biological Psychiatry recommends pregabalin as one of several first line agents for the treatment of generalized anxiety disorder, but recommends other agents such as SSRIs as first line treatment for obsessive-compulsive disorder and post-traumatic stress disorder.[12] It appears to have anxiolytic effects similar to benzodiazepines with less risk of dependence.[13][14]

Adverse effects[edit]

Adverse drug reactions associated with the use of pregabalin include:[15][16]

Pregabalin may also cause withdrawal effects after long-term use if discontinued abruptly. When prescribed for seizures, quitting “cold turkey” can increase the strength of the seizures and possibly cause the seizures to reoccur. Withdrawal symptoms include difficulty sleeping, nausea, anxiety, diarrhoea, flu or flu-like symptoms, headache, increased sweating, convulsions, pain, dizziness, nervousness, and depression. Pregabalin should be reduced gradually when finishing treatment.

Overdosage[edit]

Several renal failure patients developed myoclonus while receiving pregabalin, apparently as a result of gradual accumulation of the drug. Acute overdosage may be manifested by somnolence, tachycardia and hypertonicity. Plasma, serum or blood concentrations of pregabalin may be measured to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients.[18][19][20]

Pharmacology[edit]

Pharmacodynamics[edit]

Like gabapentin, pregabalin binds to the α2δ (alpha-2-delta) subunit of the voltage-dependent calcium channel in the central nervous system. Pregabalin decreases the release of neurotransmitters including glutamate, norepinephrine, substance P and calcitonin gene-related peptide.[21] However, unlike anxiolytic compounds (e.g., benzodiazepines) which exert their therapeutic effects through binding to GABAA, pregabalin neither binds directly to these receptors nor augments GABAA currents or affects GABA metabolism (Pfizer Inc., 2006).[22] The half-life for pregabalin is 6.3 hours.[23]

Pharmacokinetics[edit]

Absorption: Pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within one hour. Pregabalin oral bioavailability is estimated to be greater than or equal to 90% and is independent of dose. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25 to 30% and a delay in Tmax (time to reach Cmax) to approximately 2.5 hours. Administration with food, however, has no clinically significant effect on the extent of absorption.[24]

Distribution: Pregabalin has been shown to cross the blood–brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the volume of distribution of pregabalin for an orally administered dose is approximately 0.56 L/kg and is not bound to plasma proteins.[24]

Metabolism: Pregabalin undergoes negligible metabolism in humans.[25] In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The major metabolite is N-methylpregabalin.[24]

Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.[24] Renal clearance of pregabalin is 73 mL/minute.[26]

History[edit]

Pregabalin was invented by medicinal chemist Richard Bruce Silverman at Northwestern University in the United States. The drug was approved in the European Union in 2004. Pregabalin received U.S. FDA approval for use in treating epilepsy, diabetic neuropathic pain, and postherpetic neuralgia in December 2004, and appeared on the U.S. market in fall 2005.[27]

In June 2007, the FDA approved Lyrica as a treatment for fibromyalgia. It was the first drug to be approved for this indication and remained the only one until duloxetine gained FDA approval for the treatment of fibromyalgia in June 2008.[28]

Generic versions of pregabalin became available in Canada in 2013, and are expected to become available in the European Union and the U.S. in 2016 and 2018 respectively.[29][30]

Society and culture[edit]

Regulatory approval[edit]

In the United States, the Food and Drug Administration (FDA) has approved pregabalin for adjunctive therapy for adults with partial onset seizures, management of postherpetic neuralgia and neuropathic pain associated with spinal cord injury and diabetic peripheral neuropathy, and the treatment of fibromyalgia.[31] Pregabalin has also been approved in the European Union and Russia (but not in US) for treatment of generalized anxiety disorder.[32][33]

Recreational use[edit]

Pregabalin is a Schedule V drug, and is classified as a CNS depressant. The potential for abuse of pregabalin is less than the potential with benzodiazepines; additionally the euphoric effects of pregabalin disappear with prolonged use.[34]

Marketing[edit]

Lyrica is one of four drugs which Pharmacia & Upjohn, a subsidiary of Pfizer, in 2009 pleaded guilty to misbranding "with the intent to defraud or mislead". Pfizer agreed to pay $2.3 billion (£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer illegally promoted the drugs and caused false claims to be submitted to government healthcare programs for uses that were not approved by the U.S. Food and Drug Administration (FDA).[3]

Intellectual property[edit]

Pfizer's US patent on Lyrica was challenged by generic manufacturers and was upheld in 2014, giving Pfizer exclusivity for Lyrica in the US until 2018.[35]U.S. court has upheld the patent of Pfizer on its pain medicine, Lyrica. [36]

Anaesthesiology research fraud[edit]

Pregabalin is one of two Pfizer drugs that had become a mainstay in multimodal analgesia but the key research conducted by Scott Reuben between 1996 and 2009 which paved the way for these drugs has been found to be fraudulent. According to one source, this massive case of academic misconduct has left multimodal analgesia in a shambles. Many aspects of postoperative pain management concerning many of the drugs used, including pregabalin, will need to be reconsidered.[37]

See also[edit]

References[edit]

  1. ^ a b Benkert, Otto; Hippius, Hanns (2006). Kompendium Der Psychiatrischen Pharmakotherapie (in German) (6th ed.). Springer. ISBN 978-3-540-34401-8. 
  2. ^ Drug Enforcement Administration, Department of Justice (July 2005). "Schedules of controlled substances: placement of pregabalin into schedule V. Final rule". Federal register 70 (144): 43633–5. PMID 16050051. Retrieved 2012-01-22. 
  3. ^ a b "Pfizer agrees record fraud fine". BBC News. 2009-09-02. Retrieved 2011-11-06. 
  4. ^ "Portions of the Pfizer Inc. 2010 Financial Report". Sec.gov (edgar archives). Retrieved 2011-11-06. 
  5. ^ Attal N, Cruccu G, Baron R, et al. (September 2010). "EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision". Eur. J. Neurol. 17 (9): 1113–e88. doi:10.1111/j.1468-1331.2010.02999.x. PMID 20402746. 
  6. ^ Finnerup, NB; Sindrup SH; Jensen TS (September 2010). "The evidence for pharmacological treatment of neuropathic pain". Pain 150 (3): 573–81. doi:10.1016/j.pain.2010.06.019. PMID 20705215. 
  7. ^ a b Bennett, M.I. (November 2013). "Pregabalin for acute and chronic pain in adults.". Pain Med 14 (11): 1681–8. doi:10.1111/pme.12212. PMID 23915361. 
  8. ^ Linde, M; Mulleners, WM; Chronicle, EP; McCrory, DC (Jun 24, 2013). "Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults.". The Cochrane database of systematic reviews 6: CD010609. doi:10.1002/14651858.CD010609. PMID 23797675. 
  9. ^ a b Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J (August 2012). "The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis". Anesth. Analg. 115 (2): 428–42. doi:10.1213/ANE.0b013e318249d36e. PMID 22415535. 
  10. ^ Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I (2013). "Pharmacotherapy for the prevention of chronic pain after surgery in adults". Cochrane Database Syst Rev 7: CD008307. doi:10.1002/14651858.CD008307.pub2. PMID 23881791. 
  11. ^ Moore, RA; Straube, S; Wiffen, PJ; Derry, S; McQuay, HJ (Jul 8, 2009). "Pregabalin for acute and chronic pain in adults.". The Cochrane database of systematic reviews (3): CD007076. doi:10.1002/14651858.CD007076.pub2. PMID 19588419. 
  12. ^ Wensel TM, Powe KW, Cates ME (March 2012). "Pregabalin for the treatment of generalized anxiety disorder". Ann Pharmacother 46 (3): 424–9. doi:10.1345/aph.1Q405. PMID 22395254. 
  13. ^ Owen, Richard T. (September 2007). "Pregabalin: its efficacy, safety and tolerability profile in generalized anxiety". Drugs of Today 43 (9): 601–10. doi:10.1358/dot.2007.43.9.1133188. PMID 17940637. Retrieved 2012-01-22. 
  14. ^ Bandelow B, Sher L, Bunevicius R, et al. (June 2012). "Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care". Int J Psychiatry Clin Pract 16 (2): 77–84. doi:10.3109/13651501.2012.667114. PMID 22540422. 
  15. ^ Pfizer Australia Pty Ltd. Lyrica (Australian Approved Product Information). West Ryde: Pfizer; 2006.
  16. ^ Rossi, Simone, ed. (2006). Australian Medicines Handbook, 2006. Australian Medicines Handbook. ISBN 978-0-9757919-2-9. 
  17. ^ "Medication Guide (Pfizer Inc.)" (PDF). U.S. Food and Drug Administration. June 2011. Retrieved 2011-11-06. 
  18. ^ Murphy, N.G.; Mosher, L. (2008). "Severe myoclonus from pregabalin (Lyrica) due to chronic renal insufficiency". Clinical Toxicology 46: 594. 
  19. ^ Yoo, Lawrence; Matalon, Daniel; Hoffman, Robert S.; Goldfarb, David S. (2009). "Treatment of pregabalin toxicity by hemodialysis in a patient with kidney failure". American Journal of Kidney Diseases 54 (6): 1127–30. doi:10.1053/j.ajkd.2009.04.014. PMID 19493601. 
  20. ^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Biomedical Publications. pp. 1296–1297. ISBN 978-0-9626523-7-0. 
  21. ^ Micheva KD, Taylor CP, Smith SJ (April 2006). "Pregabalin Reduces the Release of Synaptic Vesicles from Cultured Hippocampal Neurons". Molecular Pharmacology 70 (2): 467–476. doi:10.1124/mol.106.023309. PMID 16641316. 
  22. ^ Strawn, JR; Geracioti Jr, TD (2007). "The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic". Neuropsychiatric disease and treatment 3 (2): 237–43. doi:10.2147/nedt.2007.3.2.237. PMC 2654629. PMID 19300556. 
  23. ^ "Pregabalin". DRUGDEX. Micromedex. Retrieved 18 October 2012. 
  24. ^ a b c d "Summary of product characteristics". European Medicines Agency. 6 March 2013. Retrieved 6 May 2013. 
  25. ^ McElroy, Susan L.; Keck, Paul E.; Post, Robert M., eds. (2008). Antiepileptic Drugs to Treat Psychiatric Disorders. INFRMA-HC. p. 370. ISBN 978-0-8493-8259-8. 
  26. ^ "LYRICA - pregabalin capsule". DailyMed. U.S. National Library of Medicine. September 2010. Retrieved 6 May 2013. 
  27. ^ Dworkin, Robert H.; Kirkpatrick, Peter (June 2005). "Pregabalin" (PDF). Nature Reviews Drug Discovery 4 (6): 455–456. doi:10.1038/nrd1756. PMID 15959952. Retrieved 2012-01-22. 
  28. ^ "Living with Fibromyalgia, Drugs Approved to Manage Pain". U.S. Food and Drug Administration. 2008-07-18. Retrieved 2011-11-06. 
  29. ^ "Drugs@FDA Website". Retrieved 2014-03-31. 
  30. ^ "services.corporate-ir.net". 
  31. ^ "Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks". Stop Medicare Fraud, US Dept of Health & Human Svc, and of Justice. Retrieved 2012-07-04. 
  32. ^ Bandelow, Borwin; Wedekind, Dirk; Leon, Teresa (July 2007). "Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention". Expert Review of Neurotherapeutics 7 (7): 769–781. doi:10.1586/14737175.7.7.769. PMID 17610384. Retrieved 2011-11-06. 
  33. ^ "Pfizer's Lyrica Approved for the Treatment of Generalized Anxiety Disorder (GAD) in Europe" (Press release). Retrieved 2011-11-06. 
  34. ^ Chalabianloo, F; Schjøtt J (January 2009). "Pregabalin and its potential for abuse". Journal of the Norwegian Medical Association 129 (3): 186–187. doi:10.4045/tidsskr.08.0047. PMID 19180163. 
  35. ^ Susan Decker for Bloomberg News. Feb 6, 2014. Pfizer Wins Ruling to Block Generic Lyrica Until 2018
  36. ^ "Pfizer's Wins Patent on Lyrica". Btvin.com. 
  37. ^ Marcus, Adam (2009-03-01). "Fraud Case Rocks Anesthesiology Community". Anesthesiology News. Retrieved March 3, 2014. 

External links[edit]