Pregabalin was approved for medical use in the United States in 2004. It was developed as a successor to gabapentin. It is available as a generic medication in a number of countries, including the United States as of 2019. In the US the wholesale cost is about US$11 per month as of October 2019. While in the United Kingdom a similar dose costs the NHS about £6 as of 2018. In 2017, it was the 72nd most prescribed medication in the United States with more than 11 million prescriptions. In the US, Pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970. It is a Class C controlled substance in the UK.
Box of 150 mg Lyrica (pregabalin) capsules from Finland
Pregabalin is useful when added to other treatments, when those other treatments are not controlling partial epilepsy. Its use alone is less effective than some other seizure medications. It is unclear how it compares to gabapentin for this use.
Pregabalin's use in cancer-associated neuropathic pain is controversial; though such use is common. There is no evidence for its use in the prevention of migraines and gabapentin has also been found not to be useful. It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial.
Pregabalin is generally not regarded as efficacious in the treatment of acute pain.[needs update] In trials examining the utility of pregabalin for the treatment of acute post-surgical pain, no effect on overall pain levels was observed, but people did require less morphine and had fewer opioid-related side effects. Several possible mechanisms for pain improvement have been discussed.
The effects of pregabalin appear after 1 week of use and is similar in effectiveness to lorazepam, alprazolam, and venlafaxine, but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychosomatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance, and, in addition, unlike benzodiazepines, it has a beneficial effect on sleep and sleep architecture, characterized by the enhancement of slow-wave sleep. It produces less severe cognitive and psychomotor impairment compared to those drugs; it also has a low potential for abuse and dependence and may be preferred over the benzodiazepines for these reasons.
A 2019 review found that pregabalin reduces symptoms, and was generally well tolerated.
It is unclear if it is safe for use in pregnancy with some studies showing potential harm.
In December 2019, the U.S. Food and Drug Administration (FDA) warned about serious breathing issues for those taking gabapentin or pregabalin when used with CNS depressants or for those with lung problems.
The FDA required new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids. The FDA also required the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids, because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression.
Among 49 case reports submitted to the FDA over the five-year period from 2012 to 2017, twelve people died from respiratory depression with gabapentinoids, all of whom had at least one risk factor.
The FDA reviewed the results of two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals. One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. The other trial showed gabapentin alone increased pauses in breathing during sleep. The three observational studies at one academic medical center showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after different kinds of surgeries. The FDA also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function.
Several people with kidney failure 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 people.
No interactions have been demonstrated in vivo. The manufacturer notes some potential pharmacological interactions with opioids, benzodiazepines, barbiturates, ethanol (alcohol), and other drugs that depress the central nervous system. ACE inhibitors may enhance the adverse/toxic effect of pregabalin. Pregabalin may enhance the fluid-retaining effect of anti-diabetic agents (thiazolidinedione).
Pregabalin is not a GABAA or GABAB receptor agonist.
The endogenousα-amino acidsL-leucine and L-isoleucine, which closely resemble pregabalin and the other gabapentinoids in chemical structure, are apparent ligands of the α2δ VDCC subunit with similar affinity as the gabapentinoids (e.g., IC50 = 71 nM for L-isoleucine), and are present in human cerebrospinal fluid at micromolar concentrations (e.g., 12.9 μM for L-leucine, 4.8 μM for L-isoleucine). It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. In accordance, while gabapentinoids like pregabalin and gabapentin have nanomolar affinities for the α2δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids has been said to likely be responsible for this discrepancy.
Pregabalin was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VDCCs in one study. However, another study found that pregabalin and gabapentin had similar affinities for the human recombinant α2δ-1 subunit (Ki = 32 nM and 40 nM, respectively). In any case, pregabalin is 2 to 4 times more potent than gabapentin as an analgesic and, in animals, appears to be 3 to 10 times more potent than gabapentin as an anticonvulsant.
The oralbioavailability of pregabalin is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 900 mg/day). Food does not significantly influence the oral bioavailability of pregabalin. Pregabalin is rapidly absorbed when administered on an empty stomach, with a Tmax (time to peak levels) of generally less than or equal to 1 hour at doses of 300 mg or less. However, food has been found to substantially delay the absorption of pregabalin and to significantly reduce peak levels without affecting the bioavailability of the drug; Tmax values for pregabalin of 0.6 hours in a fasted state and 3.2 hours in a fed state (5-fold difference), and the Cmax is reduced by 25–31% in a fed versus fasted state.
Pregabalin is eliminated by the kidneys in the urine, mainly in its unchanged form. It has a relatively short elimination half-life, with a reported value of 6.3 hours. Because of its short elimination half-life, pregabalin is administered 2 to 3 times per day to maintain therapeutic levels. The kidney clearance of pregabalin is 73 mL/minute.
Chemical structures of GABA, pregabalin and two other gabapentinoids, gabapentin and phenibut.
Pregabalin is available as a generic medication in a number of countries, including the United States as of July 2019. In the United States as of July 2019 the cost for generic pregabalin is US$0.17-0.22 per 150 mg capsule.
Since 2008, Pfizer has engaged in extensive direct-to-consumer advertising campaigns to promote its branded product Lyrica for fibromyalgia and diabetic nerve pain indications. In January 2016, the company spent a record amount, $24.6 million for a single drug on TV ads, reaching global revenues of $14 billion, more than half in the United States.
Up until 2009, Pfizer promoted Lyrica for other uses which had not been approved by medical regulators. For Lyrica and three other drugs, Pfizer was fined a record amount of US$2.3 billion by the Department of Justice, after pleading guilty to advertising and branding "with the intent to defraud or mislead." Pfizer illegally promoted the drugs, with doctors "invited to consultant meetings, many in resort locations; attendees expenses were paid; they received a fee just for being there", according to prosecutor Michael Loucks.
Professor Richard "Rick" Silverman of Northwestern University developed pregabalin there. The university holds a patent on it, exclusively licensed to Pfizer. That patent, along with others, was challenged by generic manufacturers and was upheld in 2014, giving Pfizer exclusivity for Lyrica in the US until 2018.
It was also marketed in several countries as a combination drug with mecobalamin under the brand names Agemax-P, Alphamix-PG, Freenerve-P, Gaben, Macraberin-P, Mecoblend-P, Mecozen-PG, Meex-PG, Methylnuron-P, Nervolin, Nervopreg, Neurica-M, Neuroprime-PG, Neutron-OD, Nuroday-P, Nurodon-PG, Nuwin-P, Pecomin-PG, Prebel-M, Predic-GM, Pregacent-M, Pregamet, Preganerv-M, Pregeb-M OD, Pregmic, Prejunate Plus, Preneurolin Plus, Pretek-GM, Rejusite, Renerve-P, Safyvit-PR, and Vitcobin-P, Voltanerv with Methylcobalamin and ALA by Cogentrix Pharma.
Pfizer's main patent for Lyrica, for seizure disorders, in the UK expired in 2013. In November 2018 the Supreme Court of the United Kingdom ruled that Pfizer's second patent on the drug, for treatment of pain, was invalid because there was a lack of evidence for the conditions it covered – central and peripheral neuropathic pain. From October 2015 GPs were forced to change people from generic pregabalin to branded until the second patent ran out in July 2017. This cost the NHS £502 million.
^ abcdefghijkBockbrader, H. N.; Wesche, D.; Miller, R.; Chapel, S.; Janiczek, N.; Burger, P. (2010). "A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin". Clinical Pharmacokinetics. 49 (10): 661–669. doi:10.2165/11536200-000000000-00000. PMID20818832.CS1 maint: uses authors parameter (link)
^Randinitis, Edward J.; Posvar, Edward L.; Alvey, Christine W.; Sedman, Allen J.; Cook, Jack A.; Bockbrader, Howard N. (2003). "Pharmacokinetics of Pregabalin in Subjects with Various Degrees of Renal Function". The Journal of Clinical Pharmacology. 43 (3): 277–83. doi:10.1177/0091270003251119. PMID12638396.
^Iftikhar, IH; Alghothani, L; Trotti, LM (December 2017). "Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis". European Journal of Neurology. 24 (12): 1446–1456. doi:10.1111/ene.13449. PMID28888061.
^Mishriky, B. M.; Waldron, N. H.; Habib, A. S. (January 2015). "Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis". British Journal of Anaesthesia. 114 (1): 10–31. doi:10.1093/bja/aeu293. ISSN1471-6771. PMID25209095.
^ abcdBritish National Formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 323. ISBN9780857113382.
^ abcdefghijCalandre, E. P.; Rico-Villademoros, F.; Slim, M. (2016). "Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use". Expert Review of Neurotherapeutics. 16 (11): 1263–1277. doi:10.1080/14737175.2016.1202764. PMID27345098.CS1 maint: uses authors parameter (link)
^ abcUchitel, O. D.; Di Guilmi, M. N.; Urbano, F. J.; Gonzalez-Inchauspe, C. (2010). "Acute modulation of calcium currents and synaptic transmission by gabapentinoids". Channels (Austin). 4 (6): 490–496. doi:10.4161/chan.4.6.12864. PMID21150315.CS1 maint: uses authors parameter (link)
^Bennett, Michael I.; Laird, Barry; van Litsenburg, Chantal; Nimour, Meryem (2013). "Pregabalin for the Management of Neuropathic Pain in Adults with Cancer: A Systematic Review of the Literature". Pain Medicine. 14 (11): 1681–8. doi:10.1111/pme.12212. PMID23915361.
^Howard, Paul (2017). Palliative care formulary (6 ed.). Pharmaceutical press. p. Chapter 4 Central Nervous System. ISBN978-0-85711-348-1.
^ abClarke, H.; Bonin, R. P.; Orser, B. A.; Englesakis, M.; Wijeysundera, D. N.; Katz, J. (August 2012). "The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis". Anesthesia & Analgesia. 115 (2): 428–42. doi:10.1213/ANE.0b013e318249d36e. hdl:10315/27968. PMID22415535.CS1 maint: uses authors parameter (link)
^Hamilton, T. W.; Strickland, L. H.; Pandit, H. G. (August 17, 2016). "A Meta-Analysis on the Use of Gabapentinoids for the Treatment of Acute Postoperative Pain Following Total Knee Arthroplasty". The Journal of Bone and Joint Surgery, American Volume. 98 (16): 1340–50. doi:10.2106/jbjs.15.01202. PMID27535436.
^Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N (February 2019). "Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis". Lancet. 393 (10173): 768–777. doi:10.1016/S0140-6736(18)31793-8. PMID30712879.
^Wensel, T. M.; Powe, K. W.; Cates, M. E. (March 2012). "Pregabalin for the treatment of generalized anxiety disorder". Annals of Pharmacotherapy. 46 (3): 424–9. doi:10.1345/aph.1Q405. PMID22395254.CS1 maint: uses authors parameter (link)
^ abcdBandelow, Borwin; Wedekind, Dirk; Leon, Teresa (2007). "Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention". Expert Review of Neurotherapeutics. 7 (7): 769–81. doi:10.1586/1473718.104.22.1689. PMID17610384.
^Murphy, N. G.; Mosher, L. (2008). "Severe myoclonus from pregabalin (Lyrica) due to chronic renal insufficiency". Clinical Toxicology. 46 (7): 594. doi:10.1080/15563650802255033.
^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. PMID19493601.
^Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Biomedical Publications. pp. 1296–1297. ISBN978-0-9626523-7-0.
^Pregabalin. In: Lexi-Drugs [database on the Internet]. Hudson (OH): Lexi-Comp, Inc.; 2007 [cited 2015 Oct 29].
^ abcStahl, S. M.; Porreca, F.; Taylor, C. P.; Cheung, R.; Thorpe, A. J.; Clair, A. (2013). "The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?". Trends in Pharmacological Sciences. 34 (6): 332–9. doi:10.1016/j.tips.2013.04.001. PMID23642658.CS1 maint: uses authors parameter (link)
^ abcDooley, D. J.; Taylor, C. P.; Donevan, S.; Feltner, D. (2007). "Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission". Trends in Pharmacological Sciences. 28 (2): 75–82. doi:10.1016/j.tips.2006.12.006. PMID17222465.CS1 maint: uses authors parameter (link)
^ abDavies, A.; Hendrich, J.; Van Minh, A. T.; Wratten, J.; Douglas, L.; Dolphin, A. C. (2007). "Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels". Trends in Pharmacological Sciences. 28 (5): 220–228. doi:10.1016/j.tips.2007.03.005. PMID17403543.CS1 maint: uses authors parameter (link)
^Taylor, C. P.; Angelotti, T.; Fauman, E. (February 2007). "Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery". Epilepsy Research. 73 (2): 137–150. doi:10.1016/j.eplepsyres.2006.09.008. PMID17126531.CS1 maint: uses authors parameter (link)
^ abcdDickens, D.; Webb, S. D.; Antonyuk, S.; Giannoudis, A.; Owen, A.; Rädisch, S.; Hasnain, S. S.; Pirmohamed, M. (2013). "Transport of gabapentin by LAT1 (SLC7A5)". Biochemical Pharmacology. 85 (11): 1672–1683. doi:10.1016/j.bcp.2013.03.022. PMID23567998.CS1 maint: uses authors parameter (link)
^del Amo, E. M.; Urtti, A.; Yliperttula, M. (2008). "Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2". European Journal of Pharmaceutical Sciences. 35 (3): 161–174. doi:10.1016/j.ejps.2008.06.015. PMID18656534.CS1 maint: uses authors parameter (link)
^ abMüller, C. E. (2009). "Prodrug approaches for enhancing the bioavailability of drugs with low solubility". Chemistry & Biodiversity. 6 (11): 2071–2083. doi:10.1002/cbdv.200900114. PMID19937841.CS1 maint: uses authors parameter (link)
^ abYogeeswari, P.; Ragavendran, J. V.; Sriram, D. (2006). "An update on GABA analogs for CNS drug discovery". Recent Patents on CNS Drug Discovery. 1 (1): 113–118. doi:10.2174/157488906775245291. PMID18221197.CS1 maint: uses authors parameter (link)
^Drug Enforcement Administration, Department of Justice (July 2005). "Schedules of controlled substances: placement of pregabalin into schedule V. Final rule". Federal Register. 70 (144): 43633–43635. PMID16050051.