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Pregabalin

April 07, 2024

Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal, and generalized anxiety disorder (GAD).[13][17][18] Pregabalin also has antiallodynic properties.[19][20][21] Its use in epilepsy is as an add-on therapy for partial seizures.[13] It is a gabapentinoid medication and acts by inhibiting certain calcium channels.[13][22][23] When used before surgery, it reduces pain but results in greater sedation and visual disturbances.[24] It is taken by mouth.[13]

Pregabalin
Clinical data
Pronunciation/priˈɡæbəlɪn/
Trade namesLyrica, others[1]
Other names3-isobutyl GABA, (S)-3-isobutyl-γ-aminobutyric acid
AHFS/Drugs.comMonograph
MedlinePlusa605045
License data
Pregnancy
category
Dependence
liability		Physical: High[4]
Psychological: Moderate[4]
Addiction
liability		Low[4]
Routes of
administration		By mouth
Drug class
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: High (≥90% rapidly absorbed; food has no significant effect on bioavailability)[11]
Protein binding<1%[12]
MetabolitesN-methylpregabalin[11]
Onset of actionMay occur within a week (pain)[13]
Elimination half-life4.5–7 hours[14] (mean 6.3 hours)[14][15]
Duration of actionUnknown[16]
ExcretionKidney
Identifiers
  • (3S)-3-(aminomethyl)-5-methylhexanoic acid
CAS Number
  • 148553-50-8 Y
PubChem CID
  • 5486971
DrugBank
  • DB00230 Y
ChemSpider
  • 4589156 Y
UNII
  • 55JG375S6M
KEGG
  • D02716 Y
ChEBI
  • CHEBI:64356 Y
ChEMBL
  • ChEMBL1059 Y
CompTox Dashboard (EPA)
  • DTXSID1045950
ECHA InfoCard100.119.513
Chemical and physical data
FormulaC8H17NO2
Molar mass159.229 g·mol−1
3D model (JSmol)
  • Interactive image
  • CC(C)CC(CC(=O)O)CN
  • InChI=1S/C8H17NO2/c1-6(2)3-7(5-9)4-8(10)11/h6-7H,3-5,9H2,1-2H3,(H,10,11)/t7-/m0/s1 Y
  • Key:AYXYPKUFHZROOJ-ZETCQYMHSA-N Y
  (verify)

Common side effects include headache, dizziness, sleepiness, confusion, trouble with memory, poor coordination, dry mouth, problems with vision, and weight gain.[13][25] Serious side effects may include angioedema, drug misuse, and an increased suicide risk.[13] When pregabalin is taken at high doses over a long period of time, addiction may occur, but if taken at usual doses the risk is low.[4] Use during pregnancy or breastfeeding is of unclear safety.[26]

Pregabalin was approved for medical use in the United States in 2004.[13] It was developed as a successor to the related gabapentin.[27] It is available as a generic medication.[25][28][29][30][31] In 2021, it was the 73rd most commonly prescribed medication in the United States, with more than 8 million prescriptions.[32][33] In the US, pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970.[13] It is a Class C controlled substance in the UK.[34]

Medical uses edit

 
Box of 150 mg Lyrica (pregabalin) capsules from Finland

Seizures edit

For drug-resistant focal epilepsy, pregabalin is useful as an add-on therapy to other treatments.[35] Its use alone is less effective than some other seizure medications.[36] It is unclear how it compares to gabapentin for this use.[36]

Neuropathic pain edit

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.[37] A minority obtain substantial benefit, and a larger number obtain moderate benefit.[38] It is given equal weight as gabapentin and tricyclic antidepressants as a first line agent, however the latter are less expensive as of 2010.[39] Pregabalin is as effective at relieving pain as duloxetine and amitriptyline. Combination treatment of pregabalin and amitriptyline or duloxetine offers additional pain relief for people whose pain is not adequately controlled with one medication, and is safe.[40][41]

Studies have shown that higher doses of pregabalin are associated with greater efficacy.[42]

Pregabalin's use in cancer-associated neuropathic pain is controversial,[43] though such use is common.[44] It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial.[45][46]

Pregabalin is generally not regarded as efficacious in the treatment of acute pain.[38] 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.[45][47] Several possible mechanisms for pain improvement have been discussed.[48]

Anxiety disorders edit

Pregabalin is effective for treatment of generalized anxiety disorder.[49] It is also effective for the short- and long-term treatment of social anxiety disorder and in reducing preoperative anxiety.[50][51] However, there is concern regarding pregabalin's off-label use due to the lack of strong scientific evidence for its efficacy in multiple conditions and its proven side effects.[52]

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 (PTSD).[53][54] For PTSD, pregabalin as complementary treatment seems to be effective.[51]

Generalized anxiety disorder edit

Pregabalin has anxiolytic effects similar to benzodiazepines with less risk of dependence.[55] The effects of pregabalin appear within one week of use,[56] and are similar in effectiveness to lorazepam, alprazolam, and venlafaxine, but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychosomatic anxiety symptoms.[57] 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.[57] It produces less severe cognitive and psychomotor impairment compared to benzodiazepines.[57][58]

A 2019 review found that pregabalin reduces symptoms, and was generally well tolerated.[49]

Other uses edit

Although pregabalin is sometimes prescribed for people with bipolar disorder there is no evidence showing that it is effective.[51][59]

There is no evidence and significant risk in using pregabalin for sciatica and low back pain.[60][61][62] Evidence of benefit in alcohol withdrawal as well as withdrawal from certain other drugs is limited as of 2016.[63]

There is no evidence for its use in the prevention of migraines and gabapentin has also been found not to be useful.[64]

Adverse effects edit

Exposure to pregabalin is associated with weight gain, sleepiness and fatigue, dizziness, vertigo, leg swelling, disturbed vision, loss of coordination, and euphoria.[65] It has an adverse effect profile similar to other central nervous system depressants.[66] Even though pregabalin is a depressant and anti-convulsant it can sometimes paradoxically induce seizures, particularly in large overdoses.[67] Adverse drug reactions associated with the use of pregabalin include:[68][69]

Cases of recreational use, with associated adverse effects have been reported.[71]

Withdrawal symptoms edit

Following abrupt or rapid discontinuation of pregabalin, some people reported symptoms suggestive of physical dependence. The FDA determined that the substance dependence profile of pregabalin, as measured by a personal physical withdrawal checklist, was quantitatively less than benzodiazepines.[66] Even people who have discontinued short term use of pregabalin have experienced withdrawal symptoms, including insomnia, headache, nausea, anxiety, diarrhea, flu like symptoms, nervousness, major depression, pain, convulsions, hyperhidrosis and dizziness.[72]

Pregnancy edit

It is unclear if it is safe for use in pregnancy with some studies showing potential harm.[73]

Breathing edit

In December 2019, the US 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.[74][75]

The FDA required new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids.[74] 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.[74]

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.[74]

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.[74] One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function.[74] The other trial showed gabapentin alone increased pauses in breathing during sleep.[74] 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.[74] The FDA also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function.[74]

Overdose edit

An overdose of pregabalin usually consists of severe drowsiness, severe ataxia, blurred vision and macular detachment,[76] slurred speech, severe uncontrollable jerking motions (myoclonus), tonic clonic seizures and anxiety.[77] Despite these symptoms an overdose is not usually fatal unless mixed with another depressant. 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 hypertonia. Plasma, serum or blood concentrations of pregabalin may be measured to monitor therapy or to confirm a diagnosis of poisoning in hospitalized people.[78][79][80]

Pharmacology edit

Interactions edit

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 certain anti-diabetic agents (thiazolidinediones).[81]

Pharmacodynamics edit

 
Pregabalin is not a GABAA or GABAB receptor agonist.
 
N-Type Voltage gated calcium channel

Pregabalin is a gabapentinoid and acts by inhibiting certain calcium channels.[22][23] Specifically it is a ligand of the auxiliary α2δ subunit site of certain voltage-dependent calcium channels (VDCCs), and thereby acts as an inhibitor of α2δ subunit-containing VDCCs.[22][82] There are two drug-binding α2δ subunits, α2δ-1 and α2δ-2, and pregabalin shows similar affinity for (and hence lack of selectivity between) these two sites.[22] Pregabalin is selective in its binding to the α2δ VDCC subunit.[82][83] Despite the fact that pregabalin is a GABA analogue,[84] it does not bind to the GABA receptors, does not convert into GABATooltip γ-aminobutyric acid or another GABA receptor agonist in vivo, and does not directly modulate GABA transport or metabolism.[23][82] However, pregabalin has been found to produce a dose-dependent increase in the brain expression of L-glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing GABA, and hence may have some indirect GABAergic effects by increasing GABA levels in the brain.[85][86][87] There is currently no evidence that the effects of pregabalin are mediated by any mechanism other than inhibition of α2δ-containing VDCCs.[82][88] In accordance, inhibition of α2δ-1-containing VDCCs by pregabalin appears to be responsible for its anticonvulsant, analgesic, and anxiolytic effects.[82][88]

The endogenous α-amino acids L-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).[89] It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids.[89][90] 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.[88]

Pregabalin was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VDCCs in one study.[91][92] 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).[93] In any case, pregabalin is 2 to 4 times more potent than gabapentin as an analgesic[84][94] and, in animals, appears to be 3 to 10 times more potent than gabapentin as an anticonvulsant.[84][94]

Pharmacokinetics edit

Absorption edit

Pregabalin is absorbed from the intestines by an active transport process mediated via the large neutral amino acid transporter 1 (LAT1, SLC7A5), a transporter for amino acids such as L-leucine and L-phenylalanine.[22][82][95] Very few (less than 10 drugs) are known to be transported by this transporter.[96] Unlike gabapentin, which is transported solely by the LAT1,[95][12] pregabalin seems to be transported not only by the LAT1 but also by other carriers.[22] The LAT1 is easily saturable, so the pharmacokinetics of gabapentin are dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.[22] In contrast, this is not the case for pregabalin, which shows linear pharmacokinetics and no saturation of absorption.[22]

The oral bioavailability of pregabalin is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 600 mg/day).[12] Food does not significantly influence the oral bioavailability of pregabalin.[12] 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.[22][11] 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.[12]

Distribution edit

Pregabalin crosses the blood–brain barrier and enters the central nervous system.[82] However, due to its low lipophilicity,[12] pregabalin requires active transport across the blood–brain barrier.[95][82][97][98] The LAT1 is highly expressed at the blood–brain barrier[99] and transports pregabalin across into the brain.[95][82][97][98] Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.[11] In humans, the volume of distribution of an orally administered dose of pregabalin is approximately 0.56 L/kg.[11] Pregabalin is not significantly bound to plasma proteins (<1%).[12]

Metabolism edit

Pregabalin undergoes little or no metabolism.[12][22][100] In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin.[11] The main metabolite is N-methylpregabalin.[11]

Pregabalin is generally safe in patients with liver cirrhosis.[101]

Elimination edit

Pregabalin is eliminated by the kidneys in the urine, mainly in its unchanged form.[12][11] It has a relatively short elimination half-life, with a reported value of 6.3 hours.[12] Because of its short elimination half-life, pregabalin is administered 2 to 3 times per day to maintain therapeutic levels.[12] The kidney clearance of pregabalin is 73 mL/minute.[9]

Chemistry edit

 
Chemical structures of GABA, pregabalin and two other gabapentinoids, gabapentin and phenibut.

Pregabalin is a GABA analogue that is a 3-substituted derivative as well as a γ-amino acid.[19][83] Specifically, pregabalin is (S)-(+)-3-isobutyl-GABA.[102][103][104] Pregabalin also closely resembles the α-amino acids L-leucine and L-isoleucine, and this may be of greater relevance in relation to its pharmacodynamics than its structural similarity to GABA.[89][90][102]

Synthesis edit

Chemical syntheses of pregabalin have been described.[105][106]

History edit

External videos
 
  "Richard B. Silverman, Basic Science to Blockbuster Drug", National Academy of Inventors

Pregabalin was synthesized in 1990 as an anticonvulsant. It was invented by medicinal chemist Richard Bruce Silverman at Northwestern University in Evanston, Illinois.[107] Silverman is best known for identifying the drug pregabalin as a possible treatment for epileptic seizures.[108] During 1988 to 1990, Ryszard Andruszkiewicz, a visiting research fellow, synthesized a series of molecules requested by Silverman.[109] One looked particularly promising.[110] The molecule was effectively shaped for transportation into the brain, where it activated L-glutamic acid decarboxylase, an enzyme. Silverman hoped that the enzyme would increase production of the inhibitory neurotransmitter GABA and block convulsions.[108] Eventually, the set of molecules were sent to Parke-Davis Pharmaceuticals for testing. The drug was approved in the European Union in 2004. The US received FDA approval for use in treating epilepsy, diabetic neuropathic pain, and postherpetic neuralgia in December 2004. Pregabalin then appeared on the US market under the brand name Lyrica in fall of 2005.[111] In 2017, the FDA approved pregabalin extended-release Lyrica CR for the management of neuropathic pain associated with diabetic peripheral neuropathy, and postherpetic neuralgia.[112] However, unlike the immediate release formulation, Lyrica CR was not approved for the management of fibromyalgia or as add on therapy for adults with partial onset seizures.[113][9]

Society and culture edit

Legal status edit

In the United States, the 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.[123] Pregabalin has also been approved in the European Union, the United Kingdom, and Russia for treatment of generalized anxiety disorder.[124][57][125]

Economics edit

Pregabalin is available as a generic medication in a number of countries, including the United States as of July 2019.[25][28][124] In the United States as of July 2019 the wholesale/pharmacy cost for generic pregabalin is US$0.17–0.22 per 150 mg capsule.[126]

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.[127]

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,[128][129][130] 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.[128][129]

Intellectual property edit

Professor Richard "Rick" Silverman of Northwestern University developed pregabalin there. The university holds a patent on it, exclusively licensed to Pfizer.[131][132] 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.[133][134]

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.[135]

Brand names edit

As of October 2017, pregabalin was marketed under many brand names in other countries: Algerika, Alivax, Alyse, Alzain, Andogablin, Aprion, Averopreg, Axual, Balifibro, Brieka, Clasica, Convugabalin, Dapapalin, Dismedox, Dolgenal, Dolica, Dragonor, Ecubalin, Epica, Epiron, Gaba-P, Gabanext, Gabarol, Gabica, Gablin, Gablovac, Gabrika, Gavin, Gialtyn, Glonervya, Helimon, Hexgabalin, Irenypathic, Kabian, Kemirica, Kineptia, Lecaent, Lingabat, Linprel, Lyribastad, Lyric, Lyrica, Lyrineur, Lyrolin, Lyzalon, Martesia, Maxgalin, Mystika, Neuragabalin, Neugaba, Neurega, Neurica, Neuristan, Neurolin, Neurovan, Neurum, Newrica, Nuramed, Paden, Pagadin, Pagamax, Painica, Pevesca, PG, Plenica, Pragiola, Prebalin, Prebanal, Prebel, Prebictal, Prebien, Prefaxil, Pregaba, Pregabalin, Pregabalina, Pregabaline, Prégabaline, Pregabalinum, Pregabateg, Pregaben, Pregabid, Pregabin, Pregacent, Pregadel, Pregagamma, Pregalex, Pregalin, Pregalodos, Pregamid, Pregan, Preganerve, Pregastar, Pregatrend, Pregavalex, Pregdin Apex, Pregeb, Pregobin, Prejunate, Prelin, Preludyo, Prelyx, Premilin, Preneurolin, Prestat, Pretor, Priga, Provelyn, Regapen, Resenz, Rewisca, Serigabtin, Symra, Vronogabic, Xablin, and Xil.[136]

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.[136]

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April 07, 2024
pregabalin, sold, under, brand, name, lyrica, among, others, anticonvulsant, analgesic, anxiolytic, amino, acid, medication, used, treat, epilepsy, neuropathic, pain, fibromyalgia, restless, syndrome, opioid, withdrawal, generalized, anxiety, disorder, also, a. Pregabalin sold under the brand name Lyrica among others is an anticonvulsant analgesic and anxiolytic amino acid medication used to treat epilepsy neuropathic pain fibromyalgia restless leg syndrome opioid withdrawal and generalized anxiety disorder GAD 13 17 18 Pregabalin also has antiallodynic properties 19 20 21 Its use in epilepsy is as an add on therapy for partial seizures 13 It is a gabapentinoid medication and acts by inhibiting certain calcium channels 13 22 23 When used before surgery it reduces pain but results in greater sedation and visual disturbances 24 It is taken by mouth 13 PregabalinClinical dataPronunciation p r i ˈ ɡ ae b el ɪ n Trade namesLyrica others 1 Other names3 isobutyl GABA S 3 isobutyl g aminobutyric acidAHFS Drugs comMonographMedlinePlusa605045License dataUS DailyMed PregabalinPregnancycategoryAU D 2 3 DependenceliabilityPhysical High 4 Psychological Moderate 4 AddictionliabilityLow 4 Routes ofadministrationBy mouthDrug classGabapentinoidAnticonvulsantGABA analogATC codeN02BF02 WHO QN02BF02 WHO Legal statusLegal statusAU S4 Prescription only 5 BR Class C1 Other controlled substances 6 CA only NZ Rx only 7 UK POM Prescription only Class C 8 US Schedule V 9 EU Rx only 10 In general Prescription only Pharmacokinetic dataBioavailabilityOral High 90 rapidly absorbed food has no significant effect on bioavailability 11 Protein binding lt 1 12 MetabolitesN methylpregabalin 11 Onset of actionMay occur within a week pain 13 Elimination half life4 5 7 hours 14 mean 6 3 hours 14 15 Duration of actionUnknown 16 ExcretionKidneyIdentifiersIUPAC name 3S 3 aminomethyl 5 methylhexanoic acidCAS Number148553 50 8 YPubChem CID5486971DrugBankDB00230 YChemSpider4589156 YUNII55JG375S6MKEGGD02716 YChEBICHEBI 64356 YChEMBLChEMBL1059 YCompTox Dashboard EPA DTXSID1045950ECHA InfoCard100 119 513Chemical and physical dataFormulaC 8H 17N O 2Molar mass159 229 g mol 13D model JSmol Interactive imageSMILES CC C CC CC O O CNInChI InChI 1S C8H17NO2 c1 6 2 3 7 5 9 4 8 10 11 h6 7H 3 5 9H2 1 2H3 H 10 11 t7 m0 s1 YKey AYXYPKUFHZROOJ ZETCQYMHSA N Y verify Common side effects include headache dizziness sleepiness confusion trouble with memory poor coordination dry mouth problems with vision and weight gain 13 25 Serious side effects may include angioedema drug misuse and an increased suicide risk 13 When pregabalin is taken at high doses over a long period of time addiction may occur but if taken at usual doses the risk is low 4 Use during pregnancy or breastfeeding is of unclear safety 26 Pregabalin was approved for medical use in the United States in 2004 13 It was developed as a successor to the related gabapentin 27 It is available as a generic medication 25 28 29 30 31 In 2021 it was the 73rd most commonly prescribed medication in the United States with more than 8 million prescriptions 32 33 In the US pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970 13 It is a Class C controlled substance in the UK 34 Contents 1 Medical uses 1 1 Seizures 1 2 Neuropathic pain 1 3 Anxiety disorders 1 3 1 Generalized anxiety disorder 1 4 Other uses 2 Adverse effects 2 1 Withdrawal symptoms 2 2 Pregnancy 2 3 Breathing 3 Overdose 4 Pharmacology 4 1 Interactions 4 2 Pharmacodynamics 4 3 Pharmacokinetics 4 3 1 Absorption 4 3 2 Distribution 4 3 3 Metabolism 4 3 4 Elimination 5 Chemistry 5 1 Synthesis 6 History 7 Society and culture 7 1 Legal status 7 2 Economics 7 3 Intellectual property 7 4 Brand names 8 ReferencesMedical uses edit nbsp Box of 150 mg Lyrica pregabalin capsules from FinlandSeizures edit For drug resistant focal epilepsy pregabalin is useful as an add on therapy to other treatments 35 Its use alone is less effective than some other seizure medications 36 It is unclear how it compares to gabapentin for this use 36 Neuropathic pain edit 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 37 A minority obtain substantial benefit and a larger number obtain moderate benefit 38 It is given equal weight as gabapentin and tricyclic antidepressants as a first line agent however the latter are less expensive as of 2010 39 Pregabalin is as effective at relieving pain as duloxetine and amitriptyline Combination treatment of pregabalin and amitriptyline or duloxetine offers additional pain relief for people whose pain is not adequately controlled with one medication and is safe 40 41 Studies have shown that higher doses of pregabalin are associated with greater efficacy 42 Pregabalin s use in cancer associated neuropathic pain is controversial 43 though such use is common 44 It has been examined for the prevention of post surgical chronic pain but its utility for this purpose is controversial 45 46 Pregabalin is generally not regarded as efficacious in the treatment of acute pain 38 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 45 47 Several possible mechanisms for pain improvement have been discussed 48 Anxiety disorders edit Pregabalin is effective for treatment of generalized anxiety disorder 49 It is also effective for the short and long term treatment of social anxiety disorder and in reducing preoperative anxiety 50 51 However there is concern regarding pregabalin s off label use due to the lack of strong scientific evidence for its efficacy in multiple conditions and its proven side effects 52 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 PTSD 53 54 For PTSD pregabalin as complementary treatment seems to be effective 51 Generalized anxiety disorder edit Pregabalin has anxiolytic effects similar to benzodiazepines with less risk of dependence 55 The effects of pregabalin appear within one week of use 56 and are similar in effectiveness to lorazepam alprazolam and venlafaxine but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychosomatic anxiety symptoms 57 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 57 It produces less severe cognitive and psychomotor impairment compared to benzodiazepines 57 58 A 2019 review found that pregabalin reduces symptoms and was generally well tolerated 49 Other uses edit Although pregabalin is sometimes prescribed for people with bipolar disorder there is no evidence showing that it is effective 51 59 There is no evidence and significant risk in using pregabalin for sciatica and low back pain 60 61 62 Evidence of benefit in alcohol withdrawal as well as withdrawal from certain other drugs is limited as of 2016 63 There is no evidence for its use in the prevention of migraines and gabapentin has also been found not to be useful 64 Adverse effects editExposure to pregabalin is associated with weight gain sleepiness and fatigue dizziness vertigo leg swelling disturbed vision loss of coordination and euphoria 65 It has an adverse effect profile similar to other central nervous system depressants 66 Even though pregabalin is a depressant and anti convulsant it can sometimes paradoxically induce seizures particularly in large overdoses 67 Adverse drug reactions associated with the use of pregabalin include 68 69 Very common gt 10 of people with pregabalin dizziness drowsiness Common 1 10 of people with pregabalin blurred vision diplopia increased appetite and subsequent weight gain euphoria confusion vivid dreams changes in libido increase or decrease irritability ataxia attention changes feeling high abnormal coordination memory impairment tremors dysarthria paresthesia vertigo dry mouth and constipation nausea vomiting and flatulence erectile dysfunction fatigue peripheral edema feeling the effects of drunkenness abnormal walking asthenia nasopharyngitis increased creatine kinase level Infrequent 0 1 1 of people with pregabalin depression lethargy agitation anorgasmia hallucinations myoclonus hypoaesthesia hyperaesthesia tachycardia excessive salivation hypoglycaemia sweating flushing rash muscle cramp myalgia arthralgia urinary incontinence dysuria thrombocytopenia kidney calculus Rare lt 0 1 of people with pregabalin neutropenia first degree heart block hypotension hypertension pancreatitis dysphagia oliguria rhabdomyolysis suicidal thoughts or behavior 70 Cases of recreational use with associated adverse effects have been reported 71 Withdrawal symptoms edit Following abrupt or rapid discontinuation of pregabalin some people reported symptoms suggestive of physical dependence The FDA determined that the substance dependence profile of pregabalin as measured by a personal physical withdrawal checklist was quantitatively less than benzodiazepines 66 Even people who have discontinued short term use of pregabalin have experienced withdrawal symptoms including insomnia headache nausea anxiety diarrhea flu like symptoms nervousness major depression pain convulsions hyperhidrosis and dizziness 72 Pregnancy edit It is unclear if it is safe for use in pregnancy with some studies showing potential harm 73 Breathing edit In December 2019 the US 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 74 75 The FDA required new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids 74 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 74 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 74 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 74 One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function 74 The other trial showed gabapentin alone increased pauses in breathing during sleep 74 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 74 The FDA also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function 74 Overdose editAn overdose of pregabalin usually consists of severe drowsiness severe ataxia blurred vision and macular detachment 76 slurred speech severe uncontrollable jerking motions myoclonus tonic clonic seizures and anxiety 77 Despite these symptoms an overdose is not usually fatal unless mixed with another depressant 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 hypertonia Plasma serum or blood concentrations of pregabalin may be measured to monitor therapy or to confirm a diagnosis of poisoning in hospitalized people 78 79 80 Pharmacology editInteractions edit 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 certain anti diabetic agents thiazolidinediones 81 Pharmacodynamics edit nbsp Pregabalin is not a GABAA or GABAB receptor agonist nbsp N Type Voltage gated calcium channelPregabalin is a gabapentinoid and acts by inhibiting certain calcium channels 22 23 Specifically it is a ligand of the auxiliary a2d subunit site of certain voltage dependent calcium channels VDCCs and thereby acts as an inhibitor of a2d subunit containing VDCCs 22 82 There are two drug binding a2d subunits a2d 1 and a2d 2 and pregabalin shows similar affinity for and hence lack of selectivity between these two sites 22 Pregabalin is selective in its binding to the a2d VDCC subunit 82 83 Despite the fact that pregabalin is a GABA analogue 84 it does not bind to the GABA receptors does not convert into GABATooltip g aminobutyric acid or another GABA receptor agonist in vivo and does not directly modulate GABA transport or metabolism 23 82 However pregabalin has been found to produce a dose dependent increase in the brain expression of L glutamic acid decarboxylase GAD the enzyme responsible for synthesizing GABA and hence may have some indirect GABAergic effects by increasing GABA levels in the brain 85 86 87 There is currently no evidence that the effects of pregabalin are mediated by any mechanism other than inhibition of a2d containing VDCCs 82 88 In accordance inhibition of a2d 1 containing VDCCs by pregabalin appears to be responsible for its anticonvulsant analgesic and anxiolytic effects 82 88 The endogenous a amino acids L leucine and L isoleucine which closely resemble pregabalin and the other gabapentinoids in chemical structure are apparent ligands of the a2d 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 mM for L leucine 4 8 mM for L isoleucine 89 It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids 89 90 In accordance while gabapentinoids like pregabalin and gabapentin have nanomolar affinities for the a2d 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 88 Pregabalin was found to possess 6 fold higher affinity than gabapentin for a2d subunit containing VDCCs in one study 91 92 However another study found that pregabalin and gabapentin had similar affinities for the human recombinant a2d 1 subunit Ki 32 nM and 40 nM respectively 93 In any case pregabalin is 2 to 4 times more potent than gabapentin as an analgesic 84 94 and in animals appears to be 3 to 10 times more potent than gabapentin as an anticonvulsant 84 94 Pharmacokinetics edit Absorption edit Pregabalin is absorbed from the intestines by an active transport process mediated via the large neutral amino acid transporter 1 LAT1 SLC7A5 a transporter for amino acids such as L leucine and L phenylalanine 22 82 95 Very few less than 10 drugs are known to be transported by this transporter 96 Unlike gabapentin which is transported solely by the LAT1 95 12 pregabalin seems to be transported not only by the LAT1 but also by other carriers 22 The LAT1 is easily saturable so the pharmacokinetics of gabapentin are dose dependent with diminished bioavailability and delayed peak levels at higher doses 22 In contrast this is not the case for pregabalin which shows linear pharmacokinetics and no saturation of absorption 22 The oral bioavailability of pregabalin is greater than or equal to 90 across and beyond its entire clinical dose range 75 to 600 mg day 12 Food does not significantly influence the oral bioavailability of pregabalin 12 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 22 11 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 12 Distribution edit Pregabalin crosses the blood brain barrier and enters the central nervous system 82 However due to its low lipophilicity 12 pregabalin requires active transport across the blood brain barrier 95 82 97 98 The LAT1 is highly expressed at the blood brain barrier 99 and transports pregabalin across into the brain 95 82 97 98 Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats 11 In humans the volume of distribution of an orally administered dose of pregabalin is approximately 0 56 L kg 11 Pregabalin is not significantly bound to plasma proteins lt 1 12 Metabolism edit Pregabalin undergoes little or no metabolism 12 22 100 In experiments using nuclear medicine techniques it was revealed that approximately 98 of the radioactivity recovered in the urine was unchanged pregabalin 11 The main metabolite is N methylpregabalin 11 Pregabalin is generally safe in patients with liver cirrhosis 101 Elimination edit Pregabalin is eliminated by the kidneys in the urine mainly in its unchanged form 12 11 It has a relatively short elimination half life with a reported value of 6 3 hours 12 Because of its short elimination half life pregabalin is administered 2 to 3 times per day to maintain therapeutic levels 12 The kidney clearance of pregabalin is 73 mL minute 9 Chemistry edit nbsp Chemical structures of GABA pregabalin and two other gabapentinoids gabapentin and phenibut Pregabalin is a GABA analogue that is a 3 substituted derivative as well as a g amino acid 19 83 Specifically pregabalin is S 3 isobutyl GABA 102 103 104 Pregabalin also closely resembles the a amino acids L leucine and L isoleucine and this may be of greater relevance in relation to its pharmacodynamics than its structural similarity to GABA 89 90 102 Synthesis edit Chemical syntheses of pregabalin have been described 105 106 History editExternal videos nbsp nbsp Richard B Silverman Basic Science to Blockbuster Drug National Academy of InventorsPregabalin was synthesized in 1990 as an anticonvulsant It was invented by medicinal chemist Richard Bruce Silverman at Northwestern University in Evanston Illinois 107 Silverman is best known for identifying the drug pregabalin as a possible treatment for epileptic seizures 108 During 1988 to 1990 Ryszard Andruszkiewicz a visiting research fellow synthesized a series of molecules requested by Silverman 109 One looked particularly promising 110 The molecule was effectively shaped for transportation into the brain where it activated L glutamic acid decarboxylase an enzyme Silverman hoped that the enzyme would increase production of the inhibitory neurotransmitter GABA and block convulsions 108 Eventually the set of molecules were sent to Parke Davis Pharmaceuticals for testing The drug was approved in the European Union in 2004 The US received FDA approval for use in treating epilepsy diabetic neuropathic pain and postherpetic neuralgia in December 2004 Pregabalin then appeared on the US market under the brand nameLyrica in fall of 2005 111 In 2017 the FDA approved pregabalin extended release Lyrica CR for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia 112 However unlike the immediate release formulation Lyrica CR was not approved for the management of fibromyalgia or as add on therapy for adults with partial onset seizures 113 9 Society and culture editLegal status edit United States During clinical trials a small number of users 4 reported euphoria after use which led to its control in the US 114 The Drug Enforcement Administration DEA classified pregabalin as a depressant and placed pregabalin including its salts and all products containing pregabalin into Schedule V of the Controlled Substances Act 115 66 116 Norway Pregabalin is in prescription Schedule B alongside benzodiazepines 117 118 United Kingdom On January 14 2016 the Advisory Council on the Misuse of Drugs ACMD wrote a letter to Home Office ministers recommending that pregabalin alongside gabapentin should be controlled under the Misuse of Drugs Act 1971 119 120 It was announced in October 2018 that Pregabalin would become reclassified as a class C controlled substance from April 2019 121 34 122 In the United States the 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 123 Pregabalin has also been approved in the European Union the United Kingdom and Russia for treatment of generalized anxiety disorder 124 57 125 Economics edit Pregabalin is available as a generic medication in a number of countries including the United States as of July 2019 25 28 124 In the United States as of July 2019 the wholesale pharmacy cost for generic pregabalin is US 0 17 0 22 per 150 mg capsule 126 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 127 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 128 129 130 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 128 129 Intellectual property edit Professor Richard Rick Silverman of Northwestern University developed pregabalin there The university holds a patent on it exclusively licensed to Pfizer 131 132 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 133 134 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 135 Brand names edit As of October 2017 pregabalin was marketed under many brand names in other countries Algerika Alivax Alyse Alzain Andogablin Aprion Averopreg Axual Balifibro Brieka Clasica Convugabalin Dapapalin Dismedox Dolgenal Dolica Dragonor Ecubalin Epica Epiron Gaba P Gabanext Gabarol Gabica Gablin Gablovac Gabrika Gavin Gialtyn Glonervya Helimon Hexgabalin Irenypathic Kabian Kemirica Kineptia Lecaent Lingabat Linprel Lyribastad Lyric Lyrica Lyrineur Lyrolin Lyzalon Martesia Maxgalin Mystika Neuragabalin Neugaba Neurega Neurica Neuristan Neurolin Neurovan Neurum Newrica Nuramed Paden Pagadin Pagamax Painica Pevesca PG Plenica Pragiola Prebalin Prebanal Prebel Prebictal Prebien Prefaxil Pregaba Pregabalin Pregabalina Pregabaline Pregabaline Pregabalinum Pregabateg Pregaben Pregabid Pregabin Pregacent Pregadel Pregagamma Pregalex Pregalin Pregalodos Pregamid Pregan Preganerve Pregastar Pregatrend Pregavalex Pregdin Apex Pregeb Pregobin Prejunate Prelin Preludyo Prelyx Premilin Preneurolin Prestat Pretor Priga Provelyn Regapen Resenz Rewisca Serigabtin Symra Vronogabic Xablin and Xil 136 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 136 References edit Pregabalin Drugs com www drugs com Archived 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