Pregabalin

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Pregabalin
Pregabalin.svg
Pregabalin ball-and-stick model.png
Clinical data
Pronunciation /priˈɡæbəlɪn/
Trade names Lyrica, others [1]
Other names3-Isobutyl-GABA; (S)-3-Isobutyl-γ-aminobutyric acid; Isobutylgaba; CI-1008; PD-144723
AHFS/Drugs.com Monograph
MedlinePlus a605045
License data
Pregnancy
category
Dependence
liability 		Physical: High [4]
Psychological: Moderate [4]
Addiction
liability 		Low [4] (but varying with dosage and route of administration)
Routes of
administration 		By mouth
Drug class
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Oral: ≥90% [11]
Protein binding <1% [12]
Metabolites N-methylpregabalin [11]
Onset of action May occur within a week (pain) [13]
Elimination half-life 4.5–7 hours [14] (mean 6.3 hours) [14] [15]
Duration of action 8–12 hours [16]
Excretion Kidney
Identifiers
  • (3S)-3-(aminomethyl)-5-methylhexanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.119.513 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H17NO2
Molar mass 159.229 g·mol−1
3D model (JSmol)
  • 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 Yes check.svgY
  • Key:AYXYPKUFHZROOJ-ZETCQYMHSA-N Yes check.svgY
   (verify)

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 legs 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] When used before surgery, it reduces pain but results in greater sedation and visual disturbances. [22] It is taken by mouth. [13]

Contents

Common side effects can include headache, dizziness, sleepiness, confusion, trouble with memory, poor coordination, dry mouth, problems with vision, and weight gain. [13] [23] Serious side effects may include angioedema, and drug misuse. [13] As with all other drugs approved by the FDA for treating epilepsy, the pregabalin labeling warns of an increased suicide risk when combined with other drugs. [24] [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. [25]

It is a gabapentinoid medication (GABA analogue) which are drugs that are derivatives of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. [26] [27] [28] [29] Although pregabalin is inactive at GABA receptors and GABA synapses, it acts by binding specifically to the α2δ-1 protein that was first described as an auxiliary subunit of voltage-gated calcium channels (See Pharmcodynamics). [13] [30] [31]

Pregabalin was approved for medical use in the United States in 2004. [13] It was developed as a successor to the related gabapentin. [32] It is available as a generic medication. [23] [33] [34] [35] [36] In 2022, it was the 91st most commonly prescribed medication in the United States, with more than 7 million prescriptions. [37] [38] In the US, pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970, [13] which means that the drug has low abuse potential compared to substances in Schedules I-IV, however, there is still a potential for misuse. [39] Despite the low abuse potential, there have been reports of euphoria, improved happiness, excitement, calmness, and a "high" similar to marijuana with the use of pregabalin; there is a potential for developing dependence on these substances, and withdrawal symptoms may occur if the medication is abruptly discontinued. [40] [41] It is a Class C controlled substance in the UK. [42] Therefore, pregabalin requires a prescription. [43] [44] Furthermore, the prescription must clearly set forth the dose. [45] Pregabalin has potential for misuse. It can bring about an elevated mood in users. It can also have serious side effects, particularly when used in combination with other drugs. [45] [46]

Medical uses

Box of 150 mg Lyrica (pregabalin) capsules from Finland Lyrica 150mg box in Finland 20110618.jpg
Box of 150 mg Lyrica (pregabalin) capsules from Finland

Seizures

For drug-resistant focal epilepsy, pregabalin is useful as an add-on therapy to other treatments. [47] Its use alone is less effective than some other seizure medications. [48] It is unclear how it compares to gabapentin for this use. [48]

Neuropathic pain

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. [49] A minority obtain substantial benefit, and a larger number obtain moderate benefit. [50] It is given equal weight as gabapentin and tricyclic antidepressants as a first-line agent, however, the latter are less expensive as of 2010. [51] 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. [52] [53]

Studies have shown that higher doses of pregabalin are associated with greater efficacy. [54]

Pregabalin's use in cancer-associated neuropathic pain is controversial, [55] though such use is common. [56] It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial. [57] [58]

Pregabalin is generally not regarded as efficacious in the treatment of acute pain. [50] 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. [57] [59] Several possible mechanisms for pain improvement have been discussed. [60]

Anxiety disorders

Pregabalin is effective for treatment of generalized anxiety disorder. [61] It is also effective for the short- and long-term treatment of social anxiety disorder and in reducing preoperative anxiety. [62] [63] 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. [64]

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 those of selective serotonin reuptake inhibitor (SSRI) class as first line treatment for obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). [65] [66] For PTSD, pregabalin as complementary treatment seems to be effective. [63]

Generalized anxiety disorder

Pregabalin has anxiolytic effects similar to benzodiazepines with less risk of dependence. [67] The effects of pregabalin appear within one week of use, [68] 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. [69] 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. [69] It produces less severe cognitive and psychomotor impairment compared to benzodiazepines. [69] [67]

A 2019 review found that pregabalin reduces symptoms, and was generally well tolerated. [61]

Other uses

Although pregabalin is sometimes prescribed for people with bipolar disorder, there is no evidence showing that it is effective. [63] [70]

There is no evidence and significant risk in using pregabalin for sciatica and low back pain. [71] [72] [73] Evidence of benefit in alcohol withdrawal as well as withdrawal from certain other drugs is limited as of 2016. [74]

There is no evidence for its use in the prevention of migraines and gabapentin has also been found not to be useful. [75]

Adverse effects

Exposure to pregabalin is associated with weight gain, drowsiness, fatigue, dizziness, vertigo, leg swelling, disturbed vision, loss of coordination, and euphoria. [76] It has an adverse effect profile similar to other central nervous system (CNS) depressants. [77] Even though pregabalin is a depressant and anticonvulsant, it can sometimes paradoxically induce seizures, particularly in large overdoses. [78] Adverse drug reactions associated with the use of pregabalin include: [79] [80] [81]

Cases of recreational use, with associated adverse effects, have been reported. [83]

Withdrawal symptoms

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. [77] Even people who have discontinued short-term use of pregabalin have experienced withdrawal symptoms including insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, major depression, pain, seizures, excessive sweating, and dizziness. [84]

Pregnancy

It is unclear if it is safe for use in pregnancy with some studies showing potential harm. [85]

Breathing

In December 2019, the US Food and Drug Administration (FDA) warned about serious breathing issues for those taking gabapentin or pregabalin when used with central nervous system (CNS) depressants or for those with lung problems. [86] [87]

The FDA required new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids. [86] 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. [86]

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. [86]

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. [86] One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. [86] The other trial showed gabapentin alone increased pauses in breathing during sleep. [86] 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. [86] The FDA also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function. [86]

Overdose

An overdose of pregabalin usually consists of severe drowsiness, severe ataxia, blurred vision, slurred speech, uncontrollable jerking motions (myoclonus), and anxiety. [88] In one case study, macular detachment was reported with overdose [89] Despite these symptoms an overdose is not usually fatal unless mixed with another CNS depressant. Several people with kidney failure developed myoclonus while receiving pregabalin, apparently as a result of the gradual accumulation of the drug. Acute overdosage may be manifested by drowsiness, 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. [90] [91] [92]

Interactions

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). [93]

Pharmacology

Mechanism of action

Pregabalin is a gabapentinoid medication, meaning drugs that chemically are derivatives of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. [26] [27] [28] [29] However, pregabalin, like other gabapentinoids, does not mimic GABA or influence GABA receptors. Instead, its action requires binding to a specific site on the α2δ-1 protein and secondarily to reduce the release of excitatory neurtransmitters. [94]

Pregabalin does not directly block calcium channels (it is not a calcium channel blocker), as it does not bind to the ion conducting channel protein, called α1. However, in vitro studies show that pregabalin can reduce the normal traffic of calcium channels from intracellular sites (where they do not function) to membrane sites where they are functional. [13] [30]

While the mechanism of action of pregabalin is not definitively characterized, its action in animal models of pain, seizures and anxiety requires binding to the α2δ-1 protein. [95] It has been found that this binding inhibits several actions of α2δ-1 and also inhibits the release of excitatory neurotransmitters. These excitatory neurotransmitters include glutamate, norepinephrine (noradrenaline), serotonin, dopamine, substance P, and calcitonin gene-related peptide. [94] By inhibiting the release of these neurotransmitters, pregabalin reduces excess activity of neuron networks, which helps alleviate symptoms and provides relief for patients experiencing pain, seizures, or other related symptoms. [96]

Pharmacodynamics

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

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. [30] Pregabalin is selective in its binding to the α2δ VGCC subunits and does not bind significantly to other known drug receptors. [97] [29]

Despite the fact that pregabalin is a GABA analogue, [98] it does not bind to GABA receptors, does not convert into GABA Tooltip γ-aminobutyric acid or another GABA receptor agonist in vivo , and does not directly modulate GABA transport or metabolism. [31] [97] There is currently no evidence that the effects of pregabalin are mediated by any mechanism other than binding to the α2δ-1 protein. [97] [99] In accordance, inhibition of α2δ-1 proteins by pregabalin appears to be responsible for its anticonvulsant, analgesic, and anxiolytic effects in animal models. [97] [99]

Recently, the α2δ-1 protein has been found (independent of calcium channels) to associate directly with certain NMDA-type glutamate receptors, some AMPA-type glutamate receptors and also with the extracellular matrix protein, thrombospondin, and to modulate the function of these proteins. [95] This has been proposed to contribute to the analgesic action of pregabalin animal models and in clinical use.

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 VGCC 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). [27] It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. [27] [100] 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. [99]

Pregabalin was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VGCCs in one study. [101] [102] 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). [103] In any case, pregabalin is 2 to 4 times more potent than gabapentin as an analgesic [98] [104] and, in animals, appears to be 3 to 10 times more potent than gabapentin as an anticonvulsant. [98] [104]

Pharmacokinetics

Absorption

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. [30] [97] [105] Very few (less than 10 drugs) are known to be transported by this transporter. [106] Unlike gabapentin, which is transported solely by the LAT1, [105] [12] pregabalin seems to be transported not only by the LAT1 but also by other carriers. [30] The LAT1 is easily saturable, so the pharmacokinetics of gabapentin are dose-dependent, with diminished bioavailability and delayed peak levels at higher doses. [30] In contrast, this is not the case for pregabalin, which shows linear pharmacokinetics and no saturation of absorption. [30]

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. [30] [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

Pregabalin crosses the blood–brain barrier and enters the central nervous system. [97] However, due to its low lipophilicity, [12] pregabalin requires active transport across the blood–brain barrier. [105] [97] [107] [108] The LAT1 is highly expressed at the blood–brain barrier [109] and transports pregabalin across into the brain. [105] [97] [107] [108] 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

Pregabalin undergoes little or no metabolism. [12] [30] [110] 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. [111]

Elimination

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

Pregabalin is a GABA analogue that is a 3-substituted derivative as well as a γ-amino acid. [19] [29] Because of its chemical and pharmacological similarities to gabapentin, it is sometimes called a gabapentinoid drug. Specifically, pregabalin is (S)-(+)-3-isobutyl-GABA. [112] [113] [114] 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. [27] [100] [112]

Synthesis

Chemical syntheses of pregabalin have been described. [115] [116]

History

Pregabalin was synthesized in 1990 as an anticonvulsant. It was invented by medicinal chemist Richard Bruce Silverman at Northwestern University in Evanston, Illinois. [117] During 1988 to 1990, Ryszard Andruszkiewicz, a visiting research fellow, synthesized a series of molecules requested by Silverman. [118] Upon testing in mouse seizure models by collaborators at Parke-Davis Pharmaceuticals, [119] one looked particularly promising. In vitro, it activated L-glutamic acid decarboxylase, an enzyme, but this later proved to be unimportant to prevention of seizures. Silverman had originally hoped that the enzyme would increase the production of the inhibitory neurotransmitter GABA and block convulsions. [120] After extensive development studies and clinical trials by Parke-Davis 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 the fall of 2005. [121] In 2017, the FDA approved pregabalin extended-release Lyrica CR for the management of neuropathic pain associated with diabetic peripheral neuropathy, and postherpetic neuralgia. [122] 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. [123] [9]

Society and culture

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. [133] Pregabalin has also been approved in the European Union, the United Kingdom, and Russia for treatment of generalized anxiety disorder. [134] [69] [135]

Economics

Pregabalin is available as a generic medication in a number of countries, including the United States as of July 2019. [23] [33] [134] 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. [136]

From 2008 until 2018, Pfizer 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. [137]

Up until 2009, Pfizer promoted Lyrica for other uses that 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, [138] [139] [140] 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. [138] [139]

Intellectual property

Professor Richard "Rick" Silverman of Northwestern University developed pregabalin there. The university holds a patent on it, exclusively licensed to Pfizer. [141] [142] 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. [143] [144]

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 the 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. [145]

Brand names

As of October 2017, pregabalin is marketed under many brand names: 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. [146]

It is marketed 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, Vitcobin-P, and Voltanerv with Methylcobalamin and ALA by Cogentrix Pharma. [146]

In the US, Lyrica is marketed by Viatris after Upjohn was spun off from Pfizer. [147] [148] [149]

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<span class="mw-page-title-main">Richard Bruce Silverman</span>

Richard Bruce Silverman is the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern University. His group's main focus is basic and translational research into central nervous system disorders and cancer. He is known for the discovery of pregabalin, which is marketed by Pfizer under the brand name Lyrica.

An orexigenic, or appetite stimulant, is a drug, hormone, or compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropeptide Y, which increases hunger and therefore enhances food consumption. Usually appetite enhancement is considered an undesirable side effect of certain drugs as it leads to unwanted weight gain, but sometimes it can be beneficial and a drug may be prescribed solely for this purpose, especially when the patient is suffering from severe appetite loss or muscle wasting due to cystic fibrosis, anorexia, old age, cancer or AIDS. There are several widely used drugs which can cause a boost in appetite, including tricyclic antidepressants (TCAs), tetracyclic antidepressants, natural or synthetic cannabinoids, first-generation antihistamines, most antipsychotics and many steroid hormones. In the United States, no hormone or drug has currently been approved by the FDA specifically as an orexigenic, with the exception of Dronabinol, which received approval for HIV/AIDS-induced anorexia only.

<span class="mw-page-title-main">4-Methylpregabalin</span> Chemical compound

4-Methylpregabalin is a drug developed by Pfizer and related to pregabalin, which similarly acts as an analgesic with effectiveness against difficult to treat "atypical" pain syndromes such as neuropathic pain. The effectiveness of pregabalin and its older relative gabapentin against pain syndromes of this kind has led to their widespread use, and these drugs have subsequently been found to be useful for many other medical applications, including as anticonvulsants, muscle relaxants, anxiolytics and mood stabilisers.

<span class="mw-page-title-main">PD-217,014</span> Chemical compound

PD-217,014 is a drug developed by Pfizer and related to gabapentin, which similarly binds to the α2δ calcium channels. It was developed as a potentially more potent successor to gabapentin and pregabalin, along with several other analogues such as atagabalin and 4-methylpregabalin, but while PD-217,014 produces visceral analgesic effects in animal studies with higher potency and efficacy than gabapentin, it was not developed further for clinical use because of its comparatively more complex synthesis, compared to other related analogues.

Imagabalin was an investigational drug that acts as a ligand for the α2δ subunit of the voltage-dependent calcium channel, with some selectivity for the α2δ1 subunit over α2δ2. It was under development by Pfizer as a pharmaceutical medication due to its hypothesized anxiolytic, analgesic, hypnotic, and anticonvulsant-like activity. It reached phase-III clinical trials for treatment of generalized anxiety disorder; however, the trials were terminated by the manufacturer. The drug is no longer under development.

<span class="mw-page-title-main">Gabapentinoid</span> Calcium channel blockers

Gabapentinoids, also known as α2δ ligands, are a class of drugs that are chemically derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which bind selectively to the α2δ protein that was first described as an auxiliary subunit of voltage-gated calcium channels (VGCCs).

<span class="mw-page-title-main">Mirogabalin</span> Chemical compound

Mirogabalin is a gabapentinoid medication developed by Daiichi Sankyo. Gabapentin and pregabalin are also members of this class. As a gabapentinoid, mirogabalin binds to the α2δ subunit of voltage-gated calcium channel, but with significantly higher potency than pregabalin. It has shown promising results in Phase II clinical trials for the treatment of diabetic peripheral neuropathic pain.

An analgesic adjuvant is a medication that is typically used for indications other than pain control but provides control of pain (analgesia) in some painful diseases. This is often part of multimodal analgesia, where one of the intentions is to minimize the need for opioids.

<span class="mw-page-title-main">Crisugabalin</span> Investigational drug for chronic pain

Crisugabalin (HSK16149) is a selective GABA analog in development for the treatment of chronic pain. It has a wider therapeutic index than pregabalin, which as a similar mechanism of action. It is in Phase III trials as of 2023. The drug can be administered with or without food.

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