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Pronunciation | /priˈɡæbəlɪn/ |
Trade names | Lyrica, others [1] |
Other names | 3-isobutyl GABA, (S)-3-isobutyl-γ-aminobutyric acid |
AHFS/Drugs.com | Monograph |
MedlinePlus | a605045 |
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Dependence liability | Physical: High [4] Psychological: Moderate [4] |
Addiction liability | Low [4] |
Routes of administration | By mouth |
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Pharmacokinetic data | |
Bioavailability | Oral: High (≥90% rapidly absorbed; food has no significant effect on bioavailability) [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 | Unknown [16] |
Excretion | Kidney |
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ECHA InfoCard | 100.119.513 |
Chemical and physical data | |
Formula | C8H17NO2 |
Molar mass | 159.229 g·mol−1 |
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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]
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]
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]
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]
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]
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]
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]
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]
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]
It is unclear if it is safe for use in pregnancy with some studies showing potential harm. [73]
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]
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]
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]
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 GABA 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]
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]
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]
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]
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]
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]
Chemical syntheses of pregabalin have been described. [105] [106]
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"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]
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]
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]
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]
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]
An analgesic drug, also called simply an analgesic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.
An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.
Colloquially known as "downers", depressants or central depressants are drugs that lower neurotransmission levels, or depress or reduce arousal or stimulation in various areas of the brain. Depressants do not change the mood or mental state of others. Stimulants, or "uppers", increase mental or physical function, hence the opposite drug class from depressants are stimulants, not antidepressants.
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.
Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive-compulsive disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.
Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and off-label to treat alcohol use disorder or opioid withdrawal symptoms. It is taken orally or by intrathecal pump. It is also sometimes used transdermally in combination with gabapentin and clonidine prepared at a compounding pharmacy.
Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.
Tiagabine is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder.
Phenibut, sold under the brand names Anvifen, Fenibut, and Noofen among others, is a central nervous system depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. It is usually taken by mouth as a tablet, but may be given intravenously.
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.
Gabapentin enacarbil is an anticonvulsant and analgesic drug of the gabapentinoid class, and a prodrug to gabapentin. It was designed for increased oral bioavailability over gabapentin, and human trials showed it to produce extended release of gabapentin with almost twice the overall bioavailability, especially when taken with a fatty meal. Gabapentin enacarbil has passed human clinical trials for the treatment of restless legs syndrome, and initial results have shown it to be well tolerated and reasonably effective.
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.
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.
Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor, as it is the target of the drugs gabapentin and pregabalin.
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.
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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