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, generalized anxiety disorder (GAD), and shingles.
Common side effects can include headache, dizziness, somnolence, euphoria, confusion, trouble with memory, Ataxia, dry mouth, problems with vision, and weight gain. Serious side effects may include angioedema, kidney damage and drug misuse. 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. When pregabalin is taken at high doses over a long period of time, addiction may occur, but if taken at therapeutic dose the risk is low. Use during pregnancy or breastfeeding is of unclear safety.
It is a gabapentinoid medication which is a class of drugs within the derivatives of γ-aminobutyric acid (), an inhibitory neurotransmitter.
Although pregabalin is inactive at and GABA , it acts by binding specifically to the α2δ-1 protein that was first described as an auxiliary subunit of voltage-gated .Pregabalin was approved for medical use in the United States in 2004. In the US, pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970, which means that the drug has low abuse potential compared to substances in Schedules I-IV, however, there is still a potential for misuse. It is available as a generic medication.
Studies have shown that higher doses of pregabalin are associated with greater efficacy.
Pregabalin's use in cancer-associated neuropathic pain is controversial, though such use is common.
Pregabalin is generally not regarded as efficacious in the treatment of acute pain. In trials examining the utility of pregabalin for the treatment of acute post-surgical pain, no effect on overall pain levels was observed, but people did require less morphine and had fewer opioid-related side effects. Several possible mechanisms for pain improvement have been discussed.
The 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 the selective serotonin reuptake inhibitor (SSRI) class as first line treatment for obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). For PTSD, pregabalin as complementary treatment seems to be effective.
A 2019 review found that pregabalin reduces symptoms, and was generally well tolerated.
There is no evidence and significant risk in using pregabalin for sciatica and low back pain. Evidence of benefit in alcohol withdrawal as well as withdrawal from certain other drugs is limited as of 2016.
There is no evidence for its use in the prevention of and gabapentin has also been found not to be useful.
A 2025 review found possible benefits to sleep quality in patients with fibromyalgia.
Cases of recreational use, with associated adverse effects, have been reported.
A tapered discontinuation is recommended to reduce the chances of withdrawal symptoms. Lyrica's US package insert recommends a taper period of at least one week. Best Practice Advocacy Centre New Zealand and NHS Somerset recommend a much slower withdrawal.
The FDA required new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids. The FDA also required the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids, because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression.
Among 49 case reports submitted to the FDA over the five-year period from 2012 to 2017, twelve people died from respiratory depression with gabapentinoids, all of whom had at least one risk factor.
The FDA reviewed the results of two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals. One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. The other trial showed gabapentin alone increased pauses in breathing during sleep. The three observational studies at one academic medical center showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after different kinds of surgeries. The FDA also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function.
Although generally considered to have low abuse potential, reports describe pregabalin inducing sensations of euphoria, calmness, excitement, and a "high" comparable to that of marijuana. These effects may contribute to the development of substance dependence, and drug withdrawal symptoms can occur if the medication is stopped abruptly.
While pregabalin and marijuana share certain effects, such as CNS depressant and orexigenic (appetite-stimulating) properties, they differ significantly in their pharmacodynamics. Marijuana is primarily an anxiogenic substance with mild psychedelic drug effects, whereas pregabalin is an anxiolytic agent associated with mild euphoria.
Pregabalin may independently increase the risk of angioedema, and this risk is further elevated when used in combination with other drugs known to increase the likelihood of angioedema. These include, but are not limited to, certain L-type calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers, and other agents that inhibit the renin–angiotensin–aldosterone system.
Pregabalin can also cause rare but serious adverse effects, particularly when used in combination with other CNS .
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.
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. 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. 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.
Despite the fact that pregabalin is a GABA analogue, it does not bind to , does not convert into or another GABA receptor agonist in vivo, and does not directly modulate GABA transport or metabolism. There is currently no evidence that the effects of pregabalin are mediated by any mechanism other than binding to the α2δ-1 protein. In accordance, inhibition of α2δ-1 proteins by pregabalin appears to be responsible for its anticonvulsant, analgesic, and anxiolytic effects in animal models.
Recently, the α2δ-1 protein has been found (independent of calcium channels) to associate directly with certain NMDA receptor, some AMPA receptor and also with the extracellular matrix protein, thrombospondin, and to modulate the function of these proteins. 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). It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. In accordance, while gabapentinoids like pregabalin and gabapentin have nanomolar affinities for the α2δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids has been said to likely be responsible for this discrepancy.
Pregabalin was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VGCCs in one study.
However, another study found that pregabalin and gabapentin had similar affinities for the human recombinant α2δ-1 subunit (Ki=32 nM and 40 nM, respectively). In any case, pregabalin is 2 to 4 times more potent than gabapentin as an analgesic and, in animals, appears to be 3 to 10 times more potent than gabapentin as an anticonvulsant.
The oral bioavailability of pregabalin is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 600 mg/day). Food does not significantly influence the oral bioavailability of pregabalin. Pregabalin is rapidly absorbed when administered on an empty stomach, with a Tmax (time to peak levels) of generally less than or equal to 1 hour at doses of 300 mg or less. However, food has been found to substantially delay the absorption of pregabalin and to significantly reduce peak levels without affecting the bioavailability of the drug; Tmax values for pregabalin of 0.6 hours in a fasted state and 3.2 hours in a fed state (5-fold difference), and the Cmax is reduced by 25–31% in a fed versus fasted state.
Pregabalin is generally safe in patients with liver cirrhosis.
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. Pregabalin has also been approved in the European Union, the United Kingdom, and Russia for treatment of generalized anxiety disorder.
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.
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, 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.
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.
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.
In the US, Lyrica is marketed by Viatris after Upjohn was spun off from Pfizer.
|
|