|Trade names||Lyrica, others|
|Bioavailability||High (≥90% rapidly absorbed; administration with food has no significant effect on bioavailability)|
|Onset of action||may occur within a week (pain)|
|Biological half-life||6.3 to 11.5 hours|
|Duration of action||Unknown|
|Chemical and physical data|
|Molar mass||159.23 g.mol−1|
|3D model (JSmol)|
|(what is this?)|
Pregabalin, marketed under the brand name Lyrica among others, is a medication used to treat epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder. Its use for epilepsy is as an add-on therapy for partial seizures with or without secondary generalization in adults. Some off-label uses of pregabalin include restless leg syndrome, prevention of migraines, social anxiety disorder, and alcohol withdrawal. When used before surgery it does not appear to affect pain after surgery but may decrease the use of opioids.
Common side effects include: sleepiness, confusion, trouble with memory, poor motor coordination, dry mouth, problem with vision, and weight gain. Potentially serious side effects include angioedema, drug misuse, and an increased suicide risk. When pregabalin is taken at high doses over a long period of time, addiction may occur, but if taken at usual doses the risk of addiction is low. It is classified as a GABA analogue.
Parke-Davis developed pregabalin as a successor to gabapentin and was brought to market by Pfizer after the company acquired Warner-Lambert. There is to be no generic version available in the United States until 2018. A generic version is available in Canada and the United Kingdom. In the US it costs about 300-400 USD per month. Pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970 (CSA).
- 1 Medical uses
- 2 Side effects
- 3 Overdose
- 4 Drug interactions
- 5 Pharmacology
- 6 History
- 7 Society and culture
- 8 See also
- 9 References
- 10 External links
Pregabalin is useful when added to other treatments, when those other treatments are not controlling partial epilepsy. Its use alone is less effective than some other seizure medications. It is unclear how it compares to gabapentin for this use.
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. A minority obtain substantial benefit, and a larger number obtain moderate benefit. Other first line agents, including gabapentin and tricyclic antidepressants, are given equal weight as first line agents, and unlike pregabalin, are available as less expensive generics.
Pregabalin is not recommended for certain other types of neuropathic pain such as pain that of trigeminal neuralgia  and its use in cancer-associated neuropathic pain is controversial. There is no evidence for its use in the prevention of migraines and gabapentin has been found not to be useful. It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial.
Pregabalin is generally not regarded as efficacious in the treatment of acute pain. 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 SSRIs as first line treatment for obsessive-compulsive disorder and post-traumatic stress disorder. It appears to have anxiolytic effects similar to benzodiazepines with less risk of dependence.
The effects of pregabalin appear after 1 week of use and is similar in effectiveness to lorazepam, alprazolam, and venlafaxine, but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychosomatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance, and, in addition, unlike benzodiazepines, it has a beneficial effect on sleep and sleep architecture, characterized by the enhancement of slow-wave sleep. It produces less severe cognitive and psychomotor impairment compared to those drugs; it also has a low potential for abuse and dependence and may be preferred over the benzodiazepines for these reasons.
Pregabalin has been shown to produce therapeutic effects that are similar to other controlled substances. In a study with recreational users of sedative and hypnotic drugs, a 450 mg dose of pregabalin resulted in subjective ratings of a "good drug effect" and "high" and "liking" similar to 30 mg of diazepam. In clinical studies, pregabalin showed a side effect profile similar to other central nervous system depressants.
- Very common (>10% of patients): dizziness, drowsiness.
- Common (1–10% of patients): 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, parasthesia, vertigo, dry mouth and constipation, 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 patients): 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 (<0.1% of patients): neutropenia, first degree heart block, hypotension, hypertension, pancreatitis, dysphagia, oliguria, rhabdomyolysis, suicidal thoughts or behavior.
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 patient physical withdrawal checklist, was quantitatively less than benzodiazepines. Even people who have discontinued short term and or long term use of pregabalin have experienced withdrawal symptoms, including insomnia, headache, agitation, nausea, anxiety, diarrhea, flu like symptoms, nervousness, major depression, pain, convulsions, hyperhidrosis and dizziness.
It is unclear if it is safe for use in pregnancy with some studies showing potential harm.
Several renal failure patients developed myoclonus while receiving pregabalin, apparently as a result of gradual accumulation of the drug. Acute overdosage may be manifested by somnolence, tachycardia and hypertonicity. Plasma, serum or blood concentrations of pregabalin may be measured to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients.
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 Antidiabetic Agents (Thiazolidinedione).
Pregabalin is a GABAergic anticonvulsant and depressant of the central nervous system (CNS). It is classified as a GABA analogue and gabapentinoid. It is a close analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Pregabalin binds with high affinity to the α2δ subunit-containing voltage-gated calcium channels (VDCC). It increases extracellular GABA concentrations in the brain by producing a dose-dependent increase in L-Glutamic acid decarboxylase (GAD), the enzyme responsible for making GABA.
Although pregabalin is an analogue of GABA, it does not bind directly to GABAA, GABAB, GABAϱ, or benzodiazepine receptors. Nor does it block sodium channels and is not active at opioid receptors. Gabapentinoids, such as pregabalin, are α2δ subunit modifiers that affect GABA. In contrast to the distribution of α2δ-1 and α2δ-2 subunits binding correlates partially with GABAergic neurons. Pregabalin increases the density of GABA transporter proteins and increases the rate of functional GABA transport. It also increases extracellular GABA concentrations in the brain by producing a dose-dependent increase in L-Glutamic acid decarboxylase.
Pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within one hour. Pregabalin oral bioavailability is estimated to be greater than or equal to 90% and is independent of dose. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25 to 30% and a delay in Tmax (time to reach Cmax) to approximately 3 hours. Administration with food, however, has no clinically significant effect on the extent of absorption.
Pregabalin has been shown to cross the blood–brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the volume of distribution of pregabalin for an orally administered dose is approximately 0.56 L/kg and is not bound to plasma proteins.
Pregabalin undergoes negligible metabolism in humans. In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The major metabolite is N-methylpregabalin.
|“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 Chicago, Illinois. Silverman is best known for identifying the drug pregabalin as a possible treatment for epileptic seizures. During 1988 to 1990, Ryszard Andruszkiewicz, a visiting research fellow, synthesized a series of molecules for Silverman. One looked particularly promising. 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. 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.
Society and culture
In the United States as of 2015 the cost is between 3.69 and 5.52 USD per 150 mg capsule.
- United States: During clinical trials a small number of users (~4%) reported euphoria after use, which led to its control in the US. 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.
- Norway: Pregabalin is in prescription Schedule C, the lowest schedule, although it has been suggested that it be moved to Schedule B alongside benzodiazepines.
- United Kingdom: On January 14, 2016 the Advisory Council on the Misuse of Drugs (ACMD) wrote a letter to Home Office ministers recommending that both drugs be reclassified as a Class C drug and scheduled under the Misuse of Drugs Regulations 2001 (as amended) as Schedule 3. This would mean prescriptions would only be valid for one month and there can be no refills. The letter warns there is a risk of addiction for both drugs, as well as misuse and diversion. Recreational users of pregabalin in Belfast, Northern Ireland call the drug “Budweisers" because it induces a state similar to drunkenness.
In the United States, the Food and Drug Administration (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 and Russia (but not in US) for treatment of generalized anxiety disorder.
Pregabalin is marketed by Pfizer under the trade name Lyrica. Pfizer described in an SEC filing that the drug could be used to treat epilepsy, postherpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia.
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.
Pfizer promoted Lyrica for other uses which had not been approved by medical regulators up until 2009. For this practice, along with similar illegal marketing of three other drugs, Pfizer was fined a record amount of US$2.3 billion by the Department of Justice. Lyrica sales reached a record US$3.063 billion in 2010. Lyrica is one of four drugs which Pharmacia & Upjohn, a subsidiary of Pfizer, in 2009 pleaded guilty to misbranding "with the intent to defraud or mislead". Pfizer agreed to pay US$2.3 billion (GB£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer illegally promoted the drugs and caused false claims to be submitted to government healthcare programs for uses that were not approved by the U.S. Food and Drug Administration (FDA).
Northwestern University invented pregabalin and holds a patent on it, which it exclusively licensed to Pfizer. That patent, along with others, was challenged by generic manufacturers and was upheld in 2014, giving Pfizer exclusivity for Lyrica in the US until 2018.
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