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Pregabalin (INN) ( ) is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade name Lyrica.

Recent studies have shown that pregabalin is effective at treating chronic pain in disorders such as fibromyalgia and spinal cord injury. In June 2007, pregabalin became the first medication approved by the U.S. Food and Drug Administration specifically for the treatment of fibromyalgia.

It is considered to have a low potential for abuse, and a limited dependence liability if misused, and is thus classified as a Schedule V drug in the U.S.

Lyrica is one of four drugs which a subsidiary of Pfizer in 2009 pleaded guilty to misbranding "with the intent to defraud or mislead". Pfizer agreed to pay $2.3 billion (£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 programmes for uses that were not medically accepted.

History

Pregabalin was initially developed by medicinal chemist Richard Bruce Silverman at Northwestern Universitymarker in the United Statesmarker. The drug was approved in the European Union in 2004. Pregabalin received U.S. Food and Drug Administration (FDA) approval for use in treating epilepsy, diabetic neuropathic pain, and post-herpetic neuralgia in December 2004, and appeared on the U.S. market in fall 2005.

In June 2007, the FDA approved Lyrica as a treatment for fibromyalgia. It was the first drug to be approved for this indication and remained the only one until duloxetine (Cymbalta) gained FDA approval for the treatment of fibromyalgia in June 2008.

Indications

Pregabalin is indicated for:

Adverse effects

Adverse drug reactions associated with the use of pregabalin include:

Pregabalin may also cause dependency and withdrawal effects may occur after long-term use. When prescribed for seizures, quitting "cold turkey" can increase the strength of the seizures and possibly cause the seizures to reoccur. Withdrawal symptoms include restlessness, insomnia, and anxiety. Withdrawal symptoms are similar to benzodiazepine withdrawal but the severity of the withdrawal depends on how much pregabalin has been taken and how long it has been taken. Pregabalin should be reduced gradually when finishing treatment.

Pharmacology

Pharmacodynamics

Like gabapentin, pregabalin binds to the α2δ (alpha2delta) subunit of the voltage-dependent calcium channel in the central nervous system. This reduces calcium influx into the nerve terminals. Pregabalin also decreases the release of neurotransmitters such as glutamate, noradrenaline, and substance P (Australian Medicines Handbook). Pregabalin increases neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity.[159886] Glutamic acid decarboxylase (GAD) is the enzyme that converts the excitatory neurotransmitter glutamate into the inhibitory GABA in a single step. For this reason, pregabalin greatly potentiates benzodiazepines, barbiturates & other depressants.

Pharmacokinetics

Absorption: 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 to approximately 2.5 hours. Administration with food, though, has no clinically significant effect on the extent of absorption.

Distribution: 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.

Metabolism: Pregabalin undergoes negligible metabolism in humans. Approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methyl pregabalin is the major metabolite.

Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Renal clearance of pregabalin is 73 mL/minute.

Drug interactions

No pharmacokinetic interactions have been demonstrated in vivo. The manufacturer notes some potential pharmacological interactions with opioids (pregabalin is synergistic with opioids in lower doses), benzodiazepines, barbiturates, ethanol (alcohol), and other drugs that depress the central nervous system.

Abuse

Pregabalin is a Schedule V drug, classified as a CNS depressant. The potential for abuse of pregabalin is significantly less than the potential with benzodiazepines.

References

  1. Benkert, O., Hippius, H. et al.: Kompendium der Psychiatrischen Pharmakotherapie, 6. Auflage, Springer Medizin Verlag, Heidelberg, 2007. (german) ISBN 9783540344018
  2. Free full text
  3. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of pregabalin into schedule V. Final rule. Fed Regist 2005;70(144):43633-5. PMID 16050051
  4. Pfizer agrees record fraud fine
  5. Pfizer Australia Pty Ltd. Lyrica (Australian Approved Product Information). West Ryde: Pfizer; 2006.
  6. Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  7. Medication Guide
  8. }


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