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Pregabalin is a gamma-Aminobutyric acid analog anticonvulsant and analgesic used for neuropathic pain and as an add on therapy for partial seizures with or without secondary generalization in adults.

It is considered to have a low potential for abuse and a limited dependence liability if misused and is classified as a Schedule V controlled substance in the United States.

Medical uses



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. Other first line agents, including gabapentin and tricyclic antidepressants, are given equal weight as first line agents, and unlike pregabalin, are available as inexpensive generics. It is not recommended for certain other types of neuropathic pain such as pain associated with trigeminal neuralgia or HIV infection 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. In clinical trials examining the utility of pregabalin for the treatment of acute post-surgical pain, no effect on overall pain levels was observed but patients required less morphine and suffered fewer opioid-related side effects.

Anxiety disorders

It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union and Russia. 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.

Therapeutic 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 psychic and somatic 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 and produces less severe cognitive and psychomotor impairment; it also has a low potential for abuse and dependence and may be preferred over the benzodiazepines for these reasons.

Adverse effects



Adverse drug reactions associated with the use of pregabalin include:

  • Very common (>10% of patients): dizziness, drowsiness.
  • Common (1â€"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, abnormal coordination, memory impairment, tremors, dysarthria, parasthesia, vertigo, dry mouth and constipation, vomiting and flatulence, erectile dysfunction, fatigue, peripheral edema, drunkenness, abnormal walking, asthenia, nasopharyngitis, increased creatine kinase level.
  • Infrequent (0.1â€"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.

Overdosage

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.

Discontinuation

Some people who have discontinued short term and long term use of pregabalin have experienced withdrawal symptoms, including insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain, convulsion, hyperhidrosis and dizziness.

Pharmacology



Pharmacodynamics

Like gabapentin, pregabalin binds to the α2δ (alpha-2-delta) subunit of the voltage-dependent calcium channel in the central nervous system. Pregabalin decreases the release of neurotransmitters including glutamate, norepinephrine, substance P and calcitonin gene-related peptide.

However, unlike anxiolytic compounds (e.g., benzodiazepines) which exert their therapeutic effects through binding to GABAA, pregabalin neither binds directly to these receptors nor augments GABAA currents or affects GABA metabolism (Pfizer Inc., 2006). The half-life for pregabalin is 6.3 hours.

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 (time to reach Cmax) to approximately 2.5 hours. Administration with food, however, has no clinically significant effect on the extent of absorption.

Distribution

Pregabalin has been shown to cross the bloodâ€"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. 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.

Excretion

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

History



Pregabalin was discovered by medicinal chemist Richard Bruce Silverman at Northwestern University in the United States. The drug was approved in the European Union in 2004. Pregabalin received U.S. FDA approval for use in treating epilepsy, diabetic neuropathic pain, and postherpetic 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 gained FDA approval for the treatment of fibromyalgia in June 2008.

Generic versions of pregabalin became available in Russia in 2001, in Canada in 2013, and are expected to become available in the European Union and the U.S. in 2016 and 2018 respectively.

Society and culture



Regulatory approval

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.

Regulatory status



United States

Pregabalin is a Schedule V controlled substance and is classified as a CNS depressant. The potential for abuse of pregabalin is less than the potential with benzodiazepines; additionally the euphoric effects of pregabalin disappear with prolonged use.

Marketing

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. Lyrica was promoted for other uses which had not been approved by medical regulators up until 2009. For this practice, with 3 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).

Intellectual property

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.

See also



  • 4-Methylpregabalin
  • Atagabalin
  • Phenibut

References



External links



  • Pfizer website for Lyrica
  • U.S. prescribing information
  • Lyrica (pregabalin) drug label/data at Daily Med from U.S. National Library of Medicine, National Institutes of Health.
  • Lyrica Oral at WebMD.com


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