Pregabalin

Pregabalin

Systematic (IUPAC) name
(S)-3-(aminomethyl)-5-methylhexanoic acid
Clinical data
Trade names	Lyrica, Nervalin
AHFS/Drugs.com	monograph
MedlinePlus	a605045
Licence data	US Daily Med:link
Pregnancy cat.	B3 (Au), C (U.S.)
Legal status	Prescription Only (S4) (AU) POM (UK), Schedule V (U.S.)
Routes	oral
Pharmacokinetic data
Bioavailability	≥90%
Protein binding	Nil
Metabolism	Negligible
Half-life	5–6.5 hours
Excretion	Renal
Identifiers
CAS number	148553-50-8 Y
ATC code	N03AX16
PubChem	CID 5486971
DrugBank	DB00230
ChemSpider	4589156 Y
UNII	55JG375S6M Y
KEGG	D02716 Y
ChEBI	CHEBI:64356 N
ChEMBL	CHEMBL1059 Y
Synonyms	PD-144,723
Chemical data
Formula	C8H17NO2
Mol. mass	159.23 g.mol-1
SMILES O=C(O)C[C@H](CC(C)C)CN
InChI InChI=1S/C8H17NO2/c1-6(2)3-7(5-9)4-8(10)11/h6-7H,3-5,9H2,1-2H3,(H,10,11)/t7-/m0/s1 Y Key:AYXYPKUFHZROOJ-ZETCQYMHSA-N Y
N (what is this?)  (verify)

Pregabalin (INN) /prɨˈɡæbəlɨn/ is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults.^[1] 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.^[1] It was designed as a more potent successor to gabapentin. 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, post-herpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia. Sales reached a record $3.063 billion in 2010.^[2] In Bangladesh Pregabalin is sold under the brand of Nervalin by Beximco Pharma It is effective at treating some causes of chronic pain such as fibromyalgia but not others. It is considered to have a low potential for abuse, and a limited dependence liability if misused, but is classified as a Schedule V drug in the U.S.^[3]

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 programs for uses that were not approved by the U.S. Food and Drug Administration (FDA).^[4]

Medical uses

A package of 150 mg pregabalin (Finland)

Pregabalin appears to be as effective as gabapentin for neuropathic pain; however costs more.^[5] It is effective for some people with postherpetic neuralgia and fibromyalgia.^[6] There is not enough data to state that it should be used in all neuropathic pain. It has not been found to be effective for HIV-associated peripheral neuropathy.^[7] It has not been shown to be useful for cancer related neuropathic pain.^[8] There is no evidence for use in acute pain.^[6] Pregabalin is also used for the treatment perioperative pain.^[9] There is no evidence for its use in the prevention of migraines and gabapentin has been found not to be useful.^[10]

Pregabalin may be used as a second line medication in general anxiety disorder.^[11] It appears to have anxiolytic effects similar to benzodiazepines.^[12][13]

Adverse effects

Adverse drug reactions associated with the use of pregabalin include:^[14][15]

• 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, abnormal coordination, memory impairment, tremors, dysarthria, parasthesia, vertigo, dry mouth and constipation, vomiting and flatulence, erectile dysfunction, fatigue, peripheral oedema, 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.^[16]

Pregabalin may also cause withdrawal effects after long-term use if discontinued abruptly. When prescribed for seizures, quitting “cold turkey” can increase the strength of the seizures and possibly cause the seizures to reoccur. Withdrawal symptoms include difficulty sleeping, nausea, anxiety, diarrhoea, flu or flu-like symptoms, headache, increased sweating, convulsions, pain, dizziness, nervousness, and depression. Pregabalin should be reduced gradually when finishing treatment.

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.^[17][18][19]

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.^[20] However, unlike anxiolytic compounds (e.g., benzodiazepines) which exert their therapeutic effects through binding to GABA_A, pregabalin neither binds directly to these receptors nor augments GABA_A currents or affects GABA metabolism (Pfizer Inc., 2006).^[21] The half-life for pregabalin is 6.3 hours.^[22]

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 C_max by approximately 25 to 30% and a delay in T_max (time to reach C_max) to approximately 2.5 hours. Administration with food, however, has no clinically significant effect on the extent of absorption.^[23]

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.^[23]

Metabolism: Pregabalin undergoes negligible metabolism in humans.^[24] 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.^[23]

Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.^[23] Renal clearance of pregabalin is 73 mL/minute.^[25]

History

Pregabalin was invented 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.^[26]

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.^[27]

The patent for Lyrica currently expires in March 2018 (Silverman, R. B.; Andruszkiewicz, R. U. S. Pat. 6,197,819 B1 (March 6, 2001) “Gamma Amino Butyric Acid Analogs and Optical Isomers.”). This is the earliest possible date that a generic version of Lyrica could become available. However, there are other circumstances that could come up to extend the exclusivity period of Lyrica beyond 2018. These circumstances could include things such as lawsuits or other patents for specific Lyrica uses. Once Lyrica goes off patent, there may be several companies that manufacture a generic pregabalin drug.

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.^[9] Pregabalin has also been approved in the European Union and Russia (but not in US) for treatment of generalized anxiety disorder.^[12][28]

Recreational use

Pregabalin is a Schedule V drug, and its 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.^[29]

Marketing

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 $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 programs for uses that were not approved by the U.S. Food and Drug Administration (FDA).^[30]

See also

• 4-Methylpregabalin

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
• Erowid Pregablin Vault, Pregabalin experience reports