Pregabalin

Systematic (IUPAC) name
(S)-3-(aminomethyl)-5-methylhexanoic acid
Identifiers
CAS number	148553-50-8
ATC code	N03AX16
PubChem	CID 5486971
DrugBank	APRD01198
ChemSpider	4589156
Chemical data
Formula	C8H17NO2
Mol. mass	159.23 g.mol-1
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	=90%
Protein binding	Nil
Metabolism	Negligible
Half-life	5–6.5 hours
Excretion	Renal
Therapeutic considerations
Licence data	US Daily Med:link
Pregnancy cat.	B3 (Au), C (U.S.)
Legal status	S4 (Au), POM (UK), Schedule V (U.S.)
Routes	Oral(main), IV, Insufflation
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Pregabalin (INN) (pronounced /pr?'gæb?l?n/) 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.^[1] 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^[2] and spinal cord injury.^[3] In June 2007, pregabalin became the first medication approved by the U.S. Food and Drug Administration specifically for the treatment of fibromyalgia.^[4]

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.^[5]

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 medically accepted.^[6]

[edit] History

Pregabalin was initially developed 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. 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.^[7]

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.^{[citation needed]}

[edit] Indications

Pregabalin is indicated for:

• Treatment of neuropathic pain from diabetic neuropathy or post herpetic neuralgia. There is not enough data to state that it should be used in all neuropathic pain.
• Adjunctive therapy in adults with partial seizures with or without secondary generalization
• Fibromyalgia
• Generalized anxiety disorder (approved in the European Union).^[8][9]

Its therapeutic effect appears 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 additionally unlike benzodiazepines it does not disrupt sleep architecture 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.^[10][11]

It has not been found to be effective for HIV-associated peripheral neuropathy.^[12]

[edit] Adverse effects

Adverse drug reactions associated with the use of pregabalin include:^[13][14]

• Very common (>10% of patients): dizziness, drowsiness
• Common (1–10% of patients): visual disturbance (including blurred vision, diplopia), ataxia, dysarthria, tremor, lethargy, memory impairment, euphoria, constipation, dry mouth, peripheral edema, loss or decrease of libido, erectile dysfunction, weight gain
• Infrequent (0.1–1% of patients): depression, confusion, agitation, hallucinations, myoclonus, hypoaesthesia, hyperaesthesia, tachycardia, excessive salivation, 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.^[15]

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 restlessness, insomnia, and anxiety. Pregabalin should be reduced gradually when finishing treatment.^{[citation needed]}

[edit] Pharmacology

[edit] Pharmacodynamics

Like gabapentin, pregabalin binds to the a2d (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.[1] 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.

[edit] 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.^[16]

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.^[16]

Metabolism: Pregabalin undergoes negligible metabolism in humans.^[17] Approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methyl pregabalin is the major metabolite.^[16]

Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.^[16] Renal clearance of pregabalin is 73 mL/minute.^{[verification needed]}

[edit] 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.^[13]

[edit] Misuse

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.^[18]

[edit] References

[edit] External links

• http://www.webmd.com/drugs/drug-93965-Lyrica+Oral.aspx?drugid=93965&drugname=Lyrica+Oral
• 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.
• Erowid Pregablin Vault, Pregabalin experience reports

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Pregabalin".