Pregabalin

Pregabalin

Systematic (IUPAC) name
(S)-3-(aminomethyl)-5-methylhexanoic acid
Clinical data
Trade names	Lyrica
AHFS/Drugs.com	monograph
MedlinePlus	a605045
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
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	APRD01198
ChemSpider	4589156 Y
UNII	55JG375S6M Y
KEGG	D02716 Y
ChEMBL	CHEMBL1059 Y
Chemical data
Formula	C8H17NO2
Mol. mass	159.23 g.mol-1
SMILES	eMolecules & PubChem
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. 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. Pfizer described in a SEC filing that the drug could be used to treat epilepsy, post-herpetic neuralgia and diabetic peripheral neuropathy, fibromyalgia, et al. Sales reached record $3,063 million in 2010.

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

Pregabalin is available in 25, 50, 75, 100, 150, 200, 225, and 300 mg capsules, and recently a strawberry flavoured oral solution has been developed, containing 20 mg/mL with an added sweetening agent (sucrose) to mask the chemical's bitter taste. The maximum daily recommended dose for pregabalin is 600 mg. Dosages must be monitored and increases should be based on patient's tolerance.

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. 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.

The patent for Lyrica currently expires in October 2013. 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 2013. 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 Lyrica drug.

Indications

A package of 150 mg Lyrica (Finland)

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).

Usually physicians will start the patient on a low dose of pregabalin and increase it gradually, depending on the patient's evaluation. 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.

It has not been found to be effective for HIV-associated peripheral neuropathy.

Adverse effects

Adverse drug reactions associated with the use of pregabalin include:

• Very common (>10% of patients): dizziness, drowsiness
• Common (1–10% of patients): blurred vision, diplopia, increased appetite, 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, weight gain.
• Infrequent (0.1–1% of patients): depression, lethargy, 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.

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. Because of complication risk associated with certain common side-effects in patients affected by other health issues, Pregabalin should not be used without regular medical supervision and any side effect should immediately be reported.^{[citation needed]}

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.

Pharmacology

Pharmacodynamics

Like gabapentin, pregabalin binds to the α₂δ (alpha2delta) subunit of the voltage-dependent calcium channel in the central nervous system. Pregabalin 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. 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, however, 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 major metabolite is N-methyl pregabalin.

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.

Pregnancy

Pregabalin has been assigned to pregnancy category C by the FDA. Animal studies have revealed increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity including lethality, growth retardation, and both nervous and reproduction system functional impairment. Animal studies have reported that pregabalin crosses the placenta and have shown an increased risk in male-mediated teratogenicity. There are no controlled data in human pregnancy. Pregabalin should only be given during pregnancy when there are no alternatives and benefit outweighs risk.

Misuse

Pregabalin is a Schedule V drug, classified as a CNS depressant. The potential for abuse of pregabalin is slightly less than the potential with benzodiazepines. It has a slowly growing number of abusers in the United States, due to the fact that it is far more potent than Gabapentin.

See also

• 4-Methylpregabalin

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