Pregabalin

Absorption

After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional.
Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin can be administered with or without food.

Toxicity

In a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation .
The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures.
Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway).
Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone.

Description

Pregabalin (Lyrica), an analog of GABA that is related to gabapentin, has been extensively studied in the treatment of GAD, fibromyalgia, neuropathic pain, and partial complex seizures.It appears to act even more selectively on the a2-δ subunit of calcium channels found in brain than does gabapentin. Pregabalin received FDA approval in late 2004 for use in treating neuropathic pain and epilepsy. In 2008, it became the first drug approved for the treatment of fibromyalgia.Even though prcgabalin reccived approval for the treatment of GAD in the European Union in 2006, the FDA has not approvedpregabalin for GAD in the United States as of this writing.With the consistent efficacy in clinical trials and the known safety of pregabalin in clinical expericnce, it is not completely clear what has held up approval of prcgabalin for GAD.There was reported concern of the risk-benefit ratio for the drug,given the hepatotoxicity seen in micc, but this has not proven to be a problem postrelease in humans. Pregabalin is categorized as an anticonvulsant and analgesic. The drug is under re-review currently by the FDA. Pregabalin has a potential for abuse and misuse. Pregabalin is regulated as a Schedule V compound in the United States.

The Uses of Pregabalin

S-Enantiomer of Pregabalin. A GABA analogue used as an anticonvulsant. Anxiolytic analgesic used to treat peripheral neuropathic pain and fibromyalgia.

Indications

Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury, and as adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older.

Background

Pregabalin is structurally similar to gamma-aminobutyric acid (GABA) - an inhibitory neurotransmitter. It may be used to manage neuropathic pain, postherpetic neuralgia, and fibromyalgia among other conditions. Although as per the FDA Label the mechanism of action has not been definitively defined, there is evidence that pregabalin exerts its effects by binding to the α2δ subunit of voltage-dependent calcium channels. Pregabalin is marketed by Pfizer under the trade name Lyrica and Lyrica Cr (extended release). It may have dependence liability if misused but the risk appears to be highest in patients with current or past substance use disorders.

Pharmacokinetics

Although the structure of pregabalin is similar to gamma-aminobutyric acid (GABA), it does not bind to GABA receptors. Instead, it binds the alpha2-delta subunit of presynaptic voltage-gated calcium channels in the central nervous system. Pregabalin does not modulate dopamine receptors, serotonin receptors, opiate receptors, sodium channels or cyclooxygenase activity.

Metabolism

Less than 2% of pregabalin is metabolized and it is excreted virtually unchanged in the urine.