Lyrica (pregabalin) is a modulator of voltage-gated calcium channels, designed to affect neurological transmission in multiple systems.
Lyrica is specifically indicated for the treatment of neuropathic pain associated with diabetic peripheral neuropathy, and postherpetic neuralgia. It is also indicated as an adjunctive therapy for the treatment of adult patients with partial onset seizures.
Lyrica is supplied as a hard-gelatin capsule for oral administration. Recommended initial dosing for the treatment of neuropathic pain associated with diabetic peripheral neuropathy is 50 mg thrice daily, with escalation permissible to 100 mg thrice daily within 1 week in patients with creatinine clearance of at least 60 ml/min, based on tolerability and efficacy. For the treatment of postherpetic neuralgia, recommended initial dosing is 75 mg twice daily or 50 mg thrice daily (in patients with creatinine clearance >60 ml/min), with escalation to 150 mg twice daily or 100 mg thrice daily (in patients with creatinine clearance >60 ml/min) permissible. For the adjunctive treatment of epilepsy, recommended initial dosing is 150 mg daily (as 50 mg thrice daily or 75 mg twice daily), with escalation to a maximum total daily dose of 600 mg (200 mg thrice daily or 300 mg twice daily) based on efficacy and tolerability. On conclusion of Lyrica therapy, dosing should be tapered over at least 1 week.
Neuropathic Pain associated with Diabetic Peripheral Neuropathy
Approval of Lyrica for the treatment of neuropathic pain associated with diabetic peripheral neuropathy was based on results of 3 double-blind, placebo-controlled multicenter trials. Two of these studies investigated the maximum recommended dose of the drug:
Approval of Lyrica for the treatment of postherpetic neuralgia was based on three double-blind, placebo-controlled, multicenter studies:
Approval of Lyrica for the adjunctive treatment of epilepsy was based on results of three 12-week, randomized, double-blind, placebo-controlled, multicenter trials, which enrolled patients whose disease was not adequately controlled with 1-3 concomitant anti-epileptic drugs:
Adverse events associated with the use of Lyrica may include, but are not limited to, the following:
In addition, Lyrica is a Schedule V controlled substance. Studies of the drug in recreational users of sedative/hypnotic drugs indicated subjective psychoactive effects of a magnitude similar to the benzodiazepine diazepam. Roughly 4% of subjects reported eurphoria as an adverse event in trials, compared to 1% for placebo; some sub-populations reported euphoria rates as high as 12%. In addition, abrupt termination of treatment was associated with insomnia, nausea, headache and/or diarrhea. Patients receiving Lyrica should be monitored closely for evidence of dependence, misuse or abuse.
Use of Lyrica has been associated with creatine kinase elevations, including mean maximum elevations of 60 U/l. 2% of subjects experienced creatine kinase levels greater that 3x the upper limit of normal, and 3 patients reported rhabdomyolysis during clinical trials. Patients should be advised to promptly consult a healthcare professional if they experience unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Treatment should be discontinued if significant creatine kinase elevations are noted.
Use of Lyrica has also been associated with weight gain. This weight gain was not limited to patients experiencing drug-related edema, and it did not appear to be influenced by age, gender, or baseline BMI. The drug did not appear to cause loss of glycemic control in diabetic patients. The long term effects of Lyrica-mediated weight gain (if any) have not been characterized.
Dizziness and somnolence occur regularly with Lyrica administration. Patients are advised to avoid driving or operating heavy machinery while taking the drug.
The exact mechanism of Lyrica's action has not been fully characterized. Lyrica binds to the alpha2-delta auxiliary subunit of voltage-gated calcium channels. Blockade of these channels has been shown to inhibit the calcium-dependent release of a number of neurotransmitters. The drug is a structural derivative of the inhibitory neurotransmitter GABA, though it does not bind directly to GABAa, GABAb, or benzodiazepine receptors, does not augment GABAa responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. In cultured neurons prolonged application of pregabalin increased the density of GABA transporter protein and increased the rate of functional GABA transport. The drug does not achieve its antinociceptive or antiseizure activity through blockade of sodium channels, activation of opioid receptors, alteration of cyclooxygenase enzyme activity, through activity at serotonin and dopamine receptors, or through effect on dopamine, serotonin, or noradrenaline reuptake.
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Cunningham MO, Woodhall GL, Thompson SE, Dooley DJ, Jones RS. Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. The European Journal of Neuroscience 2004 Sep;20(6):1566-76
Stahl SM. Mechanism of action of alpha2delta ligands: voltage sensitive calcium channel (VSCC) modulators. Journal of Clinical Psychiatry 2004 Aug;65(8):1033-4
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004 Aug;110(3):628-38
For additional information regarding Lyrica, neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, or epilepsy, please visit the Lyrica web page.