What is the role of pregabalin in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Pregabalin is an analogue of the neurotransmitter GABA and has analgesic, anticonvulsant, and anxiolytic effects. [50, 51] Despite being a GABA analogue, pregabalin is inactive at GABA receptors, including GABA-A, benzodiazepine, t-butylbicyclophosphorothionate (TBPS), and GABA-B radioligand binding sites. [52] Neither pregabalin nor GBP alters GABA concentration in brain tissues [53] or inhibits GABA transport in vitro. Pregabalin binds with high affinity to both the alpha2 delta-1 and alpha2 delta-2 subtypes. [54]

GBP and pregabalin binding to the alpha2 delta protein are proposed to mediate the functional effects these molecules have on calcium currents in activated neurons and on stimulated neurotransmitter release. [55] The effect is a reduced release of excitatory neurotransmitters and peptide neuromodulators under membrane hyperexcitability, which is postulated to mediate the analgesic, anxiolytic, and anticonvulsant effect. [56]

Pregabalin is active in several animal models of seizures. In the high-intensity electroshock test, pregabalin inhibited tonic extensor seizures in rats and low-intensity electroshock seizures in mice. In the DBA/2 audiogenic mouse model and clonic seizures, pregabalin prevented tonic extensor seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4–5 behavioral seizures. However, pregabalin was not effective in models of absence seizures. [57]

Pregabalin is well absorbed after oral administration. When the drug has been given orally under fasting conditions, the peak plasma concentration is 1.5 hours; however, when it is given with food, the rate of pregabalin absorption is decreased, resulting in a decrease in peak plasma concentration of approximately 25-30% and an increase in time to peak plasma concentration (Tmax) to approximately 3 hours. Oral bioavailability is 90% and it is independent of dose and presence of food. Steady state is achieved within 24-48 hours.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution after oral administration is approximately 0.5 L/kg. Pregabalin crosses the blood-brain barrier in animals and has been shown to cross the placenta in rats and is present in the milk of lactating rats.

After oral administration, approximately 90% is recovered in the urine as unchanged pregabalin. Only about 0.9% is found in urine as the N -methylated derivative.

Pregabalin is eliminated primarily by renal excretion, with a mean elimination half-life of 6.3 hours in patients with normal renal function. Pregabalin elimination is nearly proportional to creatinine clearance (CrCl). Dosage reduction in patients with renal failure is necessary. Pregabalin is effectively removed from plasma by hemodialysis (50% after 4 h of hemodialysis).

Pregabalin has no pharmacokinetic drug interactions.

Pregabalin is indicated as adjunctive therapy for partial-onset seizures in adults and children aged 1 month or older. Efficacy as add-on therapy for partial epilepsy has been demonstrated in four major trials. [58, 59, 60, 61] Patients given pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency. Subgroup analyses assessing the effect of individual doses of 50 mg pregabalin was not effective. [62]

Pregabalin’s lack of drug interactions, lack of plasma protein binding, and renal excretion make it particularly useful in patients with renal or hepatic disease and in patients on complex drug regimens. Patients with coexisting migraine headache or neuropathic pain may benefit from this drug.

Pregabalin is relatively well tolerated, although it does have some adverse effects, particularly in high doses. No significant serious idiosyncratic or systemic adverse effects have been reported.

The most common side effects of pregabalin are dizziness and drowsiness. Other important side effects include dry mouth, edema, blurred vision, weight gain, and difficulty concentrating. Pregabalin has rarely been associated with angioedema (swelling of the face, tongue, lips, and gums, throat, and larynx).

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