Abstracts

Rationale: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction. This is of considerable importance given the usual long-term course of treatment. In previous studies we have demonstrated that many AEDs induce slowing of EEG background rhythms, correlated with negative cognitive effects. Pregabalin (PGB) is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. There has been relatively little study of its effects on brain function. We measured the EEG and cognitive effects of 12 weeks of PGB in healthy volunteers. Methods: Thirty-two healthy volunteers were randomized to PGB or placebo (1:1). PGB was titrated over 8 weeks to 600mg/day or highest tolerated dose. At biweekly visits doses were adjusted up or down based on tolerance. The evaluating physician was instructed to manage subjects as if they were patients with incomplete seizure control. At baseline, and at 12 weeks of treatment, all subjects underwent EEG acquisition using a standardized protocol, and cognitive testing. Methods for quantitative EEG acquisition and analysis have been presented elsewhere. Four target measures, the peak frequency of the posterior rhythm, median power frequency, and percentage theta and delta activity were calculated from averaged occipital electrodes. Test-retest changes in all EEG and cognitive measures were Z-scored against test-retest regressions previously developed from 74 healthy volunteers. Z-scores from the placebo and PGB groups were compared using Wilcoxon tests. Subjects and investigators were blind to drug assignment. All EEG analysis was performed blind to assignment and test order. Results: Thirty of 32 subjects completed the study. Two PGB subjects discontinued due to side effects (prior to week 6). All others reached the target dose of 600mg/day (median peak blood level 9.7 µg/ml). PGB induced significant EEG background slowing. Quantitative EEG measures revealed PGB-placebo group differences for peak frequency (p<0.001), median frequency (p<0.001), and percent theta activity (P<0.01). The median decrease in peak frequency was 0.65 Hz and 50% of PGB subjects exceeded -3 SD of test-retest change (Z<-3.0) as compared to controls. Three of 6 target cognitive measures (Digit Symbol, Stroop interference, COWAT) revealed significant test-retest differences between the PGB and placebo groups, all showing negative effects with PGB (p<0.05). Cognitive effects were relatively mild (median Z<1.1) with 1 subject exceeding 3 SD of test-retest change on these measures. Conclusions: At conventional doses and titration PGB induced significant EEG background slowing and mild negative cognitive effects in healthy volunteers. The profile of robust EEG effects and relatively mild cognitive effects is similar to that previously reported with several other AEDs (type I neurotoxicity profile). The PGB effect size is intermediate, less than with carbamazepine but greater than with gabapentin. Supported by an investigator initiated research grant from Pfizer Inc.