Pregabalin as add-on therapy induces REM sleep enhancement in partial epilepsy: a polysomnographic study A. Romigi a,b , F. Izzi a , M. G. Marciani a,b , F. Torelli a , S. Zannino a , L. R. Pisani c , E. Uasone a , F. Corte a and F. Placidi a,b a Servizio di Neurofisiopatologia, Policlinico Tor Vergata, Centro di Medicina del Sonno, University of Rome ÔTor VergataÕ, Rome, Italy; b Fondazione Santa Lucia, Via Ardeatina, Rome, Italy; and c Department of Neurosciences, Department of Psychiatric and Anaesthesiological Sciences, University of Messina, First Neurology Clinic, Messina, Italy Keywords: daytime somnolence, epilepsy, polysomno- graphy, pregabalin, REM sleep, sleep Received 9 May 2008 Accepted 15 September 2008 Background and purpose: To evaluate the effects of pregabalin (PGB) adjunctive therapy on sleepwake cycle and daytime somnolence in adult patients affected by partial epilepsy. Methods: Twelve patients affected by partial epilepsy underwent a 24-h ambulatory polysomnography and a subjective evaluation of daytime somno- lence by means of the Epworth Sleepiness Scale (ESS), before and after 3 months treatment with PGB. Results: Pregabalin therapy reduced seizures by >50% in 8 out of 12 patients. It induced a significant increase of REM sleep and a decrease of stage 2 NREM sleep (S2). A significant increase of the ESS score was observed without reaching the pathological cut-off value (mean ESS score <10). No statistical corre- lation between REM sleep and seizure frequency was observed. Discus- sion: Pregabalin seems to be effective and safe in partial epilepsy. The increase of REM sleep may be indicative of an improvement of nocturnal sleep quality consid- ering the involvement of REM sleep in learning and memory processes. REM sleep enhancement may be the result of both a direct effect of PGB on sleep generators and an indirect effect due to its clinical efficacy. The increase of ESS score within normal range suggests that daytime somnolence is a minor adverse effect of PGB. Introduction Pregabalin (PGB) or S )(+)-3-isobutylgaba is a novel antiepileptic drug (AED) structurally but not functionally related to the neurotransmitter gamma- aminobutyric acid. PGB has been recently approved as an adjunctive treatment of partial epilepsy and it also has analgesic and anxiolytic properties. PGB binds with high affinity the alpha-2-delta protein subunit of volt- age-gated calcium channel, resulting in a reduction of the pre-synaptic release of excitatory neurotransmitters, such as glutamate, noradrenaline and substance P[1–3]. Pregabalin efficacy, safety and tolerability in reducing the frequency of both simple- and complex-partial sei- zures, as well as secondarily generalized tonic–clonic seizures, were shown by three multicentric placebo- controlled double-blind clinical trials, involving 1052 patients affected by drug-resistant partial epilepsy [4–6]. Antiepileptic drugs represent a key point of the mu- tual interactions between sleep and epilepsy due to their negative influence on the sleepwake cycle and daytime somnolence [7–9]. Whilst most of older AEDs impair nocturnal sleep and daytime vigilance, some newer AEDs seem to have minor or even positive effects on sleepwake cycle [7,9,10]. Previous PSG studies showed a PGB-induced SWS increase, both in healthy volunteers after acute treat- ment [11] and rats [12]. A recent polysomnographic (PSG) study performed on seizure-free epileptic patients with concomitant sleep disorders demonstrated an improvement of sleep continuity, as expressed by a significant reduction in the number of awakenings and a non-significant decrease of wakefulness after sleep onset (WASO) [13]. The purpose of this study is to evaluate the effects of add-on PGB treatment on sleepwake cycle and daytime somnolence in adult patients affected by partial epi- lepsy. To test this primary endpoint of our study, we compared the results of PSG and Epworth Sleepiness Scale (ESS) scores in 12 subjects with medically refractory seizures before and after 3 months of treat- ment with PGB add-on therapy. Methods Thirteen patients affected by partial epilepsy were prospectively enrolled in the study. Twelve patients Correspondence: Romigi Andrea, Department of Neurophysiopa- thology, Policlinico Tor Vergata, University of Rome ÔTor VergataÕ, Viale Oxford 81, Zip code 00133, Rome, Italy (tel.:+39 06 20902107; fax: +39 06 20902106; e-mail: a_romigi@inwind.it). 70 Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS European Journal of Neurology 2009, 16: 70–75 doi:10.1111/j.1468-1331.2008.02347.x