Background: Most preventive agents used for transformed migraine (TM) have not been studied specifically for the treatment of this syndrome. Openlabel trials have demonstrated the effectiveness of levetiracetam in the treatment of refractory headaches.Objective: The aim of this study was to assess the effectiveness and tolerability of levetiracetam in the preventive treatment of refractory TM. Methods:This prospective, open-label, pilot study was conducted at The New England Center for Headache, Stamford, Connecticut. We included patients aged ~18 years with refractory TM according to the criteria proposed by Silberstein et al. All participants had failed on at least 1 but not more than 3 preventive drugs. Other preventive drugs were allowed if they had been received at a stable dose for >30 days. The dosage of the levetiracetam tablets ranged from 1000 to 3000 mg/d in 2 divided doses. The treatment phase lasted 3 months. The primary end point was headache frequency (expressed as the number of headache days per month), and the secondary end point was the frequency of moderate or severe headache (d/mo). Other end points were headache score, Migraine Disability Assessment (MIDAS) Questionnaire score, and Headache Impact Test (HIT-6) score. Statistical analyses were performed in the intent-totreat (ITT) population (patients who received at least 1 dose of study medication) using data subjected to the last-observation-carried-forward algorithm. We also conducted per-protocol (PP) analyses in patients who completed the study. Results:The ITT population consisted of 36 patients (26 women, 10 men; A.M. Rapoport et aLvs baseline). At baseline, the mean number of moderate or severe headache days was 16.8 d/mo compared with 13.2, 11.9, and 9.7 d/mo at 1, 2, and 3 months, respectively (P = NS, <0.01, and <0.01, respectively). The mean MIDAS score was significantly reduced at 3 months compared with baseline (40.8 vs 62.8 d/mo; P = 0.01). The mean HIT-6 score was 59.4 at 3 months versus 63.4 at baseline (P < 0.01). In the PP population, the mean (SD) headache frequency was reduced from 26.1 (4.1) d/mo at baseline to 14.3 (4.8) d/mo at the end of the study (P < 0.001). The mean (SD) headache score was reduced from 51.3 (17.1) at baseline to 34.0 (22.0) at 3 months (P < 0.016). Conclusion:The results of this study in patients with TM support the role of levetiracetam in the preventive treatment of refractory TM. (Curr Ther Res Clin Exp. 2005;66:212-221)