Headache ISSN 0017-8748 c  2005 by American Headache Society doi: 10.1111/j.1526-4610.2005.00256.x Published by Blackwell Publishing Abstracts and Citations MIGRAINE DIAGNOSIS AND TREATMENT Sheftell FD, Dahlof CGH, Brandes JL, Agost R, Jones MW, Barrett PS. Two replicate randomized, double- blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets. Current Therapeutics. 2005;27:407-417. Background: The gastric stasis that commonly ac- companies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast- disintegrating/rapid-release formulations of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. Objective: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. Methods: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous vari- able. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief com- pared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at predetermined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, pa- tients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the pri- mary and key secondary end points, on pooled data from both studies. Results: The 2 studies comprised 2696 patients: 902 re- ceived sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients’ mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analy- sis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P ≤ 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P ≤ 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P ≤ 0.0001, both sumatriptan doses vs. placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P ≤ 0.001, both sumatriptan doses vs. placebo). In the individual stud- ies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sus- tained pain relief and a sustained pain-free response over 24 hours compared with placebo (P ≤ 0.001, both sumatrip- tan doses vs. placebo). The only drug-related and adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthe- sia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). Conclusions: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg. Comments: In the treatment of moderate to severe pain for migraine, no tablet has previously shown separation from placebo for headache relief sooner than 30 minutes until the above study. Plus, this new form of sumatriptan separates from placebo for pain free in the treatment of moderate to severe pain at 30 minutes. Since nasal sprays have their sta- tistical onset of headache relief at 10–15 minutes, the onset at 20 minutes of the rapid release tablet makes this formulation intermediate between nasal sprays and conventional tablets for onset of relief.—Stewart J. Tepper, MD This is encouraging data from this new fast-disintegrating [FD] sumatriptan formulation comparing both 50 mg and 100 mg doses versus placebo in two large scale studies. It is disappointing that a true “head to head comparison” with con- ventional tablets was not undertaken. Sumatriptan is largely absorbed from the small intestine with its larger surface area and more alkaline pH [Warner PE, Brouwer KL, Hussey EK, Dukes GE, Heizer WD, Donn KH, Davis IM, Powell JR. Sumatriptan absorption from different regions of the human gastrointestinal tract. Pharm Res. 1995;12;138–143]. Paradox- ically, dissolution of triptans in the stomach may act to inhibit or slow gastric emptying. While this does not appear to be a major factor with this new FD formulation, nausea reported as an adverse event >2% is increased in a dose-related manner [a slight excess above those reported in the U.S. data sheet for 1271