Objective: To evaluate the safety and efficacy of a 5 mg sublingual dose of zolpidem, compared to a 10 mg oral dose, at bedtime and ''as needed'' following middle-of-the-night awakenings. Methods: Participants were randomized into an oral group (oral zolpidem 10 mg and sublingual placebo at bedtime and ''as-needed'') and a sublingual group (oral placebo and sublingual zolpidem 5 mg at bedtime and ''as-needed''). Participants underwent medical evaluation, polysomnography, the psychomotor vigilance test, and completed questionnaires. Results: Of 85 patients, 67 met the criteria for insomnia (48610 years; 79% women) and were randomized. Of these, 46 completed 9265 days of treatment. Mild-to-moderate adverse events were reported by 25% of the participants, including headache, sleepiness, and dizziness. Both treatments decreased middle-of-the-night awakenings by an average of-3.162.3 days/week and increased total sleep time by 1.5 hours. Changes in sleep quality and insomnia severity scores were also favorable and comparable between groups: variation depended on continuation of treatment. Regarding PSG findings, sleep latency decreased more in the sublingual group than the oral group (-14642 vs. 10629 min; p = 0.03). The psychomotor vigilance test showed minor residual effects 30 minutes after awakening, which reversed after 2 hours. Conclusions: The safety and efficacy of both zolpidem formulations are comparable. The sublingual 5 mg dose induced sleep more rapidly. Clinical trial registration: NCT01896336
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