Sublingual zolpidem for middle-of-the-night awakening does not induce tolerance, rebound, or increased use

A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over 4 weeks, investigators reported at the congress of the European College of Neuropsychopharmacology.
“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a PRN treatment for this is needed as it may decrease overall drug exposure,” said the study’s coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

	Zolpidem tartrate sublingual tablets were found to be effective for middle-of-the-night insomnia and helped patients return to sleep rapidly. (Photo Copyright: iStockphoto/redmonkey8)

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening. The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep. Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing. In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277-84).“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said.
The drug is currently under review by the Food and Drug Administration for MOTN awakening.
In a study designed to address possible abuse liability associated with PRN use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period.
To address rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use. Dependence and tolerance also were examined.
The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness, compared with baseline. On a scale of 1-9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.
Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 after treatment with zolpidem, compared with 4.5 and 5.2, respectively, with placebo.
The study found no evidence for the development of tolerance to zolpidem’s efficacy. Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.
The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups. In fact, weekly medication use showed a decline for both the active and placebo groups, with medication use during week 4 being significantly lower than during week 1 in both arms. The mean number of tablets taken during weeks 1 and 4 were 4.9 and 4.0, respectively, for the zolpidem group and 4.9 and 4.3, respectively, for the placebo group.
There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use. On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.
Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful. “It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months – you’ll be in a coma. The effect is cumulative. It’s about 2 hours a week.”
Dr. Roth has served as a consultant to Transcept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support and had other relationships with numerous pharmaceutical companies.