Continuous Treatment With Zolpidem Superior to Intermittent Dosing in Chronic Insomnia


Patients with chronic insomnia were included in the study to understand whether priming is necessary for partial reinforcement of treatment responses.

Michael L. Perlis, PhD, director, Behavioral Sleep Medicine Program; and associate professor, department of psychiatry and the school of nursing, Perelman School of Medicine, University of Pennsylvania

Michael L. Perlis, PhD

Data from a recent study found that intermittent dosing with placebos may maintain the effects elicited by nightly standard-dose zolpidem (Ambien; Sanofi-Aventis; as well as Ambien CR, Edluar, Intermezzo, and Zolpimist), but it does not provide the additional clinical gains associated with continuous treatment.

Investigators, led by Michael L. Perlis, PhD, director, Behavioral Sleep Medicine Program; and associate professor, department of psychiatry and the school of nursing, Perelman School of Medicine, University of Pennsylvania, included 55 patients with chronic insomnia (CI) who were randomized following a baseline evaluation during phase 1 of the study. Over the course of 1 month, patients either took nightly standard-dose zolpidem (QHS; n = 39) or had intermittent dosing with standard-dose zolpidem and placebos (IDwP; n = 16) during phase 2 of the study. Investigators evaluated response rates, as well as Total Wake Time (TWT), calculated as combined Wake After Sleep Onset, Sleep Latency, and Early Morning Awakening in each study phase.

During phase 2, treatment responses were observed in 77% of patients in the QHS group, compared with 50% of those in the IDwP group (P = .09). The mean reduction in TWT during the second phase did not significantly differ between the 2 groups, with a reduction of 43 minutes in the QHS group (95% CI, –76 to –9) and a reduction of 76 minutes in the IDwP group (95% CI, –138 to –14; P = .35).

“The lack of significant differences may be taken as evidence that the two treatment conditions produced ‘comparable’ outcomes on weekly measures, despite one condition's use of 50% less medication,” Perlis et al wrote. “This is consistent with prior work on intermittent dosing.”

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Thirty-seven patients continued extended treatment in phase 3 of the study, and those in the QHS group were rerandomized to continue QHS full dose treatment (n = 15; FD/FD) or to switch to IDwP dose treatment (n = 14; FD/VD) for a period of 3 months. Those already in the IDwP group also moved forward without a change in treatment regimen, receiving variable doses (n = 8; VD/VD). 

In phase 3, continued treatment responses were seen in 73% of subjects in the FD/FD group, 57% of the FD/VD group, and 88% in the VD/VD group (P = .22). During this phase, investigators observed improvement in TWT in the FD/FD group, while TWT was stable in the FD/VD and VD/VD groups (P <.01). 

“These results suggest that partial reinforcement can maintain effects but cannot allow for the additional clinical gains afforded by continuous treatment. Given this, it may be the case that the partial reinforcement technique could be improved upon by extending phase-1 priming from 1 to 2 months. Such a change in protocol would be expected to maximize the percentage of treatment responders during acute treatment, allow for continued treatment gains during the second month of QHS dosing, and to preserve the percentage of those who remain treatment responders during extended therapy with intermittent dosing with placebos,” Perlis et al wrote. “Putting aside the issue of what is the optimal and what is the mechanism of action (what accounts for the efficacy) of intermittent dosing with placebos, it remains clear that effective acute and extended treatment can be accomplished with 50% less medication.”

Patients did not have significant differences in sex, age, or race, investigators noted. Those enrolled in phase 2 had an average age of 61.2 years (standard deviation, 8.1). Participants were predominantly White (73%). While the study is considered “preliminary,” investigators noted it was limited by its small sample size. Future research is needed to determine the effect of different treatment approaches on sleep continuity, how dependent partial reinforcement protocol is on over-encapsulation and nondisclosure, and how age may come into play.

Perlis ML, Morales KH, Vargas I, et al. Durability of treatment response to zolpidem using a partial reinforcement regiment: does this strategy require priming? Sleep Med. 2021;87:56-51. doi:10.1016/j.sleep.2021.04.041 
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