The Effect of Zolpidem on CPAP Acclimatization in Patients With OSA: A Crossover, Randomized, Double-blinded, Placebo-controlled Trial
Phase: PHASE4
Conditions: Obstructive Sleep Apnea
Sponsor: Siriraj Hospital

The Effect of Zolpidem on CPAP Acclimatization in Patients with OSA: A 
Crossover, Randomized, Double-blinded, Placebo-controlled Trial 
Piyakorn Pisalnoradej, MD1; Wish Banhiran, MD1; Navarat Kasemsuk, MD1 
1Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, 
Bangkok, Thailand 
 
Correspondence to: 
 
Keywords: Zolpidem, CPAP, OSA, acclimatization

Conflicts of interest: 
The authors have no financial relationships or conflicts of interest to disclose. 
Each author’s role: 
1. Piyakorn Pisalnoradej: Research design, data collection and analysis, review of the 
result, discussion of the result, manuscript preparation and revision 
2. Wish Banhiran: Research design, data analysis, review of the result, discussion of 
the result, supervision, critical feedback, and revision of the manuscript  
3. Navarat Kasemsuk: Research design, data collection and analysis, review of the 
result, discussion of the result, critical feedback, manuscript preparation and revision 
All authors reviewed the result and approved the final version of the manuscript. 
Financial funding: 
The authors received financial support from the Siriraj Research and Development Fund

Abstract 
Introduction: 
Objectives: 
Methods: 
Results: 
Conclusions: 
Registration: 

Introduction 
  
Obstructive sleep apnea (OSA) is a sleep disorder characterized by a cessation or 
significant decrease in airflow during sleep.1 According to a recent study, OSA may impact over 
1 billion individuals worldwide.2 In Thailand, the prevalence of snoring in children is 6.9-8.5%, 
while the prevalence of OSA in children is 0.7-1.3%.3 Moreover, OSA affects 15.4% of Thai 
male adults and 6.3% of  Thai females.4 Untreated OSA can lead to daytime sleepiness, 
decreased productivity, increased motor vehicle accidents, and worsening hypertension, atrial 
fibrillation, and stroke. Oral appliances, upper airway surgery, and continuous positive airway 
pressure (CPAP) devices are available as treatment alternatives. 
  
CPAP is the preferred therapy and has high effectiveness at all levels of OSA severity. It 
acts as a pneumatic splint to maintain upper airway patency during sleep, preventing the soft 
tissues from collapsing. Through this mechanism, it effectively eliminates the apneas and/or 
hypopneas, decreases the arousals, and normalizes the oxygen saturation.5 However, the patient's 
compliance continues to be an issue. Failure of CPAP therapy may occur in up to 25% to 50% of 
patients, with patients typically discontinuing therapy within the first 2 to 4 weeks of treatment 
and 91% of patients discontinuing CPAP therapy within the first three years of therapy.6,7 
According to the clinical guidelines of the American Academy of Sleep Medicine, all 
potential PAP titration candidates should receive adequate PAP education, hands-on 
demonstration, careful mask fitting, and acclimatization prior to titration.8 Acclimatization is a 
technique used to familiarize patients with PAP therapy for compliance. 
  
One of the main contributors to CPAP therapy failure is difficulty falling asleep.  To aid 
in the machine's adaptation, hypnotic medicine was administered.9 Sedative medications now 

came in a variety of categories. Non-benzodiazepines sometimes referred to as Z-drugs, are 
among those with the beneficial characteristics of not deteriorating OSA severity, not 
contributing to drug addiction, possessing a rapid onset, and exhibiting fewer adverse 
consequences. Zolpidem, eszopiclone and zaleplon are included in this drug class. According to 
a previous meta-analysis, eszopiclone greatly facilitated the use of CPAP.10 However, up until 
now limited research on zolpidem and zaleplon was conducted. This study aims to evaluate the 
effect of zolpidem on CPAP compliance in OSA patients as compared to a placebo. 
Material and Methods 
  
This a cross-over, randomized, double-blinded, placebo-controlled trial will be conducted 
in the otorhinolaryngology department, the faculty of medicine, Siriraj hospital, Thailand. The 
study was approved by the Siriraj Institutional Review Board (registration number 
365/2566[IRB4]). This trial will be reported according to CONSORT 2010 statement extension 
for randomized crossover trial. 
Participants 
We included OSA patients whose sleep test demonstrated apnea-hypopnea index (AHI) ≥ 
15 /hour or AHI ≥ 5 /hour with comorbid disease including hypertension, cardiovascular disease, 
and stroke. The enrolled individuals ranged in age from 18 to 75 years. All the patients were 
indicated for CPAP therapy but naïve for the device usage.  
 
People having a history of zolpidem allergies, those who currently take hypnotic 
medications, and those who were denied permission to engage in the study and/or follow its 
protocol are all excluded from participation. According to the patients' statements and a review 

of their medical records, individuals with liver diseases, including hepatitis from any cause, liver 
cirrhosis, and liver cancer, were also discarded. 
Sample size 
The nQuery Adviser Program was employed to calculate the sample size using the t-Test 
(ANOVA) for the difference of means in the 2*2 cross-over design formula. A power of 90% 
and 0.05 two-sided significant level were applied. The variable substitution of 1.8 standard 
deviation, 4.0 1st treatment mean, 2.92 2nd treatment mean, and 1.08 difference in means 
according to Quan et al11 and Bradshaw et al12 was applied. The estimated sample size for each 
group was 12. For the sole purpose of loss-to-follow up, we intended to recruit 15 participants 
per group. 
Randomization & Allocation concealment 
  
The enrolled participants will be allocated into 2 groups with different therapeutic 
sequence. The randomization was done using computer generated, permuted block 
randomization via central pharmacist allocation. The participants, physician, investigators, and 
outcomes assessors are all blinded to the randomization. 
Interventions 
The eligible participants will be informed and consented. After then, the participants in 
group 1 will receive 10 milligrams zolpidem contained in white-color opaque medicine capsule 
prepared by the pharmacist, meanwhile the participants in group 2 will receive placebo which is 
corn-starch contained in identical white-color opaque medicine capsule. The participants will be 

advised to take the medication 30 minutes prior to the bedtime until the 1-week follow up visit. 
On the second week, the participants in group 1 will alternatively receive placebo, meanwhile the 
participants in group 2 will receive 10 milligrams zolpidem in identical capsules. The wash-out 
period is 24 hours as the fact that the half-life of zolpidem is 2 hours and total zolpidem 
elimination time is 10 to 12 hours.13,14 
During the study, all participants will be treated with auto-positive airway pressure 
device (AutoPAP) with a setting of 5 to 15 cmH2O, ramp time 15 minutes, and start pressure 5 
cmH2O delivered via nasal mask. 
Outcomes 
  
The outcome assessment will be held on the end of the 1st as the 1st follow-up and the 2nd 
week as the 2nd follow-up. The primary outcome is average CPAP hour usage per night. The 
secondary outcomes including percent CPAP usage ≥ 4 hours, number of the participants with 
average CPAP usage ≥ 4 hours, and number of the participants with % CPAP usage ≥ 70. The 
baseline demographic data (age; sex; bodymass index (BMI); OSA severity; comorbid diseases; 
drug allergy), polysomnographic data (AHI); oxygen desaturation index (ODI); time with 
oxygen below 90 (T90); aousal index; lowest oxygen saturation, mean oxygen saturation), drug 
compliance, and adverse events will also be recorded. 
Statistical analysis 
  
Test of normality of the continuous data will be done using Komogorov-Smirnov. Pair t-
test and Wilcoxon Sign-Rank test will be applied for the analysis of parametric and non-
parametric continuous data respectively. In the part of categorical data, Chi-square test will be 

applied. Subgroup analysis for OSA severity and arousal index was planned with statistic one 
way ANOVA or Kruskal-Wallis H test. P-value less than 0.05 will be considered significant. 
  
 
 
 
 
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