Abstract
Importance
Snoring is highly prevalent among adults. Benzodiazepine receptor agonist (BzRA) use is also common, with higher prevalence of use with more advanced age. BzRAs cause muscle relaxation, which may impact muscle tone, airway dynamics, and thereby increase snoring. Previous studies examining the association between BzRA use and snoring were underpowered to detect clinically meaningful differences or did not report the magnitude of association.
Objective
We investigated the relation between BzRA use and snoring in women.
Design
Cross-sectional study, the Nurses’ Health Study, 2008.
Setting
Cohort of female registered nurses in the United States.
Participants
Women aged 62–86 years in 2008 who provided information on snoring and covariates of interest.
Main Outcome and Measures
The outcome was self-reported habitual snoring, defined as a few nights a week or more. We explored potential effect modification of the relation between BzRA use and snoring by age, body mass index, waist circumference, smoking, alcohol consumption, and physical activity. Logistic regression was used to adjust for potential confounders.
Results
Of 52,504 participants, 14,831 (28%) reported habitual snoring. There was a slightly higher prevalence of BzRA use among habitual snorers (11.4%) compared with non-habitual snorers (10.6%) (absolute difference 0.8%; 95% CI 0.2% to 1.4%). After multivariable adjustment, BzRA use was not associated with odds of snoring (multivariable-adjusted OR = 1.01 [0.95, 1.07]) compared with women with no BzRA use. Although there was no significant interaction with smoking (p-interaction 0.07) there was a suggestion of higher odds of snoring with BzRA use among current smokers (multivariable-adjusted OR = 1.34 [1.04, 1.73]).
Conclusions and Relevance
BzRA use is not associated with odds of snoring in middle-aged and elderly women.
INTRODUCTION
Approximately 35% of the US population snores habitually.1 Previous studies have shown adverse health outcomes associated with snoring, and that snoring is associated with greater daytime sleepiness and decreased performance.2–9 Thus, identification of modifiable factors associated with snoring is an important public health issue.
Benzodiazepine receptor agonists (BzRAs) are medications commonly used as sleep aids. Approximately 15 million prescriptions for BzRAs are written annually in the United States, and approximately 10% of the population has reported having used a BzRA.10,11 BzRAs cause muscle relaxation, which may impact muscle tone, airway dynamics, and thereby increase risk of snoring.
Previous cross-sectional studies in women have shown associations between snoring and body mass index (BMI), age, waist circumference, smoking status, physical activity, hypertension, and alcohol dependence.12,13 However, despite the fact that snoring and use of BzRAs are common, the association between use of BzRAs and risk of snoring is unclear. Previous studies were primarily comprised of younger women and were underpowered to detect differences in snoring by BzRA use or did not report the magnitude of the observed association.13,14 We investigated the relation between BzRA use and snoring, and potential effect modifiers of the relation between BzRA use and snoring, in 52,504 women in the Nurses’ Health Study (NHS).
METHODS
Study Participants
NHS is a cohort of female registered nurses originally enrolled in 1976. At study onset, there were 121,700 participants, aged 30–55 years. Questionnaires are administered every 2 years, with an average follow-up rate of more than 90% of the eligible person-time. The 2008 questionnaire included a question about snoring. The 2008 questionnaire is available at the following website: http://www.nurseshealthstudy.org/participants/questionnaires. Of the 73,693 women who answered the long-form questionnaire in 2008, 20% reported habitual snoring. After excluding participants with missing information, our study population was 52,504 women. Completion of the self-administered questionnaire was considered implied informed consent. The Partners Healthcare Institutional Review Board approved this study.
Ascertainment of snoring
Participants were asked in 2008, “Do you snore?”, with possible responses: “every night; most nights; a few nights a week; occasionally; almost never; don’t know”. Participants who reported snoring every night, most nights, or a few nights a week, were considered habitual snorers. Participants who reported snoring occasionally or almost never were considered non-habitual snorers. Significant associations between several factors and self-reported snoring have been observed using a similar manner of assessment in other cohorts.4,12–15 In addition, assessment of snoring in the NHS cohort in this manner has been associated with increased risk of colorectal cancer,16 increased risk of diabetes,17 and positive associations with biomarkers of cardiovascular disease risk.18
Ascertainment of medication use
In 2008, participants were asked if they had regularly used “minor tranquilizers (e.g. Valium, Xanax, Ativan, Librium)” or “Ambien, Sonata, or Lunesta”. Although “regularly” was not defined on the 2008 questionnaire, “regular use” was defined as use two or more times per week on our previous biennial questionnaires sent to study participants. We classified women who answered, “yes” to either of these questions as participants using benzodiazepine receptor agonist medications.
Ascertainment of covariates
Covariates were selected based on previously reported factors associated with snoring. Factors considered included age,13–15,19 BMI,13–15,19 waist circumference,13,19 alcohol consumption,13,19 smoking status,14,15,19 race and ethnicity,20 physical activity,13,19 sleep position,19 hypertension,12 anxiety, and diabetes.17 Data on covariates were obtained from the biennial questionnaires. Data from the 2008 questionnaire were used with the exception of waist circumference, which was from the 2000 questionnaire.
Statistical analysis
Analyses were performed in a cross-sectional manner using information on snoring and medication use that was collected on the 2008 questionnaire. Multiple logistic regression analyses were used to adjust for potential confounders. Given previously described associations between increased snoring and younger age, greater BMI and waist circumference, current smoking, greater alcohol consumption, and decreased physical activity, we explored potential effect modification of the relation between BzRA use and snoring by these variables. We hypothesized that risk of snoring would increase with BzRA use in older women given greater sensitivity to the effects of BzRA among the elderly.21 Obesity increases passive mechanical pressures by increasing fat deposition and redundant tissue in the neck and tongue, increasing the risk of airway obstruction.22 Thus, we hypothesized that BzRA use among women with higher BMI and greater waist circumference increases risk of snoring given higher mechanical pressures and the muscle relaxing effects of BzRAs. We also hypothesized that less physical activity decreases airway muscle tone, and increase the risk of snoring with BzRA use. Smoking has been associated with irritation of nasopharyngeal mucosa, with resulting edema and narrowing of the airway.14 Furthermore, animal models have shown that nicotine is associated with increased upper airway muscle tone,23 withdrawal of which may increase upper airway resistance and increase risk of snoring. Use of BzRA use among smokers may result in further relaxation of airway muscle tone, leading to greater risk of snoring, compared with no BzRA use. Alcohol use has been hypothesized to increase snoring by increasing the frequency and duration of obstructive events in the upper airway secondary to depression of arousal mechanisms and oropharyngeal muscle hypotonia.24,25 BzRA use may further depress arousal mechanisms and decrease oropharyngeal muscle tone, thereby increasing risk of snoring. Associations are expressed as odds ratios and 95% confidence intervals. SAS software, version 9.4 (SAS Institute Inc., Cary, North Carolina) was used to perform all statistical analyses.
RESULTS
Participant characteristics according to snoring status are shown in Table 1. Women who reported habitual snoring had a higher BMI and waist circumference, were less physically active, were more likely to be a current or past smoker, have a history of diabetes or hypertension, and report BzRA use compared with non-habitual snorers.
Table 1.
Characteristics of Participants According to Habitual Snoring, Nurses’ Health Study, 2008.
| Habitual Snorer (n=14,831) |
Non-Habitual Snorer (n=37,673) |
|
|---|---|---|
| Age, years | 71.4 (6.5) | 72.7 (6.7) |
| Body mass index, kg/m2 | 28.3 (5.8) | 26.0 (5.0) |
| Waist circumference, cm | 90.2 (13.6) | 85.7 (12.8) |
| White | 94.2% | 94.4% |
| Hispanic | 1.0% | 0.9% |
| Physical activity, METs | 8.2 [2.1 – 21.2] | 11.5 [3.2 – 26.3] |
| Smoking status | ||
| Never smoker | 42.6% | 47.2% |
| Past smoker | 51.2% | 48.2% |
| Current smoker | 5.9% | 4.5% |
| Alcohol consumption, g/day | 1.2 [0.0 – 7.9] | 1.3 [0.0 – 8.8] |
| History of hypertension | 69.9% | 64.1% |
| History of diabetes | 17.3% | 12.1% |
| Usual Sleep Position | ||
| On Side | 64.1% | 65.5% |
| On Back | 6.0% | 5.4% |
| On Front | 8.9% | 9.2% |
| Mixed | 1.1% | 1.1% |
| Benzodiazepine Receptor Agonist Use | 11.4% | 10.6% |
| History of Anxiety | 7.9% | 6.2% |
Values are mean (standard deviation) or median [interquartile range]
Percentages may not add to 100% due to missing data and rounding of decimal points.
Abbreviations: METs = metabolic equivalents
In 2008, 14,831 women reported habitual snoring (28%). There was a slightly higher prevalence of BzRA use among habitual snorers compared to non-habitual snorers (11.4% vs. 10.6%, respectively; absolute difference 0.8%; 95% CI 0.2% to 1.4%). However, after multivariate adjustment, BzRA use was not associated with odds of snoring (multivariable-adjusted odds ratio = 1.01; 95% CI: 0.95, 1.07) (Table 2).
Table 2.
Multivariable-Adjusted Odds Ratio of Habitual Snoring According to Benzodiazepine Receptor Agonist Use, Nurses’ Health Study, 2008.
| Benzodiazepine Receptor Antagonist Use |
No. of women |
Prevalence of Habitual Snoring |
Multivariable- Adjusted OR* |
95% CI |
|---|---|---|---|---|
| No | 46,814 | 28.1% | 1.00 | Reference |
| Yes | 5,690 | 29.7% | 1.01 | 0.95, 1.07 |
OR denotes odds ratio
Adjusted for age, race, ethnicity, body mass index, waist circumference, alcohol consumption, physical activity, sleep position, smoking status, hypertension, anxiety, and diabetes.
There was no statistically significant effect modification by BMI (Table 3), smoking status (Table 4), age, waist circumference, alcohol consumption, and physical activity (see eTables 1–4 in the Supplement). Although there was no overall significant interaction, there was an increased odds of snoring with benzodiazepine receptor agonist use among current smokers (multivariable-adjusted odds ratio = 1.34; 95% CI: 1.04, 1.73) compared with women without BzRA use (Table 4).
Table 3.
Multivariable-Adjusted Odds Ratio of Habitual Snoring According to Benzodiazepine Receptor Agonist Use, Stratified by Body Mass Index Categories, Nurses’ Health Study, 2008.
| Body Mass Index, kg/m2 |
No. of women |
Prevalence of Habitual Snoring |
Multivariable- Adjusted OR* |
95% CI |
|---|---|---|---|---|
| BMI < 21 kg/m2 | ||||
| No BzRA Use | 5,052 | 17.1% | 1.00 | Reference |
| BzRA Use | 697 | 19.2% | 1.02 | 0.83, 1.25 |
| 21 ≤ BMI < 24 kg/m2 | ||||
| No BzRA Use | 9,640 | 19.8% | 1.00 | Reference |
| BzRA Use | 1,212 | 21.5% | 1.03 | 0.88, 1.19 |
| 24 ≤ BMI < 30 kg/m2 | ||||
| No BzRA Use | 18,453 | 28.0% | 1.00 | Reference |
| BzRA Use | 2,152 | 30.1% | 1.03 | 0.93, 1.14 |
| 30 ≤ BMI < 35 kg/m2 | ||||
| No BzRA Use | 6,571 | 38.3% | 1.00 | Reference |
| BzRA Use | 783 | 41.3% | 1.03 | 0.88, 1.20 |
| BMI ≥ 35 kg/m2 | ||||
| No BzRA Use | 3,182 | 47.1% | 1.00 | Reference |
| BzRA Use | 372 | 54.3% | 1.22 | 0.98, 1.53 |
P-interaction = 0.35
OR denotes odds ratio
Adjusted for age, race, ethnicity, waist circumference, alcohol consumption, physical activity, sleep position, smoking status, hypertension, anxiety, and diabetes.
Table 4.
Multivariable-Adjusted Odds Ratio of Habitual Snoring According to Benzodiazepine Receptor Agonist Use, Stratified by Smoking Status, Nurses’ Health Study, 2008.
| Smoking Status | No. of women |
Prevalence of Habitual Snoring |
Multivariable- Adjusted OR* |
95% CI |
|---|---|---|---|---|
| Never Smoker | ||||
| No BzRA Use | 21,800 | 26.2% | 1.00 | Reference |
| BzRA Use | 2,293 | 26.7% | 0.96 | 0.87, 1.06 |
| Past Smoker | ||||
| No BzRA Use | 22,688 | 29.4% | 1.00 | Reference |
| BzRA Use | 3,063 | 30.6% | 1.01 | 0.92, 1.09 |
| Current Smoker | ||||
| No BzRA Use | 2,241 | 33.3% | 1.00 | Reference |
| BzRA Use | 323 | 41.8% | 1.34 | 1.04, 1.73 |
P-interaction = 0.07
OR denotes odds ratio
Adjusted for age, race, ethnicity, body mass index, waist circumference, alcohol consumption, physical activity, sleep position, hypertension, anxiety, and diabetes.
We performed secondary analyses investigating the relation between snoring and “minor tranquilizer (e.g. Valium, Xanax, Ativan, Librium)” use, and the relation between snoring and “Ambien, Sonata, or Lunesta” use. Performing these analyses separately did not materially change the results.
DISCUSSION
We found no overall association between BzRA use and snoring. Although there was no significant overall interaction between BzRA use and snoring by smoking, BzRA use among current smokers was associated with higher odds of snoring.
Snoring has been associated with adverse health effects, as well as increased daytime sleepiness and reduced performance.2–9 Benzodiazepine receptor agonists relax muscle tone, which may increase odds of snoring. However, previous studies showed mixed results on the relation between snoring and benzodiazepine use, with one cross sectional study revealing no significant association and another reporting a positive association.13,14 However, one of these studies had a low prevalence of benzodiazepine use among participants,13 and the other was in a smaller cohort of men and women with no reporting of the magnitude of the observed association.14 In our cohort of over 52,000 women, we observed no overall association between BzRA use and snoring.
It has been previously suggested that factors associated with snoring may have different effects on women by age and BMI.13 We explored the association between BzRA use and snoring by age, BMI, waist circumference, smoking status, alcohol consumption, physical activity, and sleep position, and found that although there was no significant overall interaction by any of these variables, there were significant differences in the observed associations among current smokers.
The association between higher BMI, and increased odds of snoring has been well established.13,14 Previous authors have suggested that women with higher BMI or waist circumference may have more fat deposits or redundant tissue in the oropharynx compared to normal or underweight individuals, thereby predisposing them to higher odds of snoring.13 We found no overall association between BzRA use and snoring by BMI or waist circumference.
Smoking has been associated with irritation of nasopharyngeal mucosa, with resulting edema and narrowing of the airway.14 Furthermore, animal models have shown that nicotine is associated with increased upper airway muscle tone,23 withdrawal from which may increase upper airway resistance during sleep. Previous studies have reported an association between smoking and snoring.13–15,26,27 We found that the relation between BzRA use and snoring by smoking status was of borderline statistical significance. However, there was a significantly higher odds of snoring among current smokers with BzRA use compared with current smokers without BzRA use. This may be due to muscle relaxing effects of BzRA use having a greater effect on individuals who smoke and have increased airway resistance and edema.
Older women experience altered pharmacokinetics and pharmacodynamics, resulting in longer BzRA half-life, and they may be more sensitive to the effects of BzRA compared with younger women.21 However, the association between BzRA use and snoring did not vary by age. The lack of expected differences by age may be that older cohort participants were prescribed lower doses of BzRAs, given pre-existing knowledge of sensitivity of older individuals to BzRAs.
Alcohol consumption has been hypothesized to increase snoring by increasing the frequency and duration of obstructive events in the upper airway secondary to depression of arousal mechanisms and oropharyngeal muscle hypotonia.24,25 BzRA use may further depress arousal mechanisms and decrease oropharyngeal muscle tone, thereby increasing risk of snoring. However, we observed no association between BzRA use and odds of snoring among different categories of alcohol use. Although a previous study that described an association between alcohol dependence and snoring,13 the quantity of alcohol consumed by women in our cohort was relatively low, with few women reporting thirty or more grams of daily alcohol consumption (the equivalent of two standard alcoholic drinks per day).
Our study has limitations. Our cohort is comprised predominantly of white women. Further investigation is required to examine the association between BzRA use and snoring in other populations. The study design was cross-sectional, thereby we cannot address the temporal relations of the observed associations. However, our findings represent data from the largest cohort of women studied to date on this subject. Our questionnaire did not ask about different types of BzRAs so we were only able to investigate BzRAs as a drug class. Further investigation is needed to ascertain whether differences exist in the relation between snoring and use of specific BzRA agents. Although we found no association between alcohol consumption and odds of snoring, it is possible that temporality of alcohol intake relative to sleep and BzRA use are important, which were not ascertained in our cohort. Further investigation is required to better understand these associations. Further investigation is needed to better understand the potential relation between benzodiazepine receptor agonist use and other aspects of sleep related breathing disorders. Our exposure was defined as regular use of BzRA medications. Although regular use was not defined on the 2008 questionnaire, it was defined as two or more times per week on our previous biennial questionnaires. The outcome in our study was self-reported snoring. However, a previous study in NHS demonstrated that the prevalence of snoring in women who were living with spouses or partners was similar to women who were not living with spouses or partners, which suggests no obvious bias in self-report.19 In addition, many studies have evaluated snoring using this manner of assessment, revealing associations between snoring and several well-established factors such as hypertension, diabetes, and colorectal cancer.4,12–15
In conclusion, BzRA use was not associated with odds of snoring; however, BzRA use among current smokers was associated with higher odds of snoring.
Supplementary Material
Acknowledgments
Funding: This work was supported by grant UM1 CA186107 and DK91417 from the National Institutes of Health. The sponsors of this study had no role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, in the preparation, review, or approval of the manuscript, writing of the manuscript, or in the decision to submit the manuscript for publication.
Footnotes
Authors’ contributions: BML conceived and designed the study. BML, FBH, and GCC were involved in the analysis and interpretation of the data. BML and GCC drafted the manuscript. All authors critically reviewed and revised the manuscript for important intellectual content, contributed to the writing, and are in agreement with its submission. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflicts of interest: none.
Data access, responsibility, and analysis: BML had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis
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