Clinical Gastroenterology and Hepatology
Volume 7, Issue 9 , Pages 919-920, September 2009

Sleep-Related Gastroesophageal Reflux: Evidence Is Mounting …

published online 25 May 2009.

Article Outline

 

Gastroesophageal reflux (GER) has many consequences throughout the 24-hour period, during both wakefulness and sleep. Fortunately, leaders in our field recognized the importance of monitoring esophageal pH for 24 hours instead of monitoring pH only during the postprandial period.1

Esophageal physiology and esophageal acid clearance during sleep differ greatly from wakefulness. The upper esophageal sphincter pressure decreases with sleep onset and further decreases to 8 mm Hg during stable sleep.2 Reflux events also tend to occur during the first 2 hours of sleep.3 Transient LES relaxations are confined to wake time and brief arousals, so that reflux events are much more likely to occur during arousals.4 Swallowing frequency is almost nonexistent during stable sleep, so that swallows occur during brief arousals.2 Saliva production ceases during sleep, and sleep facilitates proximal acid migration in the esophagus.5 Furthermore, esophageal clearance of refluxate is markedly prolonged during sleep and requires an arousal.6

Sleep-related GER is associated with long reflux episodes (>5 minutes), higher esophagitis grades, Barrett's esophagitis, and esophageal adenocarcinoma.7, 8 Sleep-related GER also causes esophageal symptoms. Farup et al9 noted that 74% of GER subjects experienced sleep-related GER.

Sleep-related GER not only disrupts sleep but also impacts daytime functioning. A Gallup survey conducted on behalf of the American Gastroenterological Association in 1000 people with heartburn noted that 79% of respondents had nighttime heartburn, and 75% of these people reported that it affected their sleep, and 40% believed that it impaired their daytime functioning.10 Acid reflux events also disrupt sleep architecture. Disorders of initiating and maintaining sleep were associated with reflux symptoms on validated questionnaires.11 A systematic review of 5 population-based studies showed that sleep-related GER is associated with poor sleep quality, arousals from sleep, fatigue, and impaired work productivity.12 Further knowledge about reflux-related sleep phenomena is important because treatment of sleep-related GER has the potential to improve sleep outcomes and daytime functioning. A placebo-controlled trial with esomeprazole 40 mg, 20 mg, or placebo for 6 weeks in 750 adults with sleep-related GER noted that both esomeprazole doses improved sleep quality, reduced lost work hours, and increased work productivity.13

Indeed, sleep-related GER can result in more than disturbed sleep. In this issue of Clinical Gastroenterology and Hepatology, 3 articles add to our knowledge concerning sleep-related GER.14, 15, 16 Mody et al14 examined the relationship between reflux symptoms during sleep, sleep onset, and sleep maintenance insomnia and assessed the effects of reflux-related sleep difficulties with quality of life, work productivity, and health care resource use. According to the 2006 U.S. National Health and Wellness Survey of 11,685 respondents with reflux symptoms, 68% experienced sleep difficulties, with 49% reporting sleep onset insomnia and 58% reporting sleep maintenance insomnia. Respondents with reflux symptoms during sleep time were also more likely to have sleep onset insomnia (odds ratio [OR], 1.43) and sleep maintenance insomnia (OR, 1.56) compared with respondents with reflux symptoms only during wakefulness. Furthermore, respondents with reflux with sleep difficulty had more health care provider visits, a loss of 5.5% in their work productivity, and reductions in their health-related quality of life. Thus, reflux during sleep time affects the ability to sleep and affects wake time functioning and quality of life.

Jansson et al15 performed a population-based, cross-sectional study based on 2 health surveys during 2 years in the 1980s and during 2 years in the 1990s in Norway. Assessing reflux symptoms and insomnia, they found associations between insomnia, sleeplessness, sleep onset insomnia, and risk of GER disease in 3,153 persons with severe reflux symptoms compared with 40,210 persons reporting no reflux symptoms. These effects were still significant when they adjusted for confounders, including anxiety and depression (OR, 2.2; 95% confidence interval, 1.9–2.7 for insomnia). There was a 3-fold risk of reflux among persons with insomnia compared with persons without insomnia in multivariate models adjusted for age, sex, smoking, body mass index, and socioeconomic status (OR, 3.2; 95% confidence interval, 2.2–3.7). Despite study design limitations (self-reported reflux, sleep variables, and reflux prevalence versus incidence), this population-based study with its ∼70% participatory rate from a single Norwegian county shows that the signal is a strong one. Furthermore, the interplay between insomnia and GER might be bidirectional, so that the sleep disturbance might influence reflux, and reflux might influence sleep disturbance.

This association is a complex one with many potential influences. Gagliardi et al16 show us one potential factor. Insomnia is the most common sleep complaint among Americans. Approximately 40% of adults have symptoms of insomnia within a given year, and 10%–15% of adults report chronic insomnia.17 Difficulty initiating sleep is often associated with maladaptive behaviors including racing thoughts, stimulating activities, and bright light exposure (ie, television) before bedtime. Sleep hygiene and cognitive behavioral therapy often in combination with a prescribed sleep aid improve sleep onset insomnia. However, insomnia sufferers might not have access to behavioral approaches or not be open-minded about behavior change, so physicians are quick to prescribe a medication to induce sleep. Zolpidem is the most commonly prescribed non-benzodiazepine medication for sleep, and it is now available in generic form in the U.S. It binds to gamma-aminobutyric acid (GABA)–A receptors, facilitating sleep onset, and decreases the arousal threshold, so individuals are less likely to awaken during sleep. This is in contrast to baclofen, which targets GABA-B receptors, which impact transient LES relaxations. Gagliardi et al examined 16 reflux patients and 8 control subjects who were given zolpidem 10 mg or placebo in a crossover design, and they performed polysomnography combined with esophageal pH testing during each treatment arm. Zolpidem significantly increased the esophageal acid contact times for individual GER events compared with placebo (P < .05). Furthermore, reflux events were associated with arousal or awakening 40% of the time when zolpidem was administered compared with 89% when given placebo (P < .01). This lack of an arousal response with zolpidem waned after the first 3 hours (elimination half-life of the drug is 2.5 hours). Although not studied, this effect has the potential to extend into other drugs in this class including zolpidem extended release, eszopiclone, and zaleplon. More recently, a zolpidem oral spray formulation was approved by the Food and Drug Administration. Although in the same drug class, these drugs have differing elimination half-lives, so their potential effect on sleep-related GER might be of even longer duration, especially with zolpidem extended release and eszopiclone.

Sleep-related GER causes insomnia. Patients might not realize that GER is contributing to their insomnia. When patients complain to their physician about their insomnia, they might not appreciate that GER is a contributing factor, so that instead of intensifying GER therapy during sleep time, they prescribe a non-benzodiazepine hypnotic such as zolpidem. This hypnotic prolongs esophageal acid clearance and delays the arousal response, which can further worsen reflux and thus their insomnia. To avoid this cycle, we should consider sleep-related GER as a possible cause of insomnia and treat GER during the sleep period instead of prescribing a hypnotic medication. This investigation has significant clinical relevance.

Finally, sleep is interdisciplinary, and we should consider using common definitions. When performing esophageal pH tests, supine GER refers to reflux that occurs during sleep time, which has been the standard definition since the 1970s.1 However, we might want to refer to GER that occurs during and around sleep as sleep-related GER instead of nighttime GER. More than 15 million Americans are shift workers and sleep during daylight hours.18

Therefore, sleep-related GER disrupts sleep, causes insomnia, and is associated with daytime impairment. The relationship between sleep-related GER and sleep disturbances appears to be a bidirectional one. Furthermore, common medications used to manage insomnia depress the arousal response that is vital to esophageal refluxate clearance. The data are impressive. Ask your GER patients what happens during sleep!

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References 

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 Conflicts of interest The authors disclose no conflicts.

PII: S1542-3565(09)00452-2

doi:10.1016/j.cgh.2009.05.011

Clinical Gastroenterology and Hepatology
Volume 7, Issue 9 , Pages 919-920, September 2009