Conflict of interest Ronnie Fass received research support from Wyeth, Takeda and AstraZeneca. He is a speaker for Eisai and a speaker and advisor for Takeda.
Professor Ronnie Fass, Southern Arizona VA Health Care System, GI Section (1-111-GI), 3601 South 6th Avenue, Tucson, AZ 85723-0001, USA. Email: firstname.lastname@example.org
Recent studies have demonstrated a bidirectional relationship between gastroesophageal reflux disease (GERD) and sleep where night-time reflux leads to sleep deprivation and sleep deprivation per se can exacerbate GERD by enhancing perception of intra-esophageal stimuli. Presently, treatment has primarily focused on reducing night-time reflux and thus improving sleep quality. Future studies are needed to further explore the relationship between GERD and sleep and the potential of novel therapeutic options to interrupt the vicious cycle between GERD and sleep.
Gastroesophageal reflux disease (GERD) is a chronic disorder and the most common disease that affects the esophagus. A population-based study estimated that 20% of the US adult population experience GERD-related symptoms at least once a week.1 GERD can lead to esophageal mucosal injury in a subset of patients as well as bothersome symptoms, such as heartburn and acid regurgitation, that may affect patients' reported quality of life.
Night-time reflux has been demonstrated to be more commonly associated with the development of GERD-related symptoms, complications and extra-esophageal manifestations of GERD.2 Patients with reflux during sleep are more likely to develop esophageal inflammation, peptic stricture, esophageal ulceration, Barrett's esophagus and even adenocarcinoma of the esophagus.3,4 In addition, these patients have a higher prevalence of oropharyngeal, laryngeal and pulmonary manifestations.5,6 Poor quality of sleep and a variety of sleep disturbances have been recently added to the growing list of extra-esophageal manifestations of GERD.
Recent studies have suggested a bidirectional relationship between GERD and sleep (Fig. 1).7 GERD has been shown to adversely affect sleep by awakening patients from sleep during the night or more commonly by leading to multiple short amnestic arousals, resulting in sleep fragmentation. At the same time, sleep deprivation per se can adversely affect GERD by enhancing perception of intra-esophageal acid (esophageal hypersensitivity).7 In fact, there is a potential ‘vicious cycle’ in which GERD leads to poor quality of sleep, which then in turn enhances perception of intra-esophageal stimuli that further exacerbates GERD.8
Overall, the epidemiology of nocturnal gastroesophageal reflux is not well studied. According to a Gallup Poll from 1988 in which 1000 GERD patients completed a survey, 79% of the respondents reported nocturnal heartburn.9 In a study by Farup et al., 74% of the GERD subjects with frequent GERD symptoms reported nocturnal GERD symptoms.10 In contrast, Locke et al. found in a community-based survey that 47% and 34% of the GERD sufferers reported nocturnal heartburn and nocturnal acid regurgitation, respectively.1 However, in the first two studies, only 57% and 54% of the patients, respectively, reported heartburn that awakened them from sleep during the night. Fass et al. in a large prospective, cohort study of subjects evaluated for sleep disturbances demonstrated that 24.9% reported heartburn during sleep.11 Recently, it was demonstrated that heartburn that awakens patients from sleep during the night is highly predictive for GERD.12 This effect was further accentuated in morbidly obese subjects.
In the aforementioned national survey of 1000 subjects with GERD, 75% of the participants reported that GERD symptoms affected their sleep, and 63% believed that heartburn negatively affected their ability to sleep well.9 Additionally, 42% stated that they were unable to sleep through a full night, 39% had to take naps during the day and 34% were sleeping in a seated position. Interestingly, 27% reported that their heartburn-induced sleep disturbances kept their spouse from having a good night's sleep. The prevalence of sleep disturbances among respondents increased with increase in frequency of the night-time heartburn episodes during the week.
Reports of frequent nocturnal heartburn have been more associated with impaired health-related quality of life (HRQOL) and work productivity as compared with GERD patients without night-time symptoms.13
Pathophysiology of nocturnal GERD
Sleep may alter physiological mechanisms responsible for normal esophageal clearance, resulting in increased esophageal acid exposure. Rate of swallowing is reduced during sleep leading to decrease in primary peristalsis, a pivotal defense mechanism that is responsible for volume clearance of a refluxate from the esophagus.14,15 The latter results in decrease in acid clearance and thus increase in acid mucosal contact time.16 Diminished salivary production during sleep as well as reduced delivery of saliva to the distal esophagus due to decreased primary peristalsis delays alkalization and thus normalization of esophageal pH after acid reflux has occurred. The upper esophageal sphincter basal pressure, but not the lower esophageal sphincter, progressively declines with deeper sleep stages, resulting in an increased risk for aspiration in GERD patients. Moreover, there is less conscious awareness of gastroesophageal reflux during sleep, resulting in reduction in symptom perception and thus alteration in conscious-dependent defensive behavior against gastroesophageal reflux (e.g. antacid consumption, assuming the upright position, initiating a swallow).17
Early studies have suggested that acid reflux was significantly more frequent during the first half of the supine period as compared with the second half.18 Dickman et al. demonstrated that esophageal acid exposure was the highest during the first 2 h of sleep.19 This was further accentuated in patients with Barrett's esophagus as compared to those with erosive esophagitis or non-erosive reflux disease with abnormal pH test. Patients with Barrett's esophagus had the highest esophageal acid exposure parameters throughout the sleep period. Surprisingly, there was no difference in esophageal acid exposure parameters between patients with erosive esophagitis and those with non-erosive reflux disease and abnormal pH test. The increase in esophageal acid exposure during the first hours of sleep is likely to be driven amongst others by short dinner-to-bed time. It has been shown that dinner-to-bed time less than 3 h significantly increased the risk of subjects to experience gastroesophageal reflux regardless of their phenotypic presentation of GERD (erosive esophagitis or non-erosive reflux disease).20 A recent article by Piesman et al. demonstrated that a meal consumed 2 h before going to bed was significantly more associated with supine reflux as compared to a meal consumed 6 h prior to bedtime.21 The presence of hiatal hernia, higher body mass index, and having erosive esophagitis increased the likelihood of developing supine reflux. Other factors like alcohol and/or carbonated beverage consumption, use of benzodiazepines at bedtime have all been shown to increase the risk for reported heartburn during sleep time.11,22
Dickman et al. proposed to separate reflux events to those that occur during the awake period and those that occur during the sleep period.23 This new division of acid reflux exposure underscores the important effect of sleep physiology on gastroesophageal reflux.
As was previously mentioned, sleep deprivation per se can also affect GERD. In a recent study by Schey et al., the authors exposed 10 healthy subjects and 10 GERD patients to sleep deprivation (<3 h) and normal sleep (≥7 h).7 The authors were able to demonstrate that after sleep deprivation, subjects were significantly more sensitive to esophageal acid perfusion than after a good night's sleep. This study clearly showed that sleep deprivation is likely an important central factor that can exacerbate GERD symptoms by enhancing perception of intra-esophageal stimuli.
The two pivotal underlying mechanisms for reduced quality of sleep and sleep disturbances in patients with GERD are heartburn that awakens patients from sleep during the night and short, amnestic arousals that lead to sleep deprivation. Between 47% and 57% of the GERD patients reported having heartburn that awakens them from sleep during the night.1,9,10 In the general population, approximately a quarter of the subjects reported heartburn that awakened them from sleep. Whilst night-time heartburn has been perceived by many investigators as the most important underlying mechanism for sleep deprivation in GERD patients, recent studies have shown that acid reflux events are more commonly encountered and often associated with short, amnestic arousals.24 In one study, 90% of acid reflux events were associated with short arousals during sleep.24 These arousals usually last 30 s and tend to occur during an acid reflux event. Most of the arousals occurred during stage 2 of sleep and rarely during the rapid eye movement (REM) period. While early studies in normal subjects suggested that reflux associated with transient lower esophageal sphincter relaxations can occur only during periods of arousals from sleep, further studies in GERD patients produced conflicting results.25
When assessing the risks for injury to the esophagus in patients who awake with heartburn versus those with short arousals in response to an acid reflux event, the former appears to have an important defensive effect. Patients who awake with heartburn can initiate swallows and thus primary peristalsis, deliver alkalinized saliva to the distal portion of the esophagus and consume anti-reflux treatment with an acute ameliorating effect [e.g. antacids, Gaviscon, (GlaxoSmithKlein, Middlesex, UK) over-the-counter H2RA]. In contrast, patients who respond to a reflux agent with only short arousal will be unable to activate these vital esophageal defense mechanisms leading to prolonged esophageal acid contact time and possibly esophageal mucosal injury (Table 1). Surprisingly, there is no difference in relation to the effect on sleep quality between patients with non-erosive reflux disease and those with erosive esophagitis.26
Table 1. Different esophageal physiological responses to gastroesophageal reflux during sleep (waking up with heartburn versus short, amnestic arousals)
Dickman et al. have also demonstrated that patients with more severe GERD symptoms report poorer quality of sleep.23 Interestingly, poor sleep quality on the night prior to pH testing was associated with more acid exposure the following day. The latter suggests that poor quality of sleep increases the risk for having abnormal esophageal acid exposure in addition to enhancing perception of intra-esophageal stimuli. The authors further confirmed that greater acid exposure at night was related to more reports of poor sleep quality the next day.
Obstructive sleep apnea (OSA)
The exact association between OSA and GERD remains controversial. Kerr et al. have demonstrated that precipitous drops in pH were frequently preceded by arousal (98.4%), movement of the patient (71.9%) and swallowing (80.4%).27 In this case, arousal is theorized to be caused by increased ventilatory effort.28 Arousal and movement may trigger gastroesophageal reflux by causing transient alteration in the pressure gradient across the lower esophageal sphincter (LES). Additionally, the lowered intrathoracic pressure that accompanies OSA may by itself predispose the patient to gastroesophageal reflux by exacerbating the LES pressure gradient. Treatment with nasal continuous positive airway pressure (CPAP) showed dramatic reduction in the frequency of gastroesophageal reflux by elevating intrathoracic pressure.27
Investigators have suggested that GERD is associated with OSA and that there might be a potential causal link between the two disorders.29 However, recent studies have failed to demonstrate a causal relationship between OSA and GERD. In a study by Penzel et al., 37 of 52 reflux events that occurred during sleep, involving either apnea or hypopnea, were found prior to the reflux event.30 The sequence in time did not prove a causal relationship between the respiratory and reflux events. Patients subjectively report that the quality of sleep is affected by the severity of GERD; however, objective correlation between OSA and GERD is lacking, which may suggest that both are common entities sharing similar risk factors but may not to be causally linked.29
Obstructive sleep apnea is not influenced by severity of GERD. Additionally, objective measures of disordered sleep have stronger association with age, smoking and alcohol use than GERD in men and stronger association with age and body mass index than GERD in women.29 Kim et al. could not find a relationship between OSA and GERD symptoms among 123 patients referred to a sleep disorders center.31 Furthermore, there was no relationship between the severity of OSA and the likelihood of GERD symptoms.
Chand et al. treated, in an open-label trial, 18 erosive esophagitis patients with esomeprazole 40 mg once daily for 8 weeks. The authors were only able to document improvement in subjective reports of sleep quality using the Pittsburg Sleep Quality Questionnaire.32
In another study, 42 subjects were randomized to receive either placebo or rabeprazole 20 mg twice daily for 1 week.33 Subsequently, the patients were crossed over to the other arm. Whilst rabeprazole significantly reduced reflux-related parameters, there was no difference between the drug and placebo in objective polysomnographic measurements (percentage sleep efficiency, percentage slow wave sleep, percentage REM sleep, and arousals/h). However, during rabeprazole treatment patients reported a significantly better quality of sleep and reduced mean number of remembered awakenings. The authors concluded that in GERD patients' anti-reflux treatment improve subjective sleep measures but with no impact on objective sleep measures. In contrast, Dimarino et al. demonstrated that in subjects with documented abnormal pH testing and reports of sleep disorders, standard-dose omeprazole reduced acid reflux-related arousals and awakenings, improved sleep efficiency, increased REM sleep and increased total sleep time.34 In a large study that included 635 patients with GERD and reduced quality of sleep, treatment with esomeprazole 40 mg or 20 mg daily markedly improved sleep by reducing (83.2–84.1%) the number of days with GERD-associated sleep disturbances.35 Additionally, both pantoprazole 40 mg daily and esomeprazole 40 mg daily improved sleep in GERD patients with documented sleep disturbances on the ReQuest questionnaire.36
The effect of anti-reflux surgery on sleep was evaluated in a small number of GERD patients.37 The authors primarily demonstrated improvement in subjective reports of quality of sleep but with very little difference in objective sleep parameters between baseline and post-fundoplication. There was a significant increase in the fraction of the night spent in deeper sleep (49.61% vs 58.3%, P = 0.022).
Nocturnal heartburn is very common, affecting most patients with GERD. However, patients may not report nocturnal symptoms, unless specifically asked. In a subset of GERD patients, nocturnal symptoms may not be present, but patients may display extra-esophageal manifestations of GERD. The latter may be the sole manifestation of GERD, even in patients who do not report night-time awakenings due to heartburn. Overall, proton pump inhibitors appear to be an effective therapeutic modality in controlling nocturnal heartburn symptoms and reports of sleep disturbances in most heartburn sufferers.