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William C. Orr, PhD , Clinical Professor of Medicine, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma; President and CEO, Lynn Health Science Institute, Oklahoma City, Oklahoma Disclosure: William C. Orr, PhD, has disclosed that he has received grants for clinical research from and served as an advisor or consultant to Wyeth, AstraZeneca, Janssen, and Aventis.

Sleep and Gastroesophageal Reflux

William C. Orr, PhD Posted: 06/08/2005

The marked change in physiological functioning during sleep and the ramifications for the pathogenesis of disease have only recently been appreciated, most especially in the area of respiratory physiology. There is a converging body of evidence to suggest that sleep-related gastroesophageal reflux (GER) is important in the pathogenesis of esophagitis, but in spite of this, the role of sleep in the clinical presentation of gastroesophageal reflux disease (GERD) and its numerous complications has been largely ignored. More recently, studies have appeared documenting that complaints of sleep disturbance are common in patients with significant frequent heartburn.[1,2] In fact, nighttime heartburn has also been linked to the occurrence of respiratory symptoms and is an independent risk factor for sleep complaints.[3] Thus, it is becoming increasingly apparent that the occurrence of sleep-related GER/GERD is important, not only for the pathogenesis of the complications of reflux, but also as an important element for the clinical presentation of this pathologic entity. Therefore, it is important to be aware of the importance of sleep in the overall clinical picture when patients complain of significant daytime heartburn. For example, it is well established now that individuals with significant clinical complaints of daytime heartburn not only often have nighttime heartburn, but subjectively experience their nighttime heartburn as appreciably more disturbing than their daytime symptoms [1,2] Given the clinical data as discussed in the previous section, how does sleep itself produce altered responses to acid mucosal contact? First, it should be recognized that the pattern of GER is quite different during waking and sleep states. In the waking state, reflux events are predominantly postprandial and associated with short, rapidly cleared reflux events. [4] By contrast, reflux events occurring during the sleeping interval are less frequent but are generally associated with prolonged acid contact. The prolongation of acid clearance associated with sleep is due primarily to several features of the physiologic response to acid mucosal contact that are altered during sleep. First, there is no conscious response to the discomfort associated with acid mucosal contact because this is a waking conscious phenomenon. Second, both salivation and swallowing, which are critical to prompt acid clearance and neutralization, are both markedly suppressed during sleep. Taken together, these altered responses invoked by the sleeping state result in a much greater risk for poor acid clearance, as well as in the risk for proximal migration of refluxed gastric contents. For example, it has recently been shown in a study from our laboratory that small volumes (1 mL and 3 mL) of acid infused into the distal esophagus are associated with pronounced proximal migration specifically related to the sleeping state. [3] This prolongation of acid clearance is clearly not related simply to recumbency. Additional studies in our laboratory have shown that acid clearance during polygraphically monitored sleep is significantly prolonged compared with acid clearance associated with the conscious waking state.[5,6] The clinical importance of this prolongation of acid contact during sleep is best illustrated by studies that have shown a linear relationship between the back diffusion of hydrogen ions and increasing acid mucosal contact in a rabbit model of esophagitis.[7] The prolongation of acid mucosal contact was indeed associated with increasing back diffusion of hydrogen ions, as well as with more severe pathologic lesions of the esophagus. Thus, a clear picture emerges from these studies that implicates sleep-related GER in the pathogenesis of not only esophagitis, but also respiratory complications, such as the exacerbation of bronchial asthma and chronic cough. The occurrence of significant GER and acid contact time have been noted to be quite frequent among asthmatics, and this includes both daytime and nighttime acid contact. For example, a study has documented the relationship between prolonged acid clearance and increasing bronchial reactivity in asthmatics with daytime and nighttime heartburn.[8] These physiologic data are supported by epidemiologic studies that have shown a strong link between the occurrence of nighttime heartburn at least twice a week and other respiratory conditions such as asthma.[9] Collectively, these data provide epidemiologic, clinical, and physiologic support for the important role of sleep-related GER in the complications of this phenomenon. The perceptive clinician should always delve into the various clinical manifestations of heartburn to include questioning with regard to frequency and severity of nighttime heartburn. Although most reflux patients can be adequately

treated with a single daily dose of a proton-pump inhibitor (PPI), the occurrence of nighttime heartburn and/or regurgitation at least twice a week would be a sign that more aggressive therapy may be needed to include a twice-daily dose. Not uncommonly, patients with difficult-to-manage asthma or chronic cough will have GER as a contributing factor. [10] These patients will, in approximately 70% of the cases with asthma, not have symptoms of daytime heartburn. These individuals may have nighttime regurgitation and the exacerbation of wheezing at night. The presence or absence of these symptoms should be carefully explored in evaluating patients with refractory wheezing or cough. The treatment of nighttime heartburn is conceptually no different from treating daytime heartburn. That is, heartburn is a manifestation of GER and acid mucosal contact. However, it needs to be recognized that the manifestations of nighttime GER go beyond the occurrence of nighttime heartburn. Although, as noted above, a large majority of patients with daytime heartburn also manifest nighttime heartburn, other symptoms may be indicative of a more severe problem. For example, the symptom of regurgitation associated with an acidic taste is indicative of a more serious form of GER. That is, it suggests that there is significant reflux with proximal migration, and the risk of aspiration into the tracheobronchial tree would be enhanced. Thus, before initiating treatment for patients complaining of heartburn, a thorough and comprehensive evaluation of their daytime and nighttime symptoms needs to be accomplished. Pharmacologic treatment for nighttime heartburn is largely via the use of powerful acid-suppressing agents such as PPIs. Histamine-2 receptor blockers play a lesser role. In order to achieve optimal results with PPI therapy, the pharmacodynamic effect needs to encompass the sleeping interval. That is, the period of acid inhibition and an intragastric pH > 3.0 needs to encompass the patient's normal sleeping interval. In general, this would be from 10 pm to 6 am. However, a longer suppression of acid, as measured by the intragastric pH, may not always translate into the most effective treatment for nighttime GER. The proof of efficacy is not really intragastric pH, but rather the actual suppression of GER. Often, data are presented with measures of intragastric pH over a 24-hour interval of time with the assumption that effective gastric acid suppression during sleep will always translate into effective suppression of GER. Certainly, there is a correlation, but it needs to be recognized that intragastric pH is only one element of gastric acid secretion (ie, the measurement of hydrogen ions at a very small circumscribed area within the gastric lumen). Thus, when evaluating treatment efficacy, it is always wise to pay close attention to data that actually measure esophageal pH correlated with symptom resolution. These issues should always be kept in mind, along with the 2 main aims of the treatment of nighttime GER, which are to improve quality of life and reduce the potential for serious complications such as esophagitis and other respiratory complications. Despite the availability of a variety of effective treatments for the resolution of esophagitis, nighttime GER, and its concomitant symptoms, remains somewhat more difficult to control. An evidence-based review of the management of nighttime GER favors the use of PPIs for healing esophagitis and a meta-analysis of trials evaluating the efficacy of PPIs confirmed their advantages for both short-term and long-term treatment.[11] Although effective treatment for nighttime GER cannot be effected without powerful acid suppression, the clinician should not ignore lifestyle changes. In spite of a lack of high-quality supportive evidence, patients with symptoms of nighttime GER sometimes find relief by elevating the head of the bed, changing sleep positions to the left side, not wearing tight clothing, and avoiding eating within 3 hours of bedtime.[12] By inhibiting the final step of acid secretion in the secretory canaliculus of the parietal cell, PPIs have revolutionized the treatment of GERD. Studies that directly compare various PPIs are relatively few, and it is very difficult to compare results across studies due to different measurement techniques of symptoms and/or esophageal and gastric pH. It needs to be emphasized that all of the PPIs are effective in treating patients with esophagitis, and the American College of Gastroenterology's updated guidelines for the diagnosis and treatment of GERD states the following: "PPIs provide rapid symptomatic relief and healing of esophagitis in the highest percentage of patients."[13] Reviewing the available data on comparative studies would suggest that there may be some advantage, albeit small, for esomeprazole and pantoprazole. In a study comparing esomeprazole (20 mg and 40 mg daily) to omeprazole (20 mg daily), both esomeprazole doses proved significantly more effective than omeprazole in terms of esophagitis healing after 8 weeks.[14] In terms of daytime symptom resolution, 40 mg of esomeprazole was found to be superior to both esomeprazole 20 mg and omeprazole 20 mg. However, in terms of nighttime symptom resolution, both doses of esomeprazole were significantly more effective than omeprazole. A direct comparison of lansoprazole (30 mg daily) vs esomeprazole (40 mg daily) again showed superiority for esomeprazole in terms of both healing of esophagitis and nighttime symptom resolution.[15] In another comparative study, pantoprazole (40 mg daily) was compared with omeprazole (40 mg daily) for healing of esophagitis and symptom relief. No significant differences were noted between the 2 treatment groups -- however, unfortunately, no distinction was made between daytime and nighttime heartburn symptoms.[16] In one study, 3 PPIs were compared in the resolution of heartburn symptoms: pantoprazole (40 mg daily), lansoprazole (30 mg daily), and omeprazole (20 mg daily).[17] Both omeprazole and

pantoprazole were superior to lansoprazole in the relief of heartburn symptoms. Again, there was no specific comparison of daytime vs nighttime symptoms. Recently, a phenomenon has been described in association with the use of high doses of PPIs (ie, twice daily.). This phenomenon is known as nocturnal acid breakthrough (NAB). This phenomenon should not be confused with nighttime reflux. NAB refers to a precipitous drop in the intragastric pH lasting for 1 hour or longer in patients treated with high doses of a PPI. Although the rate of NAB in GERD patients appears to be slightly higher than in healthy adults, there are currently no data to support the notion that this presents an additional risk factor for nighttime GER.[18] All PPIs may not be equally efficacious with regard to nighttime heartburn itself. However, it is extremely difficult to find data that directly compare PPIs using similar measurement techniques regarding the symptom of nighttime heartburn. One study, involving more than 600 individuals, clearly showed the efficacy of pantoprazole (20 and 40 mg daily) in controlling nighttime heartburn symptoms.[19] Compared with placebo, both 20-mg and 40-mg doses of pantoprazole significantly increased the percentage of patients who were persistently free of nighttime symptoms from the first day of treatment. As the trial progressed, more and more patients achieved complete nighttime symptom relief. Two very recent studies have directly compared esomeprazole 40 mg daily vs pantoprazole 40 mg daily and, in a separate study, vs lansoprazole 30 mg daily.[20,21] In both studies, esomeprazole was found to be more effective in terms of healing of esophagitis and symptom resolution. Only the esomeprazole/pantoprazole comparative study separately evaluated the resolution of nighttime heartburn, and in this setting, no significant difference in efficacy was noted. Nighttime heartburn suggests the presence of a more problematic form of GERD. During sleep, the esophageal mucosal response to acid contact is substantially altered, which renders the individual less capable of producing a prompt response to this event. Thus, sleep-related GER is characteristically associated with a prolonged acid mucosal contact time, which enhances the back diffusion of hydrogen ions into the esophageal mucosa. In addition, sleep-related GER is commonly associated with the provocation of bronchoconstriction and symptoms of coughing and wheezing. Specific symptoms that may suggest the presence of nighttime GER would be nighttime heartburn per se, regurgitation, sleep-related cough and wheezing, or perhaps even just a sleep disturbance in sleep patterns. The presence of these symptoms 1-2 times per week is usually indicative of significant nighttime GER. Treatment is generally with aggressive PPI acid suppression therapy. Treatment should be initiated with the notion that rapid onset and prolonged pharmacodynamic effect in terms of acid suppression are required characteristics of the PPI being used.

1.

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12. Arora AS, Castell DO. Medical therapy for gastroesophageal reflux disease. Mayo Clin Proc. 2001;76:102-106. Abstract 13. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gatroenterol. 1999;94:1434-1442. 14. Kahrilas P, Falk G, Johnson D, et al. Esomeprazole improves healing and symptoms resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther. 2000;14:12491258. Abstract 15. Castell D, Kahrilas P, Richter J, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol. 2002;97:575-583. Abstract 16. Koerner T, Schuetze K, VanLeendert R, et al. Comparable efficacy of pantoprazole 40 mg vs omeprazole MUPS 40 mg in patients with GERD II/III. Gut. 2002;51(suppl III):A166. 17. Mulder C, Westerveld B, Smith J, et al. A double-blind, randomized comparison of omeprazole multiple unit pellet system (MUPS) 20 mg lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicenter trial. Eur J Gastro Hep. 2002;14:649-656. 18. Orr WC, Harnish MJ. The efficacy of omeprazole twice daily with supplemental H2 blockade at bedtime in the suppression of nocturnal oesophageal and gastric acidity. Aliment Pharmacol Ther. 2003;17:1553-1558. Abstract 19. Richter JE, Bochenek W, and the Pantoprazole US GERD Study Group. Oral pantoprazole for erosive esophagitis. A placebo-controlled, randomized clinical trial. Am J Gastroenterol. 2000;95:3071-3080. Abstract 20. Labenz J, Armstrong D, Lauritsen K, et al. A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO study. Aliment Pharmacol Ther. 2005;21:739-746. Abstract 21. Fennerty MB, Johanson JF, Hwang C, Sostek M. Efficacy of esomeprazole 40 mg vs. lansoprazole 30 mg for healing moderate to severe erosive oesophagitis. Aliment Pharmacol Ther. 2005;21:455-463. Abstract
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Supported by an independent educational grant from Wyeth. Medscape Gastroenterology. 2005;7(1) 2005 Medscape