Journal of Neurogastroenterology and Motility 2017; 23(2): 145-148  https://doi.org/10.5056/jnm17037
Can Nocturnal Acid-breakthrough Be Reduced by Long-acting Proton Pump Inhibitors?
Hye Kyung Jeon, and Gwang Ha Kim*
Department of Internal Medicine, Pusan National University School of Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
Correspondence to: Gwang Ha Kim, MD, PhD, Department of Internal Medicine, Pusan National University School of Medicine, and Biomedical Research Institute, Pusan National University Hospital, 179, Gudeok-ro, Seo-gu, Busan 49241, Korea, Tel: +82-51-240-7869, Fax: +82-51-244-8180, E-mail: doc0224@pusan.ac.kr
Received: March 14, 2017; Accepted: March 14, 2017; Published online: April 1, 2017.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Gastroesophageal reflux disease (GERD) is a condition characterized by reflux of the gastric contents causing troublesome symptoms and complications.1 Proton pump inhibitors (PPIs) are the mainstay of treatment for GERD and significantly decrease gastric acid secretion. In spite of their potent acid suppression, PPIs cannot eliminate intragastric acidity, particularly during the night. PPIs have a relatively short plasma half-life and all proton pumps are not active at the same time. Therefore, during the night, the morning dosed PPIs are no longer effective on acid suppression of newly activated proton pumps. During the night, there is no gravity-mediated drainage and significant reduction in swallows; thus, reflux episodes are of longer duration.2 Based on these circumstances, nocturnal acid-breakthrough (NAB) has been the subject of attention to describe refractory GERD. NAB was first described as a decrease in gastric pH less than 4 for at least 60 consecutive minutes in the overnight period in patients on twice-daily PPIs treatment.3

Originally, the rationale behind measuring intragastric pH and presence of NAB was that the stomach is the source of acid in the refluxate; suppression of gastric acid may reduce the injurious effect of the refluxate in GERD. To overcome short plasma half-life of PPIs, several pharmacological attempts have been made to control NAB with different regimens and doses of PPIs. In addition, investigators have also attempted to eliminate NAB by targeting the night time histamine surge, with administration of histamine H2 receptor antagonists (H2RA) (Table).2,412

What is the treatment effect of PPIs, which are known to have a longer plasma half-life on NAB? In this issue of the Journal of Neurogastroenterology and Motility, Karyampudi et al13 evaluated esophageal acidification during NAB with ilaprazole, versus omeprazole in patients with uncomplicated GERD, in a prospective manner. A total of 58 patients with GERD prescribed 10 mg of ilaprazole or 20 mg of omeprazole once daily for more than 1 month were enrolled in this study, and underwent 24-hour impedance-pH monitoring. A total of 72.4% of patients had NAB. Despite the long-action of ilaprazole, its frequency, duration, and mean intra-gastric pH during NAB, as well as nocturnal esophageal acidification and nocturnal symptoms were comparable between the ilaprazole and omeprazole groups. Among those who had NAB, a lesser number of NAB episodes occurred in the ilaprazole group compared to the omeprazole group (P = 0.010). On the contrary, a previous study showed that 20 mg of ilaprazole provided significantly higher mean 24-hour intragastric pH than the same dose of omeprazole and that low-dose ilaprazole (5 mg and 10 mg) offered a gastric acid inhibition comparable to a routine dose of omeprazole.14 In another study, 10 mg or higher of ilaprazole may provide better control of NAB, nocturnal esophageal acidification, and nocturnal symptoms.13

Another important thing in this study was that the authors evaluated the clinical significance of NAB. The frequency and duration of nocturnal esophageal acidification and nocturnal symptoms were comparable with or without NAB. Regarding specific conditions such as Barrett’s esophagus, ineffective esophageal motility, and complicated GERD including high-grade erosive reflux disease, NAB has been reported to be more likely accompanied by esophageal reflux.1519 Therefore, if patients with these conditions show resistance to PPI treatment, the existence of NAB with nocturnal acid reflux should be considered. Otherwise, several previous studies suggested that NAB did not correlate well with esophageal acid exposure or nocturnal reflux symptom.2022 Ours et al22 reported that all subjects, whether treated with a PPI or a PPI plus H2RA, and regardless of drug schedule, were asymptomatic after treatment despite the presence of NAB; they concluded that NAB is a purely gastric phenomenon with no correlation to esophageal acid levels or symptom improvement.

In regards to uncomplicated GERD patients who have particularly normal esophageal clearance mechanisms, the clinical importance of NAB is likely to be little. NAB is common during administration of PPIs, and identification of esophageal acidification and nocturnal symptoms are essential to evaluate the “real” clinical effect of PPIs on GERD, not intragastric pH.

Tables

Summary of Published Studies About Management of Nocturnal Acid-breakthrough in Gastroesophageal Reflux Disease

AuthorsYearStudy designResults
Hatlebakk et al21998Volunteers (n = 18)1) OME 40 mg qAM2) OME 40 mg qPM3) OME 20 mg bidSplit dosing was superior.
Khoury et al41999Volunteers (n = 21)1) OME 20 mg AM + OME 20 mg PM + placebo HS2) OME 20 mg AM + placebo PM + H2RA HSBedtime H2RA did not replace an evening dose of PPI in patients requiring more than a single daily dose of PPI.
Xue et al52001GERD patients1) PPI bid (n = 60)2) PPI bid + H2RAs HS (n = 45)3) Both regimen (n = 11)A bedtime H2RA enhanced nocturnal gastric pH control and decreased esophageal acid exposure during NAB.
Fackler et al62002Volunteers (n = 18), GERD patients (n = 16)OME bid for 2 wk→ OME bid + H2RA 300 mg HS for 28 dayCombination of H2RA and PPI reduced NAB only with introduction of therapy (due to H2RA tolerance).
Orr et al72003Symptomatic GERD patients (n = 19)OME 20 mg bid for 1 wk+ H2RA or placebo HS+ nighttime provocative reflux mealIn spite of reduction of intragastric acidity, H2RA had no effect on the occurrence of gastroesophageal reflux during sleep.
Adachi et al82003Volunteers without H. pylori (n = 10)1) RAB 20 mg qAM2) RAB 20 mg qAM + H2RA HS (last day only)3) RAB 20 mg qAM + continuous H2RA HS4) RAB 10 mg bidSplit dosing was better in gastric acid suppression. Continuous H2RA was less effective.
Shimatani et al92004Volunteers without H. pylori (n = 18)1) RAB 10 mg qAM2) RAB 20 mg qAM3) RAB 10 mg bidSplit dosing was more potent and long-lasting acid suppression.
Hammer et al102004Volunteer (n = 13)1) ESM 20 mg bid2) ESM 40 mg qAMSplit dosing improved nighttime acid suppression.
Katz et al112007Nocturnal GERD patients (n = 54)1) IR-OME 40 mg HS2) LPZ 30 mg HS3) ESM 40 mg HSBedtime dosing with IR-OME was effective with night-time heartburn.
Mainie et al122008GERD patients (n = 100)1) PPI bid (n = 58)2) PPI bid + H2RA HS (n = 42)A bedtime H2RA reduced the percentage time of the intragastric pH < 4 and also NAB.

OME, omeprazole; qAM, once daily before breakfast; qPM, once daily before dinner; bid, twice a day; HS, at bed time; H2RA, histamine H2 receptor antagonist; PPI, proton pump inhibitor; GERD, gastroesophageal reflux disease; NAB, nocturnal acid-breakthrough; H. pylori, Helicobacter pylori; RAB, rabeprazole; ESM, esomeprazole; IR-OME, immediate release omeprazole; LPZ, lansoprazole.


References
  1. Vakil, N, van Zanten, SV, Kahrilas, P, Dent, J, Jones, R, and Global Consensus Group (2006). The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 101, 1900-1920.
    Pubmed CrossRef
  2. Hatlebakk, JG, Katz, PO, Kuo, B, and Castell, DO (1998). Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily. Aliment Pharmacol Ther. 12, 1235-1240.
    CrossRef
  3. Peghini, PL, Katz, PO, Bracy, NA, and Castell, DO (1998). Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol. 93, 763-767.
    Pubmed CrossRef
  4. Khoury, RM, Katz, PO, Hammod, R, and Castell, DO (1999). Bedtime ranitidine does not eliminate the need for a second daily dose of omeprazole to suppress nocturnal gastric pH. Aliment Pharmacol Ther. 13, 675-678.
    Pubmed CrossRef
  5. Xue, S, Katz, PO, Banerjee, P, Tutuian, R, and Castell, DO (2001). Bedtime H2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors. Aliment Pharmacol Ther. 15, 1351-1356.
    Pubmed CrossRef
  6. Fackler, WK, Ours, TM, Vaezi, MF, and Richter, JE (2002). Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology. 122, 625-632.
    Pubmed CrossRef
  7. Orr, WC, and Harnish, MJ (2003). The efficacy of omeprazole twice daily with supplemental H2 blockade at bedtime in the suppression of nocturnal oesophageal and gastric acidity. Aliment Pharmacol Ther. 17, 1553-1558.
    Pubmed CrossRef
  8. Adachi, K, Komazawa, Y, and Fujishiro, H (2003). Nocturnal gastric acid breakthrough during the administration of rabeprazole and ranitidine in Helicobacter pylori-negative subjects: effects of different regimens. J Gastroenterol. 38, 830-835.
    Pubmed CrossRef
  9. Shimatani, T, Inoue, M, Kuroiwa, T, and Horikawa, Y (2004). Rabeprazole 10 mg twice daily is superior to 20 mg once daily for night-time gastric acid suppression. Aliment Pharmacol Ther. 19, 113-122.
    CrossRef
  10. Hammer, J, and Schmidt, B (2004). Effect of splitting the dose of esomeprazole on gastric acidity and nocturnal acid breakthrough. Aliment Pharmacol Ther. 19, 1105-1110.
    Pubmed CrossRef
  11. Katz, PO, Koch, FK, and Ballard, ED (2007). Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms. Aliment Pharmacol Ther. 25, 197-205.
    Pubmed CrossRef
  12. Mainie, I, Tutuian, R, and Castell, DO (2008). Addition of a H2 receptor antagonist to PPI improves acid control and decreases nocturnal acid breakthrough. J Clin Gastroenterol. 42, 676-679.
    Pubmed CrossRef
  13. Karyampudi, A, Ghoshal, UC, Singh, R, Verma, A, Misra, A, and Saraswat, VA (2017). Esophageal acidification during nocturnal acid-breakthrough with ilaprazole versus omeprazole in gastroesophageal reflux disease. J Neurogastroenterol Motil. 23, 208-217.
    CrossRef
  14. Du, YQ, Guo, WY, and Zou, DW (2012). Acid inhibition effect of ilaprazole on Helicobacter pylori-negative healthy volunteers: an open randomized cross-over study. J Dig Dis. 13, 113-119.
    Pubmed CrossRef
  15. Katz, PO, Anderson, C, Khoury, R, and Castell, DO (1998). Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther. 12, 1231-1234.
    CrossRef
  16. Fouad, YM, Katz, PO, and Castell, DO (1999). Oesophageal motility defects associated with nocturnal gastro-oesophageal reflux on proton pump inhibitors. Aliment Pharmacol Ther. 13, 1467-1471.
    Pubmed CrossRef
  17. Adachi, K, Fujishiro, H, and Katsube, T (2001). Predominant nocturnal acid reflux in patients with Los Angeles grade C and D reflux esophagitis. J Gastroenterol Hepatol. 16, 1191-1196.
    CrossRef
  18. Yeh, RW, Gerson, LB, and Triadafilopoulos, G (2003). Efficacy of esomeprazole in controlling reflux symptoms, intraesophageal, and intragastric pH in patients with Barrett’s esophagus. Dis Esophagus. 16, 193-198.
    CrossRef
  19. Janiak, P, Thumshirn, M, and Menne, D (2007). Clinical trial: the effects of adding ranitidine at night to twice daily omeprazole therapy on nocturnal acid breakthrough and acid reflux in patients with systemic sclerosis--a randomized controlled, cross-over trial. Aliment Pharmacol Ther. 26, 1259-1265.
    Pubmed CrossRef
  20. Ghoshal, UC, Chourasia, D, Tripathi, S, Misra, A, and Singh, K (2008). Relationship of severity of gastroesophageal reflux disease with gastric acid secretory profile and esophageal acid exposure during nocturnal acid breakthrough: a study using 24-h dual-channel pH-metry. Scand J Gastroenterol. 43, 654-661.
    Pubmed CrossRef
  21. Weigt, J, Kandulski, A, Büsch, F, and Malfertheiner, P (2009). Nocturnal gastric acid breakthrough is not associated with night-time gastroesophageal reflux in GERD patients. Dig Dis. 27, 68-73.
    Pubmed CrossRef
  22. Ours, TM, Fackler, WK, Richter, JE, and Vaezi, MF (2003). Nocturnal acid breakthrough: clinical significance and correlation with esophageal acid exposure. Am J Gastroenterol. 98, 545-550.
    Pubmed CrossRef


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