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• W1976572732 abstract "The apparent superiority of the proton pump inhibitors (PPIs) over the H2-receptor antagonists (H2RAs) in the management of gastroesophageal reflux disease (GERD) has convinced most physicians and payers that these drugs cannot be bettered. However, there is convincing evidence that more than 50% of patients taking a PPI are dissatisfied with their treatment,1Fass R. Sifrim D. Management of heartburn not responding to proton pump inhibitors.Gut. 2009; 58: 295-309Crossref PubMed Scopus (256) Google Scholar and more than 20% take twice daily PPIs or supplement their treatment with over-the-counter remedies.2Chey W.D. Mody R.R. Izat E. Patient and physician satisfaction with proton pump inhibitors (PPIs): are there opportunities for improvement?.Dig Dis Sci. 2010; 55: 3415-3422Crossref PubMed Scopus (31) Google Scholar For these patients who have an unsatisfactory response to once daily PPI, increasing to twice a day (before breakfast and before dinner) is a common practice, as suggested in the 2008 American Gastroenterological Association statement.3Kahrilas P.J. Shaheen N.J. Vaezi M.F. et al.American Gastroenterological Association: American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease.Gastroenterology. 2008; 135: 1383-1391Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar Among patients on PPI twice a day, 39% increased the dose because of poor symptom control at night,2Chey W.D. Mody R.R. Izat E. Patient and physician satisfaction with proton pump inhibitors (PPIs): are there opportunities for improvement?.Dig Dis Sci. 2010; 55: 3415-3422Crossref PubMed Scopus (31) Google Scholar and in a recent U.S. survey of GERD patients taking PPIs, >80% reported severe symptoms at night.4Chey W.D. Mody R. Chen L. et al.Nighttime symptoms and sleep impairment among patients with gastro-esophageal reflux disease (GERD) receiving prescription (Rx) proton pump inhibitors (PPIs).Gastroenterology. 2008; 134: A323-A324Google Scholar In total, 22% of responders were on PPI twice a day, and 42% supplemented prescribed PPIs with over-the-counter PPIs, H2-RAs, or antacids. Not surprisingly, the practice of prescribing PPIs in high dose or twice daily is increasing,5Targownik L.E. Metge C. Roos L. et al.The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use.Am J Gastroenterol. 2007; 102: 942-950Crossref PubMed Scopus (67) Google Scholar despite high dose or twice a day PPIs not being approved for GERD in any jurisdiction. Indeed, it is remarkable that 20 years after their introduction, the PPIs are still marketed and prescribed as “one drug, once a day for all acid related disorders.” This “off-the-peg” approach flies in the face of our understanding of the pathophysiology of the underlying diseases and the fickle pharmacology of the PPIs. Thus, a renewed appreciation of these issues should prompt us to tailor drug therapy as we do in many other diseases.Thus, the large multicenter study conducted in a community setting by Fass et al6Fass R. Inadomi J. Han C. et al.Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release.Clin Gastroenterol Hepatol. 2012; 10: 247-253Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar offers us an opportunity to revisit the use of acid suppression in GERD. These authors have shown that a modified release PPI with an extended plasma residence time, dexlansoprazole-MR, when given once daily was as effective as a PPI twice a day for controlling symptoms in patients with difficult to control reflux disease. It is unfortunate that their study was limited to a single arm and was a single-blinded design, with descriptive analyses for most outcomes. The study would have been improved with a comparator arm, as the authors acknowledge. This would have provided the opportunity for double-blinding and comparison with stepping down to a single dose of the original PPI (or continuing the PPI twice a day). Details of “night-time symptoms” would also have been valuable, and this combined information would have made the authors' conclusions more robust. Studies have shown that stepping down to a PPI once daily is effective in those who were well-controlled on twice a day treatment and did not have erosive disease.7Coté G.A. Ferreira M.R. Rozenberg-Ben-Dror K. et al.Programme of stepping down from twice daily proton pump inhibitor therapy for symptomatic gastro-oesophageal reflux disease associated with a formulary change at a VA medical center.Aliment Pharmacol Ther. 2007; 25: 709-714Crossref PubMed Scopus (19) Google Scholar Importantly, also in this study, we do not see any evidence for dependency and the postulated but poorly evidenced rebound phenomenon.8Howden C.W. Kahrilas P.J. Just how “difficult” is it to withdraw PPI treatment?.Am J Gastroenterol. 2010; 105: 1538-1540Crossref PubMed Scopus (16) Google ScholarUnlike the standard delayed release PPIs (DR-PPIs), the dexlansoprazole-MR formulation is characterized by a dual delayed release mechanism that provides an extended plasma residence time and increased area under the curve when compared with lansoprazole. This is associated with an improved antisecretory effect, with 24-hour intragastric pH maintained >4 for about 17 hours.9Metz D.C. Vakily M. Dixit T. et al.Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.Aliment Pharmacol Ther. 2009; 29: 928-937Crossref PubMed Scopus (90) Google Scholar, 10Vakily M. Zhang W. Wu J. et al.Pharmacokinetics and pharmaco-dynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials.Curr Med Res Opin. 2009; 25: 627-638Crossref PubMed Scopus (82) Google ScholarTwo important reasons, among others, for the failure of DR-PPIs are the short plasma residence time and consequent short duration of antisecretory effect of these drugs and also the need for them to be given 30 minutes before a meal to activate the acid pumps for optimal antisecretory efficacy. The DR-PPIs all have a short plasma half-life of 1–1.5 hours, which means that there is little or no drug in the circulation 5–7 hours after dosing. Although the PPIs all bind covalently to the H+ K+ adenosine triphosphatase, which extends the duration of the antisecretory effect for those pumps that are blocked during the 5–7 hours of drug exposure, it is only the “activated” pumps inserted into the secretory canalicular membrane that are blocked. Those pumps at rest in the cytosol or that are newly synthesized after the period of drug exposure will not be inhibited and so will have the capacity to secrete acid (pH 1). The net consequence is that the volume of gastric acid secretion is significantly reduced, but the acidity remains at profoundly acidic pH.A substantial proportion of esophagitis patients do not heal after standard dose PPI for 8 weeks. The weighted healing rate for all grades of erosive esophagitis for 5 marketed PPIs at standard dose for 8 weeks ranges from 81% (omeprazole 20 mg once in the morning) to 86% (esomeprazole 40 mg once in the morning) in published clinical trials (our database on file). Moreover, a significant proportion of dissatisfied patients complain of symptoms in the evening or at night, and most patients reflux after midnight, when the supine time is associated with more reflux events.11Orr W.C. Reflux events and sleep: are we vulnerable?.Curr Gastroenterol Rep. 2006; 8: 202-207Crossref PubMed Scopus (15) Google Scholar Such observations prompted interest in the concept of nocturnal acid breakthrough, which has not been found clinically helpful because it occurs in around 70% of both healthy volunteers and GERD patients and has not been a useful predictor of pathologic nocturnal esophageal reflux.12Peghini P.L. Katz P.O. Bracy N.A. et al.Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors.Am J Gastroenterol. 1998; 93: 763-767Crossref PubMed Scopus (293) Google Scholar, 13Gerson L.B. Triadafilopoulos G. Sahbaie P. et al.Time esophageal pH <4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors.BMC Gastroenterol. 2008; 8: 15Crossref PubMed Scopus (4) Google ScholarData on esomeprazole 40 mg once in the morning for 7 days emphasize this problem; we found the intragastric pH to be 2 or below for 19% of the 24 hours and 40% of the time period between midnight and 7:00 am.14Wang C.C. Yuan Y. Chen Y. et al.Night-time pH holding time: what is hidden by the % of time pH <4?.Am J Gastroenterol. 2008; 103 (no 130): S51Crossref Google Scholar Thus, nocturnal acidification continues to be a key mechanism for refractory GERD; increased nighttime acidity is associated with more severe disease, nocturnal symptoms, sleep disturbance, and obstructive sleep apnea.15Galmiche J.P. Zerbib F. Bruley des Varannes S. Review article: respiratory manifestations of gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2008; 27: 449-464Crossref PubMed Scopus (56) Google Scholar Moreover, a low intragastric pH is relevant in patients who have the potential to reflux, especially those with supine reflux.About 78% of GERD patients experience nocturnal symptoms and show a poor response on standard PPI therapy.16Shaker R. Castell D.O. Schoenfeld P.S. et al.Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association.Am J Gastroenterol. 2003; 98: 1487-1493Crossref PubMed Scopus (361) Google Scholar, 17Tytgat G.N. Are there unmet needs in acid suppression?.Best Pract Res Clin Gastroenterol. 2004; 18: 67-72Crossref PubMed Scopus (19) Google Scholar It is probable that patients with nonerosive reflux disease (NERD) have no better control of nocturnal symptoms, but this has not been studied. A recent review found no significant difference in acid secretory capacity between patients with NERD or erosive esophagitis.18Wang C. Hunt R.H. Precise role of acid in nonerosive reflux disease.Digestion. 2008; 78: 31-41Crossref PubMed Scopus (17) Google Scholar However, in most studies, patients with erosive esophagitis show a better symptom response than those with NERD,19Dean B.B. Gano Jr, A.D. Knight K. et al.Effectiveness of proton pump inhibitors in non-erosive reflux disease.Clin Gastroenterol Hepatol. 2004; 2: 656-664Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar although this has seldom been studied in the same population.20Fass R. Erosive esophagitis and nonerosive reflux disease (NERD): comparison of epidemiologic, physiologic, and therapeutic characteristics.J Clin Gastroenterol. 2007; 41: 131-137Crossref PubMed Scopus (209) Google Scholar Symptom resolution at 4 weeks in response to standard dose DR-PPIs is 70%–80% in those with erosive esophagitis and 20%–30% lower in NERD, which accounts for 50%–85% of patients with reflux.20Fass R. Erosive esophagitis and nonerosive reflux disease (NERD): comparison of epidemiologic, physiologic, and therapeutic characteristics.J Clin Gastroenterol. 2007; 41: 131-137Crossref PubMed Scopus (209) Google Scholar, 21El-Serag H.B. Epidemiology of nonerosive reflux disease.Digestion. 2008; 78: 6-10Crossref PubMed Scopus (67) Google Scholar However, a recent meta-analysis of multicenter studies in well-defined NERD patients contradicts these observations, showing similar responses in each group.22Weijenborg P.W. Cremonini F. Smout A.J.P.M. et al.PPI-therapy is as effective in well-defined NERD patients as in patients with reflux esophagitis: a meta-analysis.Gut. 2011; 60: A37Google Scholar This emphasizes the importance of acid reflux in the true NERD patient, which differentiates them from those with functional heartburn who do not respond to increased acid suppression; the clinical profile is valuable, and further investigation with pH-metry and impedance is controversial.Reflux symptoms are related to the degree and duration of esophageal acid exposure, and PPIs tend to normalize esophageal acidity, leading to improvement in reflux symptoms and healing of erosive esophagitis.23Bell N.J. Burget D. Howden C.W. et al.Appropriate acid suppression for the management of gastro-oesophageal reflux disease.Digestion. 1992; 51: 59-67Crossref PubMed Scopus (537) Google Scholar An intragastric pH ≥4 maintained for at least 16 hours has been generally accepted as the threshold to accelerate healing of erosive esophagitis with acid-suppressing drugs.23Bell N.J. Burget D. Howden C.W. et al.Appropriate acid suppression for the management of gastro-oesophageal reflux disease.Digestion. 1992; 51: 59-67Crossref PubMed Scopus (537) Google Scholar, 24Howden C.W. Burget D.W. Hunt R.H. Appropriate acid suppression for optimal healing of duodenal ulcer and gastro-oesophageal reflux disease.Scand J Gastroenterol Suppl. 1994; 201: 79-82Crossref PubMed Scopus (41) Google Scholar, 25Hunt R.H. Importance of pH control in the management of GERD.Arch Intern Med. 1999; 159: 649-657Crossref PubMed Scopus (159) Google Scholar With a standard dose DR-PPI for 5–8 days, the % time pH ≤3 ranged from 27.8%–44.1% and 36.1%–65.7% for the 24-hour and nighttime periods, respectively.26Yuan Y. Hunt R.H. Intragastric pH holding time pH <3 at steady state in healthy volunteers (HV) after once daily PPIs: a predictor for low erosive esophagitis (EE) healing rates?.Gastroenterology. 2009; 136: M1900Google Scholar Any increase in the time for which the pH ≤3 in the 24-hour period is associated with an increased proportion of unhealed erosive esophagitis at 8 weeks. Thus, a holding time of pH ≤3, or perhaps better pH ≤2, might be a more suitable predictor for nonhealing of erosive esophagitis, and prospective studies would be helpful.26Yuan Y. Hunt R.H. Intragastric pH holding time pH <3 at steady state in healthy volunteers (HV) after once daily PPIs: a predictor for low erosive esophagitis (EE) healing rates?.Gastroenterology. 2009; 136: M1900Google ScholarWe have a good understanding of pH, but the threshold required to trigger reflux symptoms and whether this differs from that which results in injury are not clear. Does poorly controlled acid exposure at night perpetuate symptoms and/or mucosal damage? We do know that symptoms are readily reproduced in heartburn sufferers at levels of pH above the “magic threshold” of 4, including pH 5 and 6.27Smith J.L. Opekun A.R. Larkai E. et al.Sensitivity of the esophageal mucosa to pH in gastroesophageal reflux disease.Gastroenterology. 1989; 96: 683-689Abstract Full Text PDF PubMed Scopus (175) Google Scholar Our concept that “acid equals symptoms” is too simplistic, as research into inflammation and the neural network in the distal esophagus now testifies.These observations question whether the criteria for esophageal acid exposure are too insensitive with respect to symptoms. The Johnson–DeMeester criteria (% time of pH <4 for >4.2% of the time)28Johnson L.F. Demeester T.R. Twenty-four-hour pH monitoring of the distal esophagus: a quantitative measure of gastroesophageal reflux.Am J Gastroenterol. 1974; 62: 325-332PubMed Google Scholar give equal weight to solutions of pH 4 and pH 1, despite a 1000-fold difference in H+ concentration. However, using these criteria might not be sensitive enough to detect short periods of high acidity because the result is expressed as % of time pH <4, which might hide pH values as low as ≤2 when symptoms or mucosal damage are increasingly likely. New approaches to the expression and definition of acid reflux are required to increase sensitivity and determine the implications of short periods of acidity in the esophagus such as the area under the H+ ion activity time curve18Wang C. Hunt R.H. Precise role of acid in nonerosive reflux disease.Digestion. 2008; 78: 31-41Crossref PubMed Scopus (17) Google Scholar or the integrated acidity.13Gerson L.B. Triadafilopoulos G. Sahbaie P. et al.Time esophageal pH <4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors.BMC Gastroenterol. 2008; 8: 15Crossref PubMed Scopus (4) Google ScholarWe do not know whether the degree or the duration of suppression is the more important parameter of gastric acid inhibition. Symptoms in patients with esophageal hypersensitivity might be triggered by lesser acidity than can be tolerated by control patients, and short durations of acid exposure sensitized the esophagus to perception of weakly acidic and mixed reflux in patients with NERD.29Ribolsi M. Emerenziani S. Caviglia R. et al.Short duration of acid exposure sensitizes the esophagus to perception of weakly acidic and mixed reflux in nonerosive reflux disease (NERD) patients.Gastroenterology. 2008; 134: A593Google Scholar Problematically, acid-mediated reflux symptoms might last minutes or longer, even when the Johnson–DeMeester score is normal, especially in patients on a once daily DR-PPI, when nocturnal acidity is poorly controlled.14Wang C.C. Yuan Y. Chen Y. et al.Night-time pH holding time: what is hidden by the % of time pH <4?.Am J Gastroenterol. 2008; 103 (no 130): S51Crossref Google ScholarSo how does a double-dose PPI perform? Healing studies have not been done, but this regimen does not completely inhibit gastric acid secretion or relieve all persisting reflux symptoms in patients who are taking a PPI. A study has shown that 16% of patients had pathologic esophageal acid exposure on pH monitoring, despite double-dose PPI.30Karamanolis G. Vanuytsel T. Sifrim D. et al.Yield of 24-h esophageal pH and bilitec monitoring in patients with persisting symptoms on PPI therapy.Dig Dis Sci. 2008; 53: 2387-2393Crossref PubMed Scopus (45) Google Scholar However, the authors did not define “double-dose” and whether this referred to twice daily or a twice the usual dose given once daily. Although PPIs are commonly given twice a day to patients not responding to once daily PPI or those with nocturnal symptoms, as in the study reported by Fass et al,6Fass R. Inadomi J. Han C. et al.Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release.Clin Gastroenterol Hepatol. 2012; 10: 247-253Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar little is known of intragastric pH profiles in patients taking a PPI twice daily. Esomeprazole 40 mg twice daily in healthy volunteers still resulted in 15% of the nighttime with intragastric pH ≤4.31Yuan Y. Hunt R.H. Intragastric acid suppressing effect of proton pump inhibitors twice daily at steady state in healthy volunteers: evidence of an unmet need?.Am J Gastroenterol. 2008; 103 (no 128): S50Crossref Google Scholar Thus, in those who reflux, this period of acidity is still some 4-fold longer than the Johnson–DeMeester criteria for acid reflux. In a recent Canadian study of GERD patients refractory to PPI therapy, pH readings with the most strict pH criteria were abnormal in 30% of patients on once daily PPIs and in 25% of those on a twice daily PPI.32Mackalski B.A. Ilnyckyj A. Esophageal pH testing in patients refractory to proton pump inhibitor therapy.Can J Gastroenterol. 2008; 22: 249-252Crossref PubMed Scopus (12) Google ScholarOne of the most important questions is how to manage patients who fail PPI therapy. Unfortunately, there is no agreed definition of PPI failure or how best to determine whether PPI failure is a result of insufficient acid control. Some authors have suggested that failure of heartburn to respond to a twice daily PPI should be the limit for continuing empiric therapy.3Kahrilas P.J. Shaheen N.J. Vaezi M.F. et al.American Gastroenterological Association: American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease.Gastroenterology. 2008; 135: 1383-1391Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar Gastroenterologists should first exclude improper PPI use, dose timing, poor compliance, etc. Fass and Sifrim1Fass R. Sifrim D. Management of heartburn not responding to proton pump inhibitors.Gut. 2009; 58: 295-309Crossref PubMed Scopus (256) Google Scholar have proposed that lack of satisfactory symptomatic response to once daily PPI is sufficient for establishing PPI failure, particularly because there are no approved indications for PPIs to be used twice daily in GERD.With such evidence of unmet clinical need in the current treatment of GERD and similarly in the wider arena of acid-related disorders such as upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drug–related disease, concerns have been increasingly discussed.17Tytgat G.N. Are there unmet needs in acid suppression?.Best Pract Res Clin Gastroenterol. 2004; 18: 67-72Crossref PubMed Scopus (19) Google Scholar, 33Hunt R.H. Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in 2005.Aliment Pharmacol Ther. 2005; 22: 10-19Crossref PubMed Scopus (38) Google Scholar, 34Katz P.O. Scheiman J.M. Barkun A.N. Review article: acid-related disease—what are the unmet clinical needs?.Aliment Pharmacol Ther. 2006; 23: 9-22Crossref PubMed Scopus (54) Google ScholarNew therapies under investigation include drugs that provide a faster onset of action and a more predictable control of acidity over time.35Scarpignato C. Hunt R.H. Proton pump inhibitors: the beginning of the end or the end of the beginning?.Curr Opin Pharmacol. 2008; 8: 677-684Crossref PubMed Scopus (53) Google Scholar, 36Sachs G. Shin J.M. Hunt R. Novel approaches to inhibition of gastric acid secretion.Curr Gastroenterol Rep. 2010; 12: 437-447Crossref PubMed Scopus (61) Google Scholar Improved acid suppression can be achieved by extending the antisecretory effect to provide true control for most of the 24-hour period when required. This can be expected to improve the healing of severe grades of erosive esophagitis and to improve symptom control.35Scarpignato C. Hunt R.H. Proton pump inhibitors: the beginning of the end or the end of the beginning?.Curr Opin Pharmacol. 2008; 8: 677-684Crossref PubMed Scopus (53) Google Scholar, 37Vakil N. New pharmacological agents for the treatment of gastroesophageal reflux disease.Rev Gastroenterol Disord. 2008; 8: 117-122PubMed Google Scholar The new drugs with a longer plasma residence time provide significantly better acid suppression than conventional DR-PPIs, especially during the nighttime,38Hunt R.H. Armstrong D. Yaghoobi M. et al.Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z.Aliment Pharmacol Ther. 2008; 28: 187-199Crossref PubMed Scopus (46) Google Scholar, 39Hunt R.H. Armstrong D. James C. et al.Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers.Am J Gastroenterol. 2005; 100: 1949-1956Crossref PubMed Scopus (76) Google Scholar although therapeutic efficacy has not yet been studied in GERD patients.In conclusion, more than 60 million patients suffer from reflux disease in the U.S., and about 20% are not doing well on their current treatment. Thus, a substantial number of patients fail to respond adequately to standard dose or even twice daily PPI. Their management constitutes a serious challenge, and standard definitions for PPI failure and treatment success are urgently needed. Acid still plays an important role in erosive esophagitis and NERD, and there remain significant questions on the role of acid in pathogenesis and as a target for optimal treatment. Current criteria for esophageal acid exposure are insensitive in respect of symptoms.New approaches must individualize therapy to best address the unmet needs and to improve erosive esophagitis healing rates and symptom control across the spectrum of disease. In this way, patients with mild and less frequent symptoms would be treated effectively by shorter-acting acid suppression, and those with severe disease such as those with the higher LA grades, those with Barrett's esophagus, scleroderma, etc would be treated by the new generation of antisecretory therapy. The study by Fass et al6Fass R. Inadomi J. Han C. et al.Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release.Clin Gastroenterol Hepatol. 2012; 10: 247-253Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar starts to address one of the clinical challenges and points us in the right direction. The next chapter is awaited with interest. The apparent superiority of the proton pump inhibitors (PPIs) over the H2-receptor antagonists (H2RAs) in the management of gastroesophageal reflux disease (GERD) has convinced most physicians and payers that these drugs cannot be bettered. However, there is convincing evidence that more than 50% of patients taking a PPI are dissatisfied with their treatment,1Fass R. Sifrim D. Management of heartburn not responding to proton pump inhibitors.Gut. 2009; 58: 295-309Crossref PubMed Scopus (256) Google Scholar and more than 20% take twice daily PPIs or supplement their treatment with over-the-counter remedies.2Chey W.D. Mody R.R. Izat E. Patient and physician satisfaction with proton pump inhibitors (PPIs): are there opportunities for improvement?.Dig Dis Sci. 2010; 55: 3415-3422Crossref PubMed Scopus (31) Google Scholar For these patients who have an unsatisfactory response to once daily PPI, increasing to twice a day (before breakfast and before dinner) is a common practice, as suggested in the 2008 American Gastroenterological Association statement.3Kahrilas P.J. Shaheen N.J. Vaezi M.F. et al.American Gastroenterological Association: American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease.Gastroenterology. 2008; 135: 1383-1391Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar Among patients on PPI twice a day, 39% increased the dose because of poor symptom control at night,2Chey W.D. Mody R.R. Izat E. Patient and physician satisfaction with proton pump inhibitors (PPIs): are there opportunities for improvement?.Dig Dis Sci. 2010; 55: 3415-3422Crossref PubMed Scopus (31) Google Scholar and in a recent U.S. survey of GERD patients taking PPIs, >80% reported severe symptoms at night.4Chey W.D. Mody R. Chen L. et al.Nighttime symptoms and sleep impairment among patients with gastro-esophageal reflux disease (GERD) receiving prescription (Rx) proton pump inhibitors (PPIs).Gastroenterology. 2008; 134: A323-A324Google Scholar In total, 22% of responders were on PPI twice a day, and 42% supplemented prescribed PPIs with over-the-counter PPIs, H2-RAs, or antacids. Not surprisingly, the practice of prescribing PPIs in high dose or twice daily is increasing,5Targownik L.E. Metge C. Roos L. et al.The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use.Am J Gastroenterol. 2007; 102: 942-950Crossref PubMed Scopus (67) Google Scholar despite high dose or twice a day PPIs not being approved for GERD in any jurisdiction. Indeed, it is remarkable that 20 years after their introduction, the PPIs are still marketed and prescribed as “one drug, once a day for all acid related disorders.” This “off-the-peg” approach flies in the face of our understanding of the pathophysiology of the underlying diseases and the fickle pharmacology of the PPIs. Thus, a renewed appreciation of these issues should prompt us to tailor drug therapy as we do in many other diseases. Thus, the large multicenter study conducted in a community setting by Fass et al6Fass R. Inadomi J. Han C. et al.Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release.Clin Gastroenterol Hepatol. 2012; 10: 247-253Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar offers us an opportunity to revisit the use of acid suppression in GERD. These authors have shown that a modified release PPI with an extended plasma residence time, dexlansoprazole-MR, when given once daily was as effective as a PPI twice a day for controlling symptoms in patients with difficult to control reflux disease. It is unfortunate that their study was limited to a single arm and was a single-blinded design, with descriptive analyses for most outcomes. The study would have been improved with a comparator arm, as the authors acknowledge. This would have provided the opportunity for double-blinding and comparison with stepping down to a single dose of the original PPI (or continuing the PPI twice a day). Details of “night-time symptoms” would also have been valuable, and this combined information would have made the authors' conclusions more robust. Studies have shown that stepping down to a PPI once daily is effective in those who were well-controlled on twice a day treatment and did not have erosive disease.7Coté G.A. Ferreira M.R. Rozenberg-Ben-Dror K. et al.Programme of stepping down from twice daily proton pump inhibitor therapy for symptomatic gastro-oesophageal reflux disease associated with a formulary change at a VA medical center.Aliment Pharmacol Ther. 2007; 25: 709-714Crossref PubMed Scopus (19) Google Scholar Importantly, also in this study, we do not see any evidence for dependency and the postulated but poorly evidenced rebound phenomenon.8Howden C.W. Kahril" @default.
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• W1976572732 title "Acid Suppression for Reflux Disease: “Off-the-Peg” or a Tailored Approach?" @default.
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