Letter to the Editor
Could proton pump inhibitors cause cancer? Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.
Expert Rev. Clin. Pharmacol. 7(2), 109–110 (2014)
Paul Rosch New York Medical College, Valhalla, New York 10595, USA and The American Institute of Stress, 9112 Camp Bowie West Blvd. #228 Fort Worth, Texas 76116, USA [email protected]
informahealthcare.com
Response to: Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev. Clin. Pharmacol. 6(4), 443–451 (2013).
There is significant evidence to support the view that long-term use of proton pump inhibitors is contributing to the current epidemic of esophageal adenocarcinoma. As emphasized in this comprehensive review of adverse effects of proton pump inhibitors (PPIs), these drugs are often taken by gastroesophageal reflux disease (GERD) patients for much longer periods than the recommended 4–6 weeks [1]. Not included in these possible complications was esophageal adenocarcinoma, which was rare two or three decades ago, but has had such a dramatic and progressive rise in recent years [2,3] that it has now been described as an ‘epidemic’ [4]. The authors state there is no explanation for this, but the fact that this escalation started with the advent of PPIs in the late 1980s and mirrors their increased sales may be more than coincidence. This popularity may be partially explained by increased self-medication, since they have been available over the counter for the last 10 years. But they are also being prescribed for longer periods of time, especially in patients without GERD in whom biopsies show dysplastic changes consistent with Barrett’s esophagus. These and others with Barrett’s may take PPIs for years, or perpetually, despite the lack of any evidence that PPIs prevent or delay the development of esophageal adenocarcinoma [5]. In point of fact, endoscopic studies show that patients with few or no GERD complaints taking PPIs have higher rates of Barrett’s and esophageal adenocarcinoma than others receiving them for severe GERD symptoms [6].
10.1586/17512433.2014.867233
This seems unusual, since it is generally assumed that these lesions are the result of endothelial irritation from gastric contents or other caustic agents. But such an injury should begin at the surface and develop immediately, and there is no evidence of any such direct response. Animal studies regarding reflux esophagitis induced by esophagoduodenostomy reveal that the earliest sign of esophageal inflammation is an infiltration of the submucosa by white cells that is cytokine-mediated and precedes the development of surface lesions by weeks [7]. This immune system response is supported by transmission electron microscopy, which showed no evidence of inflammation in the esophageal mucosa in response to acute stress, hydrochloric acid, ethanol, aspirin or prednisolone [8]. One possible explanation is that bile and pancreatic enzymes that would have previously been inactivated by hydrochloric acid can irritate and cause metaplasia in esophageal tissue in patients with reflux disease taking PPIs for protracted periods [9]. Achlorhydria is associated with an increased incidence of carcinoid and adenocarcinoma of the stomach, and based on animal studies, one US FDA review stated, “due to genotoxic and tumorigenic potentials associated with esomeprazole and/or omeprazole …, approval of esomeprazole for long term use is not recommended” [101]. Proving a link in humans may be difficult because of the time lag, but gastric carcinoid has been reported in 2 patients taking a PPI for 12–13 years [10]. The FDA also advises
Ó 2014 Informa UK Ltd
ISSN 1751-2433
109
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.
Letter to the Editor
Rosch
that no more than three 14-day treatment courses for approved indications should be used in 1 year, but in one study of patients on long-term therapy, there was no justification for treatment in almost 75% [11]. ICU patients are often given PPIs prophylactically to prevent stress ulcers, and in one report, these were continued following discharge in more than half, despite the absence of symptoms [12]. Another factor contributing to long-term use is that asymptomatic healthy people on PPIs develop dyspepsia and GERD complaints when they try to stop the drug due to rebound acid hypersecretion, which can occur after only 4 weeks [13]. As one editorial noted, “The current finding that these drugs induce symptoms means that such liberal mis-prescribing is likely to be creating the disease the drugs are designed to treat and
2
3
Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev. Clin. Pharmacol. 6(4), 443–451 (2013). Lepage C, Rachet B, Jooste V, Faivre J, Coleman MP. Continuing rapid increase in esophageal adenocarcinoma in England and Wales. Am. J. Gastroenterol. 103(11), 2694–2699 (2008). Poulsen AH, Christensen S, McLaughlin JK et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br. J. Cancer 100(9), 1503–1507 (2009).
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
severity, proton pump inhibitor use, and esophageal carcinogenesis. Arch. Surg. 146(7), 851–858 (2011).
References 1
causing patients with no previous need for such therapy to require intermittent or long-term treatment”. It seems plausible that they may also be contributing to esophageal adenocarcinoma, rather than preventing it.
7
8
Souza RF, Huo X, Mittal V et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 137, 1776–1784 (2009). Zhang DH, Zhou LY, Dong XY et al. Factors influencing intercellular spaces in the rat esophageal epithelium. World J. Gastroenterol. 16(9), 1063–1069 (2010).
9
Rosch PJ. Could proton pump inhibitors cause cancer? Arch. Intern. Med. 170(19), 1775–1776 (2010).
Edgren G, Adami H-O, Vainio EW, Nyren O. A global assessment of the oesophageal adenocarcinoma epidemic. Gut 62, 1406–1414 (2013).
10
Jianu CS, Fossmark R, Viset T et al. Gastric carcinoids after long-term use of a proton pump inhibitor. Aliment. Pharmacol. Ther. 36(7), 644–649 (2012).
5
Triadafilopoulos G. Proton pump inhibitors for Barrett’s oesophagus. Gut 46, 144–146 (2000).
11
6
Nason KS, Wichienkuer PP, Awais O et al. Gastroesophageal reflux disease symptom
4
110
Reimer C, Bytzer P. Clinical trial: long-term use of proton pump inhibitors in primary care patients – a cross sectional analysis of 901 patients. Aliment. Pharmacol. Ther. 30(7), 725–732 (2009).
12
Ladan Mohebbi L, Hesch K. Stress ulcer prophylaxis in the intensive care unit. Proc. Bayl. Univ. Med. Cent. 22(4), 373–376 (2009).
13
Niklasson A, Lindstro¨m L, Simre´n M, Lindberg G, Bjo¨rnsson E. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial. Am. J. Gastroenterol. 105(7), 1531–1537 (2010).
14
McColl KE, Gillen D. Evidence that proton-pump inhibitor therapy induces the symptoms it is used to treat. Gastroenterology 137(1), 20–22 (2009).
Website 101
US FDA. Pharmacology Review – Nexium, 64 (2000). www.accessdata.fda.gov/drugsatfda_docs/ nda/2001/21154_Nexium_pharmr.pdf
Expert Rev. Clin. Pharmacol. 7(2), (2014)
Could proton pump inhibitors cause cancer? Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.
Expert Rev. Clin. Pharmacol. 7(2), 109–110 (2014)
Paul Rosch New York Medical College, Valhalla, New York 10595, USA and The American Institute of Stress, 9112 Camp Bowie West Blvd. #228 Fort Worth, Texas 76116, USA [email protected]
informahealthcare.com
Response to: Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev. Clin. Pharmacol. 6(4), 443–451 (2013).
There is significant evidence to support the view that long-term use of proton pump inhibitors is contributing to the current epidemic of esophageal adenocarcinoma. As emphasized in this comprehensive review of adverse effects of proton pump inhibitors (PPIs), these drugs are often taken by gastroesophageal reflux disease (GERD) patients for much longer periods than the recommended 4–6 weeks [1]. Not included in these possible complications was esophageal adenocarcinoma, which was rare two or three decades ago, but has had such a dramatic and progressive rise in recent years [2,3] that it has now been described as an ‘epidemic’ [4]. The authors state there is no explanation for this, but the fact that this escalation started with the advent of PPIs in the late 1980s and mirrors their increased sales may be more than coincidence. This popularity may be partially explained by increased self-medication, since they have been available over the counter for the last 10 years. But they are also being prescribed for longer periods of time, especially in patients without GERD in whom biopsies show dysplastic changes consistent with Barrett’s esophagus. These and others with Barrett’s may take PPIs for years, or perpetually, despite the lack of any evidence that PPIs prevent or delay the development of esophageal adenocarcinoma [5]. In point of fact, endoscopic studies show that patients with few or no GERD complaints taking PPIs have higher rates of Barrett’s and esophageal adenocarcinoma than others receiving them for severe GERD symptoms [6].
10.1586/17512433.2014.867233
This seems unusual, since it is generally assumed that these lesions are the result of endothelial irritation from gastric contents or other caustic agents. But such an injury should begin at the surface and develop immediately, and there is no evidence of any such direct response. Animal studies regarding reflux esophagitis induced by esophagoduodenostomy reveal that the earliest sign of esophageal inflammation is an infiltration of the submucosa by white cells that is cytokine-mediated and precedes the development of surface lesions by weeks [7]. This immune system response is supported by transmission electron microscopy, which showed no evidence of inflammation in the esophageal mucosa in response to acute stress, hydrochloric acid, ethanol, aspirin or prednisolone [8]. One possible explanation is that bile and pancreatic enzymes that would have previously been inactivated by hydrochloric acid can irritate and cause metaplasia in esophageal tissue in patients with reflux disease taking PPIs for protracted periods [9]. Achlorhydria is associated with an increased incidence of carcinoid and adenocarcinoma of the stomach, and based on animal studies, one US FDA review stated, “due to genotoxic and tumorigenic potentials associated with esomeprazole and/or omeprazole …, approval of esomeprazole for long term use is not recommended” [101]. Proving a link in humans may be difficult because of the time lag, but gastric carcinoid has been reported in 2 patients taking a PPI for 12–13 years [10]. The FDA also advises
Ó 2014 Informa UK Ltd
ISSN 1751-2433
109
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.
Letter to the Editor
Rosch
that no more than three 14-day treatment courses for approved indications should be used in 1 year, but in one study of patients on long-term therapy, there was no justification for treatment in almost 75% [11]. ICU patients are often given PPIs prophylactically to prevent stress ulcers, and in one report, these were continued following discharge in more than half, despite the absence of symptoms [12]. Another factor contributing to long-term use is that asymptomatic healthy people on PPIs develop dyspepsia and GERD complaints when they try to stop the drug due to rebound acid hypersecretion, which can occur after only 4 weeks [13]. As one editorial noted, “The current finding that these drugs induce symptoms means that such liberal mis-prescribing is likely to be creating the disease the drugs are designed to treat and
2
3
Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev. Clin. Pharmacol. 6(4), 443–451 (2013). Lepage C, Rachet B, Jooste V, Faivre J, Coleman MP. Continuing rapid increase in esophageal adenocarcinoma in England and Wales. Am. J. Gastroenterol. 103(11), 2694–2699 (2008). Poulsen AH, Christensen S, McLaughlin JK et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br. J. Cancer 100(9), 1503–1507 (2009).
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
severity, proton pump inhibitor use, and esophageal carcinogenesis. Arch. Surg. 146(7), 851–858 (2011).
References 1
causing patients with no previous need for such therapy to require intermittent or long-term treatment”. It seems plausible that they may also be contributing to esophageal adenocarcinoma, rather than preventing it.
7
8
Souza RF, Huo X, Mittal V et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 137, 1776–1784 (2009). Zhang DH, Zhou LY, Dong XY et al. Factors influencing intercellular spaces in the rat esophageal epithelium. World J. Gastroenterol. 16(9), 1063–1069 (2010).
9
Rosch PJ. Could proton pump inhibitors cause cancer? Arch. Intern. Med. 170(19), 1775–1776 (2010).
Edgren G, Adami H-O, Vainio EW, Nyren O. A global assessment of the oesophageal adenocarcinoma epidemic. Gut 62, 1406–1414 (2013).
10
Jianu CS, Fossmark R, Viset T et al. Gastric carcinoids after long-term use of a proton pump inhibitor. Aliment. Pharmacol. Ther. 36(7), 644–649 (2012).
5
Triadafilopoulos G. Proton pump inhibitors for Barrett’s oesophagus. Gut 46, 144–146 (2000).
11
6
Nason KS, Wichienkuer PP, Awais O et al. Gastroesophageal reflux disease symptom
4
110
Reimer C, Bytzer P. Clinical trial: long-term use of proton pump inhibitors in primary care patients – a cross sectional analysis of 901 patients. Aliment. Pharmacol. Ther. 30(7), 725–732 (2009).
12
Ladan Mohebbi L, Hesch K. Stress ulcer prophylaxis in the intensive care unit. Proc. Bayl. Univ. Med. Cent. 22(4), 373–376 (2009).
13
Niklasson A, Lindstro¨m L, Simre´n M, Lindberg G, Bjo¨rnsson E. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial. Am. J. Gastroenterol. 105(7), 1531–1537 (2010).
14
McColl KE, Gillen D. Evidence that proton-pump inhibitor therapy induces the symptoms it is used to treat. Gastroenterology 137(1), 20–22 (2009).
Website 101
US FDA. Pharmacology Review – Nexium, 64 (2000). www.accessdata.fda.gov/drugsatfda_docs/ nda/2001/21154_Nexium_pharmr.pdf
Expert Rev. Clin. Pharmacol. 7(2), (2014)
