ISSN: 2469-584X McCullough. J Clin Gastroenterol Treat 2020, 6:072 DOI: 10.23937/2469-584X/1510072 Volume 6 | Issue 1 Journal of Open Access Clinical Gastroenterology and Treatment REVIEW ARTICLE A Role for Pre-Polymerized Sucralfate in the Management of Erosive and Non-Erosive Gastroesophageal Reflux Disease Ricky Wayne McCullough, MD, ScM, FAcadTM1,2* 1Translational Medicine Clinic and Research Center, Storrs, USA Check for 2Department of Internal Medicine and Emergency Medicine, Veterans Administration Medical Center, updates Warren Alpert Brown University School of Medicine, USA *Corresponding author: Ricky Wayne McCullough MD, ScM, FAcadTM, Translational Medicine Clinic and Research Center, 1768 Storrs Road, Storrs Connecticut, 06268, USA; Department of Internal Medicine and Emergency Medicine, Veterans Administration Medical Center, Warren Alpert Brown University School of Medicine, Rhode Island, 02903, USA Abstract Keywords Clinical outcomes from standard sucralfate do not justify Polymerized sucralfate, NERD, GERD, Regulatory dichot- role in the management of erosive and non-erosive gas- omy troesophageal reflux disease. Pre-polymerized sucralfate, sometimes called high potency sucralfate or polymerized cross-linked sucralfate is a new sucralfate formulation rec- Introduction ognized by the US FDA in 2005. Positive clinical data from The superior performance of acid-controlling ther- three randomized controlled trials using pre-polymerized sucralfate for GERD and NERD was first reported in 2014 apies, namely proton pump inhibitors (PPI) and hista- AGA’s Digestive Disease Week (DDW). mine-2 receptor antagonists (H2RA), eroded the early Gastric refluxate contains protonic acid, dissolved bile ac- but tenuous role of sucralfate in the treatment of gas- ids and proteases each of which cause classic mucosal re- troesophageal reflux disease (GERD), which role had actions in the esophageal epithelium. These reactions are resulted from off-labeled use (mission creep) of su- symptomatic but may or may not involve erosions. Pre-po- cralfate’s original prescription indication for duodenal lymerized sucralfate utilizes biophysical means to exclude all three irritants from epithelial mucosa. ulcers. The clinical performance of standard sucralfate dosed at 14 mg per kg (1 gram) four times daily was Being non-systemic, the entire clinical effect of any sucral- fate rests in the surface concentration of sucralfate achieved. inconsist and underwhelmed clinicians and led to its Pre-polymerized sucralfate, presented in 2014 DDW, and exclusion from most clinical guidelines for GERD [1- discussed here, achieves a surface concentration that is 4]. Sucralfate had been largely unimpressive for either 800% greater than standard sucralfate on normal mucosal erosive GERD (eGERD) or for NERD, non-erosive gas- lining and 2,400% greater on inflamed or acid-injured mu- cosa. troesophageal reflux disease. There were two notable exceptions - a trial conducted by Simon, et al. [5] in To understand the biomolecular basis of its clinical effect, this review re-introduces the reader to mucosal barrier, dis- NERD patients using a mucoadherent gel formulation closes the exact site of engagement of sucralfate, and how of sucralfate (twice as potent as sucralfate suspension transient sucralfate-mediated biostructural changes in ex- in terms of retention within gastrointestinal (GI) tract tra-cellular mucin is translated into intra-cellular signaling [6,7] and a trial conducted by Vermieidien, et al. [8] that modules the mucosal reaction to refluxate. using sucralfate suspension for eGERD. In the former A broad-based literature review will not only aid under- study [5], a 14 mg/kg dose of sucralfate gel (1 gram) giv- standing of the molecular basis of sucralfate’s clinical ef- fects, but will also provide context for an informed impres- en twice daily for 42 days resulted in symptom relief for sion of whether pre-polymerized sucralfate has a role in the 71% of NERD patients compared to 29% on placebo. In management of GERD and NERD. the latter study [8], a similar dose of sucralfate suspen- Citation: McCullough RW (2020) A Role for Pre-Polymerized Sucralfate in the Management of Erosive and Non-Erosive Gastroesophageal Reflux Disease. J Clin Gastroenterol Treat 6:072. doi. org/10.23937/2469-584X/1510072 Accepted: March 28, 2020: Published: March 30, 2020 Copyright: © 2020 McCullough RW. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. McCullough. J Clin Gastroenterol Treat 2020, 6:072 • Page 1 of 19 • DOI: 10.23937/2469-584X/1510072 ISSN: 2469-584X sion (1 gram) given four times daily for 56 days resulted quency is known as esophageal reflux hypersensi- in symptomatic relief in 72% of eGERD patients with a tivity syndrome [18]. Non-erosive heartburn that corresponding healing rate of 68%. Given that sucral- is unrelated to reflux episodes is termed functional fate works by coating the mucosa [9], a perception pre- heartburn. Non-erosive heartburn associated with vailed that a its suspension was better than the tablet abnormally frequent reflux is classic NERD as oppose which must dissolve before coating, and (by extension) to functional NERD of esophageal reflux hypersensi- its gel was better than suspension due to mechanical tivity and functional heartburn. retention of sucralfate coating [6,7] by the gel. This per- Symptom perception to acid and mucosal integrity ception implied that the formulation of administered are inextricably linked [19-21] and it so happens that sucralfate could be determinative of its clinical effect. whether erosive GERD, or either of the two functional In 2005, the US Food and Drug Administration (FDA) NERD or classic NERD syndromes, symptomatic reflux is recognized a new formulation sucralfate, pre-polym- associated with some degree of histomorphologic alter- erized sucralfate [10], which it currently regulates as a ations in the esophageal mucosa [22,23]. In essence, re- medical device, a form of a barrier therapy. gardless of clinical phenotype, symptomatic heartburn signals a material breach of esophageal epithelium, if Comparatively, low doses of pre-polymerized su- even the mucosal reaction is cellular and escapes gross cralfate suspension (1.5 gram bid versus 1 gram qid) visible changes in tissue appearance. unexpectedly demonstrated efficacy in both eGERD and NERD patients with 1 week 80% complete healing of Regardless of tissue appearance by endoscopy, eGERD and 4 week 83% reversal of symptomatic NERD these tissue biopsy reveal cellular alterations facili- [11]. tated by reactionary immune events in the mucosa [24-27]. These events are effectuated by pro-inflam- Obviously a review of any plausible role of sucral- matory cytokines [28,29] and present as dilated in- fate in the management of eGERD and NERD requires tercellular spaces within the esophageal epithelium an understanding of how medicinal formulation [22,30]. (namely pre-polymerization) meets and results in clin- ical function. This report will underscore particulars of Afferent innervation of the esophagus by the va- three randomized controlled trials that used low dose gus nerve is a shared characteristic of all Rome IV pre-polymerized sucralfate to achieve positive out- GERD patients [31] and there are differential submu- comes in undifferentiated NERD and in erosive GERD. cosal depths of neurosensory nociception, with affer- But first what is the nature of the disease, and specif- ent pain fibers being more shallow in the proximal ically, what is the pathophysical challenge posed by esophagus [32]. Heartburn sensation arises from fir- GERD against which pre-polymerized sucralfate must ing of sensory neurons in the distal esophagus, and work? In short there are three main irritants in gastric indicates a histochemical disturbance within the mu- refluxate creating two mucosal reactions. cosa which excite submucosal nociceptors [33] and upregulate afferent neurons to release painful neu- The Challenge of Reflux Disease - Several Irri- rokinnins and to elevate hyperalgesia by increasing tants, Several Mucosal Reactions the expression of nociceptors. Nociceptors are in flux Whether erosive or non-erosive, the symptoms and voltage gated receptors classified as acid sensing ion signs of GERD arise from a mucosal reaction to the back- channels (ASIC) [34] and as transient receptor poten- wash of gastric refluxate. Physiologic reflux is asymp- tial vanilloid receptors (TRPV) [35]. These receptors tomatic, endoscopically normal and presumably with- require continual transmucosal flux of ions (positive out histomorphological consequences [12]. Continuous with negative ion exchange) to keep afferent neurons manometric recordings of esophageal pH and show that switched-on during GERD episodes. there are short episodes of acid reflux in the normal The lack of symptom response in some GERD pa- population generally following meals and uncommon- tients to PPI’s, H2RA’s and antacids imply existence of ly at night when recumbent [13-15]. Early observations histochemical processes exclusive of pH. In fact, obser- included that a) Complete absence of lower esophageal vations that both pH-responsive and pH- non-respon- sphincter (LES) pressure was essential for reflux; b) At sive NERD patients exhibit dilated intercellular spaces in low LES any elevation of intrabdominal pressure in- the esophageal