Now and Future: GERD and Nocturnal Acid Reflux Treatments Aaron M. Clark Amenity Health, Inc. EXECUTIVE SUMMARY With at least 10% of the US population suffering from gastroesophageal reflux disease (GERD) and the majority (89%) of this population also suffering from nocturnal acid reflux, the treatment of GERD and nocturnal acid reflux has become a major topic of discussion for the medical community at large. The dangers posed specifically by nocturnal acid reflux are particularly significant as prolonged esophageal acid exposure has been linked to leading to serious health complications, such as erosive esophagitis, peptic stricture, esophageal ulcerations, Barrett’s esophagus, and adenocarcinoma of the esophagus. Additionally, patients who suffer from nocturnal acid reflux experience a diminished health-related quality of life as sleep deprivation takes its toll health-wise and on productivity in the workplace. The current treatment options for GERD and nocturnal acid reflux include lifestyle changes, medications, and surgery. While lifestyle changes are recommended, Proton Pump Inhibitor (PPI) medications, have become the mainstay of treatment. However, this class of medication has been linked by the FDA with serious health risks. Surgical procedures are often ineffective at providing desired symptom relief and come with negative side effects. Amenity Health developed the Medcline reflux relief system to address this need for nocturnal acid reflux patients. Validated by a clinical study at the Medical University of South Carolina, sleeping on Medcline has been proven to decrease patient esophageal acid exposure without the side effects posed by PPIs and surgery. TM TM 2 Now and Future: GERD and Nocturnal Acid Reflux Treatments SYMPTOMS OF GERD AND NOCTURNAL ACID REFLUX At least 10% of Americans have been diagnosed with gastroesophageal reflux disease (GERD)1. While the most common complaints from those suffering from GERD are of heartburn and acid reflux, there are many less obvious symptoms such as dysphagia (difficulty swallowing), chronic cough, asthma, hoarseness, laryngitis, chronic sinusitis, headaches, and dental erosions2. Symptoms are produced by the abnormal reflux of gastric contents (stomach acid) from the stomach back up into the esophagus3. The majority of GERD sufferers also experience nocturnal acid reflux. In fact, in a survey of 11,685 survey respondents with GERD, 88.9% experienced nighttime symptoms, 68.3% experienced sleep difficulties, 49.1% experienced difficulty initiating sleep, and 58.2% experienced difficulty maintaining sleep4. Symptoms specific to nocturnal acid reflux, include nighttime awakenings caused by coughing or choking, regurgitation of fluid or food, and an acidic/bitter taste. DANGERS SPECIFIC TO NOCTURNAL ACID REFLUX Increased Esophageal Exposure During sleep, the body’s natural defense mechanisms against refluxed stomach contents, including saliva production and swallowing, are greatly reduced5. Also, during the night, though reflux episodes tend to be less frequent than during the day, nighttime episodes are longer in duration6. Both of these factors lead to increased nighttime acid exposure making nocturnal acid reflux, in fact, more serious than daytime acid reflux7. Nocturnal acid reflux has been found to be an underlying risk factor for developing more serious health complications, such as erosive esophagitis, peptic stricture, esophageal ulcerations, Barrett’s esophagus, and adenocarcinoma of the esophagus8. In fact, while the risk of esophageal adenocarcinoma increases eightfold for those suffering with daytime acid reflux symptoms, the risk increases to 11-fold for those with nighttime symptoms9. Esophageal adenocarcinoma is actually the fastest growing cancer in terms of incidence in the United States10. Diminished Health-Related Quality of Life Beyond esophageal damage, nighttime symptoms are very disruptive to sleep, often leading to sleep deprivation. Over time, sleep deprivation takes its toll resulting in a substantially diminished health-related quality of life as compared to those without nighttime symptoms11 . Sleep deprivation causes difficulties in concentration; vision disturbances; slower reaction times; lower capabilities and efficiency of task performance; increased number of errors; and slurred speech. Longer–term health consequences include increased sensitivity to pain; changes in the immune response and hormonal secretion patterns; increased risk of obesity; diabetes; and increases in cardiovascular disease12. The treatment of GERD itself and the secondary consequences of nighttime symptoms as related to sleep deprivation result in a marked economic burden on the healthcare system13. • 30 million in US suffer from GERD • 88.9% experience nighttime symptoms • $75 billion in lost productivity each year Lost Productive Time There are also significant indirect costs to nocturnal acid reflux and GERD in terms of lost productive time. A 2005 study found a 10% reduction in productivity caused by nighttime symptoms and the resultant sleep deprivation. When extrapolated based on 2005 salary data, the study found that based on the estimated 14.5 million people of working age with GERD in the US, this 10% reduction in productivity costs US employers up to $75 billion/year14. TREATMENT OPTIONS Currently within the medical community, there are three main treatment protocols for nocturnal acid reflux and GERD. Treatment aims to relieve symptoms, improve patient healthrelated quality of life, and reduce the potential for developing serious complications from chronic damage to the esophagus. Current treatments include one or more of the following: (a) lifestyle changes, including changes to diet, weight loss, and sleep positioning; (b) medications, including antacids, H2 blockers, PPIs; and/or (c) surgical procedures. Lifestyle Changes Diet and Weight Loss When diagnosing GERD, many doctors will first look at a patient’s diet to determine if there are any changes that can be made to decrease symptoms. It has been found that meals that are smaller and lower in fat tend to create less acid exposure than meals that are larger and higher in fat15. It is often recommended that patients avoid coffee, tea, carbonated 3 beverages, alcohol, citrus fruits, tomatoes, chocolate, mint or peppermint, fatty or spicy foods, onions, and garlic. Because individuals react so differently to food, patients are often asked to pay attention to the foods that seem to trigger symptoms and avoid them as much as possible. Weight loss is also recommended as extra pressure around the abdomen increases acid reflux. Sleep Positioning During sleep the body naturally produces less saliva and swallowing decreases resulting in increased acid clearance time in the esophagus5. Increased acid clearance time means that refluxed stomach acid lingers in the esophagus potentially causing serious erosion and long-term damage. Additionally, when laying flat on the back at night (supine position) gravity cannot help clear acid back to the stomach. Doctors often recommend sleeping at an incline to help with acid clearance time. Traditionally, there are two methods to sleep in an inclined position – head of bed elevation (HOB) or sleeping on a bed wedge. HOB is typically achieved by putting blocks or risers under the bed frame so that the entire head of the bed is elevated. Studies have shown a reduction in nocturnal acid exposure, acid clearance time, and symptom improvement16. Though potentially effective, many who try HOB complain that sliding down throughout the night is a consistent issue and/or their sleep-mate is disturbed17. Another traditional method of achieving elevated sleep positioning is utilizing a bed wedge. Studies have shown that while sleeping on a wedge does produce a decrease in distal esophageal acid exposure, it does not decrease the number of reflux episodes throughout the night17. Critics of this technique site that wedges elevate only the head, rather than the entire upper torso of the body, so it does not give any advantage of gravity in clearing reflux and further may cause neck pain18. As with HOB, patients also have a tendency to slide down the wedge throughout the night. Head of Bed Elevation (HOB) Bed Wedge In looking at both traditional methods, HOB and the use of a bed wedge have been shown to provide similar, but limited, levels of relief17. 4 Many studies have found that GERD patients are more likely to reflux when lying flat on the right side and that acid clearance time is slower when lying on the right side so episodes last longer19. These findings suggest that GERD patients should be advised to sleep on their left side to decrease reflux episodes and the duration of those episodes. Additionally, right-side episodes tend to be more distressing and destructive as they are predominately liquid in nature20. Medications In addition to OTC antacids, there are two classes of medications generally used to treat GERD, both of which act to suppress gastric acid secretion - Proton Pump Inhibitors (PPIs) and Histamine 2 Receptor Antagonist (H2 blockers). Brand names for PPIs include Prilosec®(omeprazole), Prevacid® (lansoprazole), AcipHex® (rabeprazole), Protonix® (pantoprazole), Nexium® (esomeprazole); Zegarid® (omeprazole). Brand names for H2 blockers include Tagamet® (cimetidine), Pepcid® (famotidine), Axid® (nizatidine), and Zantac® (ranitidine). Which medication, or combination of medication used, varies based on severity and individual response to each class of medication. Antacids OTC antacids, such as Tums® or Rolaids®, act to neutralize acid in the esophagus but do not significantly alter overall gastric pH levels21. Additionally, while antacids can provide immediate symptom relief, they do not prevent subsequent heartburn episodes and often offer short-lived relief. Histamine 2 Receptor Antagonist (H2 blockers) Histamine 2 Receptor Antagonist (H2 blockers) block the action of histamine on acid producing cells, thus reducing stomach acid production. H2 blockers have been found to provide long-term symptom control in about 50% of GERD patients, especially those with mild-to-moderate symptoms and also promote esophageal healing in 44–58% of treated patients22. H2 blockers are often prescribed to patients who continue to be symptomatic on standard or double-dose PPIs23. Also, over-the-counter H2 blockers are often used as an on-demand solution because of their rapid effect on symptoms1. Though H2 blockers can provide symptom relief, tachyphylaxis develops quickly, meaning that patients build up a resistance over time so doses have to continue to increase. Patient’s built– up resistance to H2 blockers limits their regular use in clinical practice24. Now and Future: GERD and Nocturnal Acid Reflux Treatments Proton Pump Inhibitors (PPIs) Proton pump inhibitors reduce the production of acid by blocking the enzyme in the wall of the stomach that produces acid. In 2009, more than 119 million PPI prescriptions were written in the US. $13.5 billion is spent on PPIs in the US annually, making them the second biggest-selling drug class after cholesterol lowering agents25. PPIs came onto the market in the 80s and quickly have become the treatment of choice for GERD and nocturnal Acid Reflux due to their profound and consistent inhibitory effect on acid secretion1. Though PPIs do provide symptom relief, they do not provide a long-term cure for GERD. Additionally, recent population-based studies, along with multiple FDA safety announcements, have suggested that long-term PPI use may pose significant health risks to patients. As a result of the risks posed by long-term exposure to PPIs, there is growing interest by patients and physicians alike to discover non-PPI-related therapeutic strategies for GERD1. Treating GERD with PPIs is also problematic in that up to 40% of those on a daily PPI are refractory, meaning they still experience symptoms34. Serious Health Complications with Long-term PPI Use • Increased risk of contracting Clostridium Difficile, a serious and potentially deadly bacterial infection26. • Increased risk of hip, wrist, and spine fractures with high doses or long-term use of prescription PPIs27. • Possible connection to low serum magnesium levels if taken for prolonged periods of time (in most cases, longer than one year). In approximately onefourth of the cases reviewed, supplementation did not improve low serum magnesium levels after the PPI had to be discontinued28. • Possible cause of cardiovascular disease, which may also increase the likelihood of a heart attack29. • Increased risk for vitamin B12 deficiency, which can cause tiredness, weakness, constipation, and a loss of appetite, and more seriously, balance problems, memory difficulties, and nerve problems30. • Increased risk of developing community-acquired pneumonia31. • Increased risk of acquiring microscopic colitis32 leading to chronic diarrhea. • Increased incidence of small intestinal bacterial overgrowth (SIBO)33. This ineffectiveness has also been found specifically in nocturnal acid reflux patients as well. A survey of over 600 GERD patients on PPIs found that the majority of patients continued to experience heartburn, with 83% experiencing nocturnal symptoms and 32% reporting severe or very severe nocturnal symptoms35. It has also been found that even when doses of PPIs are increased, patients continue to experience less than satisfactory symptomatic response36. The estimated cost per person, per year of patients on a oncea-day PPI is $2,000 to $4,500 for brand name prescription PPIs37. Surgical Treatments for GERD For patients who are unresponsive to lifestyle changes and drug therapy, surgery is often explored. While other medical procedures have been developed, such as Transoral Incisionless Fundoplication (TIF), Radio-Frequency Ablation, and Stretta® therapy, the most common surgery performed is called Nissen Fundoplication. Nissen Fundoplication During this laparoscopic procedure, the surgeon wraps the top part of the patient’s stomach around the lower part of the esophagus attempting to tighten the lower esophagus to prevent acid from refluxing from the stomach back into the esophagus. The tightening of the lower esophagus, creating what is often referred to as a “one way valve,” often leads to unintended consequences. In fact, after the procedure, 60% of patients developed new symptoms, such as dysphagia, choking, epigastric pain, gas/bloating, inability to belch, nausea, and/or diarrhea38. Additionally problematic is that fact that follow up studies have found that 40% of Nissen Fundoplication patients had symptoms return, had esophagitis come back, needed medicine for recurrent symptoms, and/or needed another operation after seven years39. The estimated cost of a Nissen Fundoplication procedure is $18,000. LINX® Reflux Management System Another surgical option for patients who are unresponsive to lifestyle changes and medications is the LINX® Reflux Management System. The LINX® device (which consists of a series of titanium beads, each with a magnetic core, connected together with titanium wires to form a ring shape) is surgically implanted around the lower end of the esophagus. The device opens as food is digested down into the stomach, then tightens up so that stomach contents cannot reflux back up into the esophagus. 5 The average LINX® surgical procedure is $15,000 - $20,000. AMENITY HEALTH OFFERS MEDCLINE™ TO TREAT NOCTURNAL ACID REFLUX Medical research suggests that developing new therapeutic strategies for GERD, in lieu of indefinite or high-dose PPI treatments or invasive surgical procedures, should be a high priority for pharmaceutical and medical device companies1. Amenity Health developed Medcline™ to address this need. Medcline™ is the much needed treatment alternative for nocturnal acid reflux. The Medcline™ reflux relief system (see Figure 1) leverages proven techniques for nighttime symptom relief and protection against the serious health complications associated with long-term esophageal acid exposure. Its patented Cradle-Loc™ design places patients in an ideal sleeping position with their entire torso elevated and gently holds them on their left side for maximum results. 15-20˚ Figure 1: Medcline™ is comprised of an ergonomic incline base and companion body pillow. Under the direction of Donald O. Castell, MD, the Medical University of South Carolina conducted a study to validate the effectiveness of Medcline™. The study compared Medcline™ to a traditional bed wedge and found that when users slept on their left side, Medcline™ provides41: • 87% reduction in esophageal acid exposure time (see Figure 2) • 38% reduction in nighttime acid reflux episodes • 2x more comfort than a wedge Medcline™ is a Class I Medical Device listed with the FDA 6 4% 3% Percent Time pH < 4.0 The most common patient complaint following the LINX® procedure include difficulty swallowing (76 events in 68 patients). The second most common complaint is pain (25 events in 24 patients)40. Additionally, patients who have the LINX® device must not be exposed to, or undergo, Magnetic Resonance Imaging (MRI) as this could cause serious injury to the patient, as well as damage to the device. 2% 1% 0 Medcline™ Sleep Assist Device Bed Wedge Figure 2: Medcline™ shows significantly less esophageal acid exposure compared to a traditional bed wedge. and cleared for patient use. Medcline™ also meets the IRS Guidelines to be classified as an FSA/HSA-approved medical expenditure. Patients can purchase Medcline™ directly from Amenity Health. Looking Ahead Medcline™ is currently being utilized in a clinical study with Cleveland Clinic. This study aims to quantify health-related quality of life improvements when sleeping on Medcline™, as well as accessing patients’ ability to decrease medication usage over time. In addition to patients with a GERD or nocturnal acid reflux diagnosis, Amenity Health is continually researching new applications for Medcline™, including thoracic patients for lung transplants and idiopathic pulmonary fibrosis (IPF); scleroderma patients; non-tuberculosis mycobacteria patients; esophagectomy recovery patients; and silent reflux patients. Now and Future: GERD and Nocturnal Acid Reflux Treatments References 1 Hershcovici,Tiberiu, Fass, Ronnie. Gastro-oesophageal reflux disease, beyond proton pump inhibitor therapy. 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