Therapeutic TherapeuticOptions Options FOCUS FOCUS ONON GASTROESOPHAGEAL GASTROESOPHAGEAL REFLUX REFLUX DISEASE DISEASE Gastroesophageal Gastroesophageal refluxreflux disease disease (GERD) (GERD) is oneisof one theofmost the most common common gastrointestinal gastrointestinal disorders, disorders, with an with an estimated estimated prevalence prevalence of 10–20% of 10–20% 1,2 1,2 in developed in developed Western Western countries. countries. WhileWhile somesome refluxreflux of gastric of gastric contents contents into the intoesophagus the esophagus occurs occurs normally, normally, GERDGERD can be can defined be defined as as refluxreflux that causes that causes troublesome troublesome symptoms symptoms and/or and/or esophageal esophageal 1 1 mucosal mucosal injury.* injury.* Despite Despite beingbeing associated associated with low withdiseaselow diseaserelated related mortality, mortality, GERDGERD imposes imposes an important an important burden burden of illness, of illness, with evidence with evidence to suggest to suggest that that health-related health-related quality quality of lifeofislife is worseworse in patients in patients with GERD with GERD than in than in thosethose with diabetes, with diabetes, hypertension, hypertension, 3 3 mild heart mild heart failure, failure, and arthritis. and arthritis. or cause or cause pathologic pathologic refluxreflux include include reduced reduced LES tone, LES tone, hiatalhiatal hernia, hernia, esophageal esophageal peristaltic peristaltic dysfunction, dysfunction, esophageal esophageal hypersensitivity, hypersensitivity, increased increased intragastric intragastric pressure, pressure, and and 1,4,5 1,4,5 delayed delayed gastric gastric emptying. emptying. Several Several medications medications may reduce may reduce LES LES tone (e.g., tone anticholinergic (e.g., anticholinergic agents, agents, benzodiazepines, benzodiazepines, beta-agonists, beta-agonists, dihydropyridine dihydropyridine calcium calcium channel channel blockers, blockers, estrogens, estrogens, nitrates, nitrates, opioids, opioids, progesterone, progesterone, theophylline) theophylline) or cause or cause mucosal mucosal damage damage (e.g., (e.g., bisphosphonates, bisphosphonates, iron preparations, iron preparations, nonsteroidal nonsteroidal anti-inflammatory anti-inflammatory 6 6 drugs,drugs, potassium potassium chloride). chloride). A definite A definite relationship relationship between between GERDGERD and obesity and obesity has been has been 2 2 established. established. Evidence Evidence shows shows that obesity increases increases the risk the risk This article This article provides provides a briefa overview brief overview that obesity of GERD of GERD in adults, in adults, with awith focus a focus on on of reflux of reflux symptoms, symptoms, prolonged prolonged the pharmacological the pharmacological management management esophageal esophageal acid exposure, acid exposure, and and 1 1 of core ofsymptoms core symptoms and complications and complications GERDGERD complications. complications. Increased Increased with prescription with prescription medications. medications. abdominal abdominal pressure pressure is theispivotal the pivotal mechanistic mechanistic factorfactor in obesityin obesity1 1 PATHOGENESIS PATHOGENESIS & RISK & RISK FACTORS FACTORS related related GERD.GERD. Pregnancy Pregnancy is also is also a well-established a well-established GERDGERD risk risk Transient Transient lowerlower esophageal esophageal sphincter sphincter factor. factor. As with As obesity, with obesity, pregnancy pregnancy (LES)(LES) relaxations relaxations represent represent the the is associated is associated with increased with increased primary primary mechanism mechanism responsible responsible intragastric intragastric pressure; pressure; pregnancypregnancy1 1 for gastroesophageal for gastroesophageal reflux.reflux. related related hormonal hormonal changes changes also also resultresult in reduced in reduced LES tone. LES 1,4 tone.1,4 TheseThese relaxation relaxation events events are are triggered triggered by gastric by gastric distension distension and serve and serve to enable to enable gas venting gas venting SYMPTOMS SYMPTOMS & COMPLICATIONS & COMPLICATIONS 1 1 from from the stomach the stomach (belching). (belching). OtherOther factors factors that predispose that predispose to to Heartburn Heartburn and regurgitation and regurgitation are are * the two themost two most typical typical symptoms symptoms of of 1,2 1,2 GERD.GERD. Classic Classic heartburn heartburn manifests manifests as a painful as a painful retrosternal retrosternal burning burning sensation sensation that isthat fairly is fairly brief in brief in duration duration (several (several minutes); minutes); however, however, somesome patients patients describe describe anginaangina1 like chest like chest pain.1 pain. Regurgitation Regurgitation is is characterized characterized by the bybackflow the backflow of of gastric gastric content content into the intomouth, the mouth, not innot association in association with nausea with nausea or or 1 1 retching. retching. Reflux Reflux and heartburn and heartburn are most are most common common during during the day, the day, especially especially postprandially, postprandially, but but 1 1 both both can also can occur also occur nocturnally. nocturnally. Less typical Less typical symptoms symptoms of GERD of GERD include include dysphagia, dysphagia, dyspepsia, dyspepsia, epigastric epigastric pain, pain, nausea, nausea, bloating, bloating, 2 2 and belching. and belching. While While all ofall these of these symptoms symptoms may be may indicative be indicative of of GERD,GERD, they also they overlap also overlap with with 2 2 otherother conditions. conditions. Extraesophageal Extraesophageal manifestations manifestations may include may include chronic chronic cough, cough, asthma, asthma, and laryngitis and laryngitis accompanied accompanied by hoarseness, by hoarseness, although although establishing establishing that such that such problems problems are caused are caused by GERD by GERD may may 1,2 not be not possible. be possible. It is1,2currently It is currently unclear unclear whether whether a trueaassociation true association existsexists between between GERDGERD and pharyngitis, and pharyngitis, sinusitis, sinusitis, pulmonary pulmonary fibrosis, fibrosis, recurrent recurrent 1 1 otitis otitis media, media, or sleep or sleep apnea. apnea. Esophageal Esophageal complications complications associated associated with pathologic with pathologic refluxreflux include include erosive erosive esophagitis, esophagitis, esophageal esophageal stricture, stricture, and Barrett’s and Barrett’s A broader * A broader definition definition proposed proposed in the 2013 in the guidelines 2013 guidelines for the for diagnosis the diagnosis and management and management of GERD offrom GERD the from American the American CollegeCollege of Gastroenterology of Gastroenterology is as follows: is as follows: “GERD “GERD 2 should be should defined be defined as symptoms as symptoms or complications or complications resulting resulting from the from reflux theofreflux gastric of contents gastric contents into theinto esophagus the esophagus or beyond, or beyond, into theinto oralthe cavity oral(including cavity (including larynx) or larynx) lung.”or lung.”2 THERAPEUTIC THERAPEUTIC OPTIONS OPTIONS JANUARY/FEBRUARY/MARCH JANUARY/FEBRUARY/MARCH 2014 2014 I I esophagus (the replacement of normal squamous mucosa by potentially precancerous metaplastic columnar cells).1,4,5 In addition, patients with GERD are at increased risk of esophageal adenocarcinoma.4 CLASSIFICATION & DIAGNOSIS Gastroesophageal reflux disease can be classified according to the presence or absence of esophageal injury on endoscopic examination. When no esophageal abnormalities or erosions are present, as is the case in most instances, patients are said to have non-erosive reflux disease (NERD; also referred to as endoscopynegative reflux disease).1-3 If endoscopy shows mucosal damage, erosive reflux disease, or erosive esophagitis, is said to exist.1,2 A diagnosis of GERD is generally established using some combination of symptom presentation, endoscopy, ambulatory reflux monitoring, and response to antisecretory drug therapy.2 In many instances, a presumptive diagnosis of GERD is based on the presence of typical symptoms of heartburn and regurgitation.2 Further details and recommendations regarding diagnosis are available in the 2013 guidelines for the diagnosis and management of GERD from the American College of Gastroenterology (ACG)2 (see References, below, for URL). MANAGEMENT Nonpharmacological Interventions Lifestyle and dietary modifications often recommended for patients with GERD are summarized in Box 1. It is notable that, with the exception of elevation of the head of the bed, evidence for the efficacy of these interventions does not come from randomized controlled trials.2 It is also worth mentioning that smoking cessation, while sensible to recommend for overall health benefits, has not been shown to improve GERD symptoms or esophageal pH in clinical studies.2 Pharmacotherapy Medications that suppress gastric acid are the mainstay of treatment for GERD.4 The primary therapeutic alternatives include antacids and alginates, histamine2-receptor II Box 1 – Lifestyle and dietary interventions for GERD1,2,5 Weight loss • Recommended for patients who are overweight (BMI of 25.0–29.9) or obese (BMI ≥30), or for patients whose symptom onset was concurrent with weight gain within the normal BMI range (18.5–24.9) Head of bed elevation • Recommended for patients with nocturnal symptoms Avoidance of late evening meals (i.e., 2–3 hours before bedtime) • Recommended for patients with nocturnal symptoms Elimination of specific foods/beverages • Routine global elimination of foods and beverages that have been reported to cause symptoms (e.g., chocolate, mint, coffee/ tea/caffeinated beverages, carbonated beverages, alcohol, acidic or spicy foods, fried/fatty foods) is not recommended; however, it is reasonable to suggest avoiding specific foods and beverages that, in the patient’s experience, trigger symptoms Consumption of smaller/more frequent meals • Suggested by some experts for postprandial symptoms Avoidance of lying down after meals • Reasonable to suggest if postprandial recumbency brings about symptoms BMI = body mass index; GERD = gastroesophageal reflux disease antagonists (H2RAs), and proton pump inhibitors (PPIs). The choice of drug depends on the severity and frequency of symptoms, as well as the presence or absence of esophageal mucosal injury.4 esophagitis, and for maintenance of symptom control and healing.1,3-5 Still, H2RAs may be reasonable for selected patients with nonerosive disease,4 especially if cost is a significant concern. Dosing recommendations and other pertinent information about antisecretory medications used to treat GERD are presented in Table 1. According to the ACG guidelines,2 a PPI is recommended to treat extraesophageal symptoms in patients who also have typical symptoms of GERD. In the absence of typical GERD symptoms, though, the guidelines suggest considering reflux monitoring prior to a trial of PPI therapy.2 Initial Treatment For patients with mild and infrequent symptoms, as-needed treatment with over-the-counter antacids, alginates, and low-dose H2RAs is often sufficient.1,3 When choosing between antacids and H2RAs, it should be kept in mind that antacids have a quicker onset of action, whereas H2RAs have a longer duration of action.4 Regular treatment with standard-dose H2RAs is an option for patients with frequent mild symptoms and non-erosive disease.4 In patients with moderate to severe symptoms, and those with erosive esophagitis, PPI treatment is generally considered first-line therapy.1-4 PPIs are superior to H2RAs with respect to reduction of heartburn and healing of Assessment of symptomatic response to antisecretory therapy should generally take place after four to eight weeks.3 However, it should be kept in mind that the proportion of patients whose symptoms respond to therapy may continue to increase up to 16 weeks.3 When there is partial, but inadequate, response to therapy with a course of standard-dose PPI given once daily, good adherence and proper administration (see Table 1) should be verified. After these variables are ruled out as causes for lack of response, THERAPEUTIC OPTIONS JANUARY/FEBRUARY/MARCH 2014 Table 1. Antisecretory medications for GERD1-7 Drug Standard Oral Adult Dosea Commentsb Histamine2-receptor antagonists Cimetidine 600 mg twice daily Famotidine 20 mg twice daily Nizatidine 150 mg twice daily Ranitidine 150 mg twice daily • All H2RAs are similarly effective in GERD, and are less effective than PPIsc • Generally reserved for treatment of mild and infrequent (e.g., <3 times/week) symptoms in patients with NERD Proton pump inhibitors Dexlansoprazole 30 mg once daily Esomeprazole 20 mg once daily Lansoprazole 30 mg once daily Omeprazole 20 mg once daily Pantoprazole 40 mg once daily Rabeprazole 20 mg once daily • All standard-dose PPIs are similarly effective in GERD, and are more effective than H2RAsc • Complete symptom relief with PPIs can be expected in ~70–80% of patients with erosive reflux disease and ~60% of patients with NERD; others may obtain partial relief • An 8-week course of therapy is recommended in the ACG guidelines for both symptom relief and healing of erosive esophagitisd • PPIs should generally be administered 30–60 minutes before the first meal of the day to ensure maximal pH control and efficacy;e the product monograph for dexlansoprazole indicates it may be administered without regard to food • Maintenance therapy should be titrated to the lowest dose that provides effective symptom control; dosing may be “continuous”,f “intermittent”,f or “on-demand”;f periodic reassessment of the need for continued therapy is recommended ACG = American College of Gastroenterology; GERD = gastroesophageal reflux disease; H2RA = histamine2-receptor antagonist; NERD = non-erosive reflux disease; PPI = proton pump inhibitor a. For proton pump inhibitors, quoted standard doses are from the RxFiles Drug Comparison Charts6 and are based on a report from the Canadian Agency for Drugs and Technologies in Health.8 Other references3,5 cite a higher standard dose for esomeprazole (40 mg). For dexlansoprazole and esomeprazole, monograph-approved daily doses for healing of reflux esophagitis are twice those listed (i.e., dexlansoprazole 60 mg, esomeprazole 40 mg).7 b. It is notable that comments do not focus on safety aspects of the treatment options, including use during pregnancy; however, online guidelines 2 and other sources5 provide a more detailed discussion of this subject matter (see References, below, for URLs). c. Several references2,3,5 cite a large meta-analysis that demonstrated superior erosive esophagitis healing rates for PPIs compared with H2RAs (84% vs. 52%). Some data indicate esomeprazole 40 mg/day results in small improvements (~4%) in healing rates compared with other PPIs; however, the clinical relevance of such differences is debatable and results have not been consistently replicated. 2,3 The RxFiles Drug Comparison Charts6 report that there are no clinically important differences among standard doses of PPIs for treatment of esophagitis or NERD, noting that patient variation in response may be seen. d. When dosing is increased to twice daily administration due to inadequate response, 8-week courses of therapy are recommended by some experts prior to repeat symptom assessment.1 e. Once daily therapy administered prior to the evening meal may be more effective for nocturnal acid control.4 Twice daily therapy should be administered 30–60 minutes before breakfast and dinner.5 f. According to a Canadian consensus conference document on GERD, “continuous” therapy is taken daily for an indefinite period of time; “intermittent” therapy is taken daily for a finite period of time (usually 2–8 weeks); and “on-demand” therapy is taken daily for a period sufficient to resolve symptoms, at which point it is discontinued until symptoms recur.3 Continuous therapy is recommended following peptic stricture dilation to improve dysphagia and reduce the need for repeated dilations.2 a trial of twice daily PPI (i.e., twice the standard dose) may be considered.2,3 Alternatively, switching to a different PPI at the standard dose may improve symptoms, but it should be noted that this approach is based on limited data.2 Adding a bedtime dose of an H2RA to ongoing PPI therapy has been shown to further reduce nocturnal acid secretion; however, data indicate that this effect lasts only a few weeks.1 In addition, concomitant therapy with PPIs and H2RAs has not been supported by studies using THERAPEUTIC OPTIONS JANUARY/FEBRUARY/MARCH 2014 clinical endpoints.3,5 Nonetheless, the ACG guidelines state that bedtime H2RA therapy can be added to daytime PPI therapy in selected patients with objective evidence of night-time reflux, noting that tachyphylaxis of pH control may develop after a month III of therapy.2 As-needed, as opposed to continuous, H2RA dosing may help mitigate tachyphylaxis.2 Prokinetic or promotility agents, either alone or in conjunction with standard therapies, are not recommended for routine initial treatment of GERD.2,3 Neither domperidone nor metoclopramide appear to be very effective for GERD.3 In fact, some evidence suggests they are ineffective.1 Although data for cisapride indicate some benefit in patients with GERD,1,3 the drug is no longer commercially marketed.† Treatment of Refractory Disease No consensus exists as to what constitutes refractory GERD.2 Some experts define refractory GERD as reflux-related symptoms or mucosal lesions not responding to a high dose of PPI1 (e.g., twice daily therapy). In any case, good compliance and proper PPI administration (see Table 1) should be confirmed and optimized as appropriate.2 For patients who have only received standarddose PPI treatment, a trial of twice daily therapy should be considered, especially if there References 1. Bredenoord AJ, Pandolfino JE, Smout AJ. Gastro-oesophageal reflux disease. Lancet. 2013 Jun 1;381(9881):1933-42. 2. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28. Available from: http://gi.org/guideline/ diagnosis-and-managemenof-gastroesophagealreflux-disease/ 3. Armstrong D, Marshall JK, Chiba N, Enns R, Fallone CA, Fass R, Hollingworth R, Hunt RH, Kahrilas PJ, Mayrand S, Moayyedi P, Paterson WG, Sadowski D, van Zanten SJ; Canadian Association of Gastroenterology GERD was partial response to once daily dosing.1,2 A trial of a different PPI is also an option for patients with refractory symptoms.2 Further evaluation and/or diagnostic testing should be considered for PPI non-responders.1,2 Patients with refractory symptoms (despite PPI optimization) who have objective evidence of ongoing reflux as the cause of symptoms should be considered for additional anti-reflux therapies.1,2 Examples of such therapies include surgery and baclofen, which inhibits transient LES relaxations and has been shown to reduce postprandial and nocturnal reflux activity.2,4 The suggested dose of baclofen is 5–20 mg three times daily.2 Clinicians and patients should be aware that central side effects (e.g., drowsiness, dizziness, lightheadedness) are common with baclofen, and that long-term data in patients with GERD are lacking.2,4 Patients in whom all objective testing (e.g., endoscopy, ambulatory reflux monitoring) is negative are unlikely to have GERD and PPI therapy in such individuals should be discontinued.2 Consensus Group. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults – update 2004. Can J Gastroenterol. 2005 Jan;19(1):15-35. Available from: http://farncombe.mcmaster. ca/documents/Armstrongetal. CanJGastroenterol200519115-35.pdf 4. Drugs for peptic ulcer disease and GERD. Treat Guidel Med Lett. 2011 Sep;9(109):55-60. 5. Kahrilas PJ. Clinical practice. Gastroesophageal reflux disease. N Engl J Med. 2008 Oct 16;359(16):1700-7. Author manuscript available from: http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3058591/ pdf/nihms209815.pdf Maintenance Treatment The majority of patients with GERD will require some form of maintenance therapy to control symptoms and/or maintain esophageal healing.3 Indeed, data suggest that 70–100% of patients with esophagitis and approximately 75% of patients with NERD will relapse within six months of treatment discontinuation.3 The ACG guidelines recommend maintenance PPI therapy for patients who have symptoms after a PPI is discontinued, as well as for patients who initially presented with complications, including erosive esophagitis and Barrett’s esophagus.2 Stepdown maintenance therapy with H2RAs is an option for patients with NERD if these agents provide adequate symptom relief.2 The lowest medication dosage and frequency that provide effective control of symptoms should be employed in longterm maintenance therapy.2,3 Dosing strategies may include intermittent or on-demand treatment2,3 (see Table 1). 6. RxFiles Drug Comparison Charts – 9th Edition. Editors: Jensen B, Regier L. Saskatoon, SK: Saskatoon Health Region; 2012. Available from: www.RxFiles.ca 7. Canadian Pharmacists Association. e-CPS [database on the Internet; cited 2013 Oct 16]. Ottawa: Canadian Pharmacists Association; 2013. 8. Canadian Agency for Drugs and Technologies in Health. Evidence for PPI use in gastroesophageal reflux disease, dyspepsia and peptic ulcer disease: scientific report. COMPUS Optimal Therapy Report. 2007 Mar;1(2). Available from: http://www.cadth.ca/ media/compus/reports/compus_ Scientific_Report_final.pdf † Cisapride is available via Health Canada’s Special Access Programme. Disclaimer: The Drug Information and Research Centre (DIRC) of the Ontario Pharmacists Association provides this material to health professionals for informational purposes only. It is provided without warranty of any kind by DIRC and DIRC assumes no responsibility for any errors, omissions or inaccuracies therein. It is the responsibility of the health professional to use professional judgment in evaluating this material in light of any relevant clinical or situational data. IV THERAPEUTIC OPTIONS JANUARY/FEBRUARY/MARCH 2014