Alternative Therapeutic Approaches to Chronic Proton Pump Inhibitor Treatment

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: REVIEWS Alternative Therapeutic Approaches to Chronic Proton Pump Inhibitor Treatment RONNIE FASS The Neuroenteric Clinical Research Group, Southern Arizona VA Health Care System and University of Arizona Health Sciences Center, Tucson, Arizona This article has an accompanying continuing medical education activity on page e40. Learning Objectives At the end of this activity, the successful learner will know the adverse effects of prolonged therapy with PPIs, some of the factors to consider when assessing a patient failing standard PPI therapy, and what the evidence is for factors that are considered to worsen GERD. Chronic consumption of proton pump inhibitors (PPIs) by patients with gastroesophageal reflux disease is very common, primarily because of their potent and profound effect on acid secretion that results in an unsurpassed rate of symptom resolution and esophageal healing. However, there have been a growing number of reports over the past few years about various side effects caused by chronic PPI treatment. Concerns have been raised by patients and physicians alike about the common practice of prescribing PPIs, often more than once daily, on a long-term basis. As a result, there has been a resurgence of interest in alternative therapeutic modalities for chronic PPI treatment. These include novel endoscopic and surgical techniques, as well as other available therapeutic strategies that are likely to be revisited, such as histamine-2 receptor antagonists, intermittent and on-demand PPI treatment, and antireflux surgery, among others. Keywords: Anti-Reflux Medications; GERD; Heartburn. Gastroesophageal reflux disease (GERD) is the most common outpatient gastroenterologic diagnosis in the United States, with a prevalence rate of 10% to 20% and an annual incidence of 0.38% to 0.45% in the Western world. 1 In the United States, 20% of the adult population experiences GERD-related symptoms weekly 2 and 7% experience them daily. 3 GERD significantly reduces healthrelated quality of life and imposes a marked economic burden on the health care system. 4 Acid suppression, most notably with proton pump inhibitors (PPIs), is currently the mainstay of therapy for GERD. Introduction of the PPI class of drugs revolutionized the management of GERD. However, resolution of esophageal mucosal inflammation seems to be much more predictable than resolution of symptoms in patients with GERD who receive PPI treatment. Consequently, failure of PPI treatment to resolve GERD-related symptoms has become the most common presentation of GERD in gastrointestinal practice in the past decade and has driven the use of more than 1 PPI dose per day. In addition, GERD is a chronic, relapsing disorder with periods of exacerbations and remissions. However, none of the currently available antireflux medications for GERD, including PPIs, provides long-term cure of the disorder. As a result, chronic PPI treatment, which in some is life long, has been a favorable therapeutic strategy in clinical practice, further driving PPI use. During a period of only 7 years ( ), treatment of GERD patients with at least double-dose PPIs has increased by nearly 50%. 5 In a recent US survey of 617 GERD patients taking PPIs, 71% used PPIs once a day, 22.2% twice a day, and 6.8% more than twice a day or on an as-needed basis. 6 Approximately 42.1% of all patients supplemented their prescription PPI with other antireflux regimens including over-the-counter (OTC) antacids and histamine-2-receptor antagonists (H 2 RAs). Although more than 85% of patients still experienced GERDrelated symptoms, 72.8% were satisfied or very satisfied with their PPI treatment. 6 A survey by the American Gastroenterological Association in patients with GERD revealed that 38% reported an incomplete response to PPI treatment. 7 Most of the nonresponders supplemented their PPI therapy with other antireflux medications, primarily OTC antacids. In The 2000 Gallup Study of Consumers Use of Stomach Relief Products, 8 36% of patients reported taking nonprescription medication in addition to a prescription medication for GERD. Of those, 56% stated that they use their prescription medication daily but still need to supplement it with nonprescription medication for breakthrough symptoms. Interestingly, 28% stated that only the combination of prescription and nonprescription medications relieves their symptoms, and 24% reported that prescription medication works better in the long run but nonprescription medication acts faster. In the past decade, there has been a growing number of publications reporting diverse adverse events caused by chronic PPI treatment. 9 The adverse events include increased risk of hip, wrist, and spine fractures; community-acquired pneumonia; Abbreviations used in this paper: EE, erosive esophagitis; GERD, gastroesophageal reflux disease; H 2 RA, histamine-2 receptor antagonist; LES, lower esophageal sphincter; NERD, nonerosive reflux disease; OTC, over-the-counter; PPI, proton pump inhibitor; TLESR, transient lower esophageal sphincter relaxation by the AGA Institute /$36.00 doi: /j.cgh

2 April 2012 ALTERNATIVE APPROACHES TO CHRONIC PPI 339 Clostridium difficile colitis; microscopic colitis; bacterial overgrowth; vitamin/mineral/electrolyte deficiencies; fundic gland polyps in the stomach; and rebound acid secretion In addition, concerns also have been raised about the potential of certain PPIs (omeprazole and esomeprazole) to inhibit the antiplatelet effect of clopidogrel when administered concomitantly. 12 Overall, duration and dosing of PPI treatment have been shown to be important risk factors for the aforementioned adverse events. Admittedly, most of these reports were population-based, rather than carefully designed prospective trials. They lacked clear evidence of cause and effect and many showed only modest risk. The growing evidence of overuse of PPIs and concerns about the ever-growing number of newly described adverse events caused by chronic PPI treatment have attracted the attention of physicians, patients, institutions, advocacy groups, and thirdparty payers. There has been increasing interest by both patients and physicians in alternative therapeutic approaches to chronic PPI treatment. The full impact of the recent bad press has yet to be determined regarding prescription-writing patterns and patient compliance with long-term treatment. The increasing number of potential adverse events listed on PPI package inserts is likely to generate patient inquiries about therapeutic alternatives to both long-term PPI use and high-dose PPIs. There is also a potential risk that regulatory agencies may intervene in the future and limit use of PPIs in clinical practice (Table 1). Reducing Expectations Heartburn patients commonly are treated empirically without knowing their underlying phenotypic presentation of GERD. Patients with erosive esophagitis who receive a PPI once daily show healing rates that exceed 85% of all newcomers However, even in this highly responsive group of GERD patients, symptom resolution is still 15% to 20% lower than the expected healing rates. 21,22 Complete symptom resolution was established several decades ago as the desirable clinical end point for antireflux treatment. However, we now recognize that complete symptom resolution Table 1. Alternative Therapeutic Approaches to Chronic PPI Treatment Medical Antacids/Gaviscon Sucralfate Baclofen Prokinetics H 2 RAs PPIs On demand Intermittent Combination with antacids/gaviscon, sucralfate, baclofen, prokinetics, H 2 RA Nonmedical Compliance Lifestyle modifications Endoscopic treatment Antireflux surgery Linx Complementary and alternative medicine Psychological intervention with PPI treatment is difficult to achieve in many patients, even those with erosive esophagitis. Moreover, complete symptom resolution in patients with nonerosive reflux disease (NERD), who account for the majority of GERD patients, also has been an elusive target. Most patients with NERD show mildly abnormal esophageal acid exposure. 23,24 The lower the acid exposure time is in the esophagus, the less likely it is that the NERD patient will respond to a PPI once daily. 25 Studies also have shown that the proportion of NERD patients responding to a standard dose of PPI is approximately 20% to 30% lower than that documented in patients with erosive esophagitis. In a systematic review of the literature, the PPI symptomatic response pooled rate was 36.7% (95% confidence interval, ) in patients with NERD and 55.5% (95% confidence interval, ) in patients with erosive esophagitis. 26 The therapeutic gain was 27.5% in NERD patients as compared with 48.9% in erosive esophagitis patients. Patients with NERD also showed longer lag time to sustained symptom resolution when compared with patients with erosive esophagitis (2- to 3-fold). 26 Moreover, patients with NERD showed similar symptomatic response to half- and full-dose PPIs, unlike patients with erosive esophagitis who showed an incremental increase in healing and symptom resolution. 26 Differences in therapeutic response parameters between NERD and erosive esophagitis patients are primarily owing to the common inclusion of functional heartburn patients into the NERD group. However, even after excluding functional heartburn patients, most NERD patients show only modest abnormal esophageal acid exposure, and their symptomatic response rate to PPI treatment is still lower than that observed in erosive esophagitis patients. Therapeutic studies have shown that between 40% and 60% of NERD patients receiving a PPI once a day achieved complete symptom resolution during the last week of treatment (commonly week 4). In a multicenter, randomized, double-blind, placebo-controlled study, omeprazole 20 mg once daily was compared with placebo for controlling symptoms of 209 patients with NERD. 27 At week 4, 57% of patients in the omeprazole group were free of heartburn, 75% were free of acid regurgitation, and 43% were completely asymptomatic. In another study, NERD patients were randomized to omeprazole 20 mg/d, omeprazole 10 mg/d, or placebo. 25 The study investigators found that at 4 weeks, 46% of the patients treated with omeprazole 20 mg/d, 31% treated with omeprazole 10 mg/d, and 13% of those who received placebo daily reported complete relief of heartburn. Miner et al 28 enrolled 203 patients with NERD who were randomized to either rabeprazole 20 mg once daily or placebo. After 4 weeks, only 56.7% of patients receiving rabeprazole reported satisfactory symptom relief when compared with 32.2% of those receiving placebo (P.008). The aforementioned studies suggest that complete symptom resolution in many patients with NERD, and even those with erosive esophagitis treated with a PPI once daily, is a difficult clinical end point to achieve. Although physicians strive, and patients demand, complete symptom resolution, both have to adjust their expectations when treating GERD-related symptoms. Presently, we have to accept a certain level of residual symptoms, which appear to have a very limited impact on the quality of life of GERD patients treated with a PPI. Rather than chasing residual GERD-related symptoms with increased dosing of PPIs or adding other antireflux medications, the physician should discuss the impact of these symptoms on the patient s everyday activities during a clinic visit. It also is important to educate and adjust

3 340 RONNIE FASS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 4 patient s expectations about symptom improvement versus symptom resolution during PPI treatment. Compliance Assessment of patient compliance with any medication prescribed for GERD-related symptoms is our low hanging fruit. Thus, evaluation of proper compliance and adequate dosing time should be the first management step when assessing patients with heartburn who are not responding to antireflux treatment, before instituting any other intervention. 21 Studies have shown that poor compliance is pervasive among patients in general and specifically those with GERD. Several factors may contribute to patient compliance. These factors include knowledge about the treated disorder and the prescribed drug, perceived severity of symptoms, side effects, number of pills or additional medications, and the patient s age and personality. 22 GERD is primarily a symptom-driven disease, and many patients continue to take medications as long as they experience symptoms. When symptoms resolve, many patients commonly lose the incentive to take their medication, and this leads to discontinuation of treatment. 22 Even with PPI treatment, long-term compliance has been one of the most common causes for PPI failure. In 1 survey, only 55% of GERD patients took their PPI once daily for 4 weeks as prescribed. In contrast, 37% took their PPI for 12 days or fewer in a month. 8 Another study showed that fewer than 50% of patients were compliant with a PPI once daily after 3 months of treatment. 29 Both studies showed that compliance should be assessed before any dose escalation or diagnostic intervention is entertained in patients who failed once-daily PPI. Lifestyle Modifications The value of lifestyle modifications in GERD has been known for a long time (Table 2). However, with the development of potent antireflux treatment, the role of lifestyle modifications in GERD has been questioned. In addition, there is very little evidence in the literature to support most of the proposed lifestyle modifications in GERD. Moreover, many GERD patients fail to adopt lifestyle modifications on a longterm basis. Most importantly, by imposing lifestyle modifications on GERD patients, we may alter their quality of life. However, the value of lifestyle modifications in GERD needs to be revisited because of concerns about the potential adverse effects of long-term use of PPIs. In a systematic review of the various lifestyle modifications, Kaltenbach et al showed that elevation of the head of the bed and weight loss are effective in improving GERD-related symptoms. 30 Many other lifestyle modifications also might have therapeutic value in preventing or ameliorating GERD-related symptoms, but studies are still lacking. In the meantime, patients should be advised to avoid lifestyle activities that appear to trigger their GERD symptoms. 7 Table 2. Risk Factors for Gastroesophageal Reflux Disease: What Is the Evidence? Factor Decrease lower esophageal sphincter pressure Increase intraesophageal ph Worsen GERD symptoms Tobacco B B B Alcohol B (no effect) B B Obesity B B B Coffee and caffeine E E C (no effect) Chocolate B B E Spicy foods E E C Citrus B (no effect) E C Carbonated B E C beverages Fatty foods D B E Mint D E E Recumbent E B B position Right decubitus B B E position Late evening meal E B (no effect) E NOTE. Evidence levels are as follows: A, 1 well-designed randomized controlled clinical trials with consistent evidence; B, cohort or case-control trials, nonrandomized, or uncontrolled clinical trials; C, case reports, flawed clinical trials, population studies; D, expert or investigator opinion; E, insufficient evidence, or trials with significantly conflicting data. Data from Kaltenbach et al. 30 Antacids and Gaviscon Antacids have been around for a long time and have remained very popular among consumers of OTC medications. They primarily are used as needed (on demand) for episodic heartburn, commonly postprandial. Antacids are basic compounds composed of different combinations of acid-neutralizing agents such as aluminum and magnesium hydroxide, calcium carbonate, sodium citrate, and sodium bicarbonate. They provide rapid but transient symptom relief and do not contribute to healing of erosive esophagitis (EE) or prevention of GERD complications. 31,32 Side effects are dose-related and were noted more frequently in the past when these drugs were used extensively to treat peptic ulcer disease. In general, magnesiumcontaining antacids can cause diarrhea, and aluminum-containing antacids can cause constipation. Alginate-based formulations have been used for the symptomatic treatment of heartburn for decades under various brand names including Gaviscon (Reckitt Benckiser, Kingston upon Thames, United Kingdom). Alginate-based formulations usually contain sodium or potassium bicarbonate. In the presence of gastric acid, a foamy raft is created above the gastric contents. The alginate raft can preferentially move into the esophagus in place or ahead of acidic gastric contents during reflux episodes or, alternatively, can physically prevent reflux of gastric contents into the esophagus. 33 The use of antacids or Gaviscon alone is unlikely to replace the need for chronic PPI treatment in many GERD patients. However, PPIs have been prescribed liberally, even for GERD patients with mild symptoms who could be controlled symptomatically with on-demand antacids or Gaviscon. Furthermore, adding antacids or Gaviscon to the treatment regimen of those who failed once-daily PPI may prevent the need for chronic use of more than standard-dose PPI daily in a subset of patients. Thus far, however, we still are devoid of studies showing the value of adding antacids or Gaviscon to GERD patients who failed once-daily PPI as compared with adding placebo.

4 April 2012 ALTERNATIVE APPROACHES TO CHRONIC PPI 341 Sucralfate Sucralfate, an aluminum salt of a sulfated disaccharide, is considered a mucosal protectant that binds to inflamed tissue and creates a protective barrier. It is supposed to block diffusion of gastric acid and pepsin across the esophageal mucosa and inhibit the erosive action of pepsin and possibly bile. Sucralfate stimulates secretion of mucus, bicarbonate, and growth factors implicated in ulcer healing. The binding of this agent to an ulcer base is enhanced at ph values less than 3.5. It has been shown that sucralfate is equally effective as H 2 RAs and alginic acid plus antacids in controlling GERD symptoms in patients with EE However, healing of esophageal inflammation is limited to low grades of EE. Sucralfate seems to be better than placebo in improving symptoms in patients with NERD. 37 Sucralfate has minimal side effects, but it can bind to other drugs if taken simultaneously, although the clinical consequences are negligible. Sucralfate is rarely prescribed today as the sole treatment for GERD, primarily because of its limited efficacy compared with PPIs and the need for multiple dosing (4 times/d). However, it is used commonly for GERD treatment in pregnant women because it has not shown any maternal or fetal adverse events. 38 The specific value of the drug in the refractory GERD patient population remains to be elucidated further. If the use of chronic PPI treatment ever becomes restricted to a specific patient population in the future, the value of sucralfate, primarily as an adjunct to once-daily PPI, may be revisited. Histamine-2 Receptor Antagonists The introduction of the PPI class of drugs led to a sharp decline in prescriptions for H 2 RAs. Studies clearly have shown the superiority of PPIs over H 2 RAs in healing erosive esophagitis and controlling symptoms of patients with GERD. 21 However, because of the growing concern about long-term PPI consumption, the value of H 2 RAs is likely to be re-evaluated for at least certain subsets of GERD patients. H 2 RAs reduce gastric acid output by competitive inhibition of histamine at H 2 receptors on parietal cells. H 2 RAs reduce pepsin output by an unknown mechanism and reduce gastric acid volume as well. 39 As a class, the different H 2 RAs are considered equivalent in suppressing gastric acid output when administered in equipotent doses. The pharmacokinetic differences among the agents seem to be clinically nonsignificant. 40 Although H 2 RAs are effective in controlling basal acid secretion, they are less effective in suppressing postprandial acid secretion. H 2 RAs could be positioned in controlling symptoms and healing of mild to moderate EE (up to 70% of EE patients). In a meta-analysis, the efficacy of 8 weeks of H 2 RA treatment in healing EE was 64% for grade I and 55.5% for grade II. 41 More severe forms of EE require greater acid suppression, which H 2 RAs are less able to provide. Clinical trials with higher doses of H 2 RAs have attempted to address this concern but yielded conflicting results. 42,43 The value of H 2 RAs in NERD scarcely has been studied. However, several studies have shown that between 40% and 50% of NERD patients report symptom relief after receiving an H 2 RA twice daily for 4 weeks. 44,45 One study even suggested that the effect of H 2 RAs on symptom relief of NERD patients was enhanced by the presence of Helicobacter pylori infection. 45 One of the main appeals of H 2 RAs is their use as an ondemand therapy. Their rapid effect on GERD symptoms, which is unsurpassed by any of the currently available PPIs, makes this class of drugs a very popular OTC remedy for many GERD sufferers who never or rarely seek medical attention. H 2 RAs are particularly helpful in relieving postprandial heartburn for up to 12 hours in GERD patients with mild disease. 46 They also are effective in preventing postprandial heartburn if given 30 minutes before a meal. 47 Studies have suggested that the rapid development of tachyphylaxis in patients receiving H 2 RAs on a chronic basis hampers their routine use in clinical practice. 48 Regardless, H 2 RAs appear to be efficacious even if given over a long period of time for a subset of patients with NERD, for patients with mild erosive esophagitis, and specifically for those who wish to use them on demand for postprandial heartburn. Transient Lower Esophageal Sphincter Relaxation Reducers Several transient lower esophageal sphincter relaxation (TLESR) reducers have been under development, including ã- aminobutyric acid B receptor agonists, metabotropic glutamate receptor 5 antagonists, cannabinoid receptor agonists, and 5-hydroxytryptamine 4 agonists. TLESR reducers have been niched primarily as an add-on treatment for patients who failed once-daily PPI. In general, the development of TLESR reducers has met many obstacles, including undesirable sideeffect profile and modest clinical efficacy over placebo. 49 Consequently, further development of many of the aforementioned TLESR reducers has been halted, raising concerns about the future of this class of drugs. However, the fate of these compounds has not yet been sealed, and further development of other TLESR reducers, using lessons of the aforementioned compounds, is likely to proceed with better chances of success. Baclofen, an aminobutyric acid B agonist, reduces TLESR rate (by 40%-60%) and reflux episodes (by up to 48%), increases lower esophageal sphincter (LES) basal pressure, and accelerates gastric emptying. 50 Baclofen has been shown to significantly reduce both weakly acidic and duodenogastroesophageal reflux as well as duodenogastroesophageal reflux related symptoms. 51,52 The main limitations of baclofen include a short half-life and a variety of central nervous system related side effects. Potentially, baclofen can be used as a sole treatment in a subset of patients with mild GERD or as an add-on to a PPI instead of doubling the PPI dose in patients who failed once-daily PPI. Prokinetics Prokinetic drugs have been presumed to improve GERD by increasing LES basal pressure, improving esophageal peristalsis, accelerating esophageal acid clearance, and facilitating gastric emptying. However, the benefit of these compounds in controlling heartburn and healing EE has been relatively modest, primarily owing to a lack of effect on the rate or duration of TLESRs. Moreover, the current use of prokinetic agents has been hampered by side effects that limit their use in GERD. Presently, only metoclopramide, a dopamine-receptor antagonist and a cholinomimetic, is approved in the United States. Other prokinetic agents, such as domperidone, itopride, and mosapride, are not approved. Metoclopramide use in GERD has been greatly limited by modest clinical efficacy and various

5 342 RONNIE FASS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 4 neurologic adverse effects, of which some may not be reversible after drug cessation. 53 On Demand/Intermittent Proton Pump Inhibitor Treatment Another attractive therapeutic strategy for chronic PPI treatment is the administration of the drug intermittently or on demand. Although none of these therapeutic approaches currently are approved in the United States, many GERD patients prefer to consume their PPIs or other antireflux medications on an as-needed basis. 29 This is primarily because treatment for many GERD patients is symptom-driven. In addition, GERD is generally not a progressive disorder, and thus most patients may not require daily PPI. Intermittent therapy is physician-driven and is defined as administration of a short, predetermined course of therapy when symptoms recur (usually 1 or 2 weeks duration). On-demand therapy is patient-driven and is defined as consumption of medical therapy when and during periods that patients desire. Both therapeutic approaches are convenient and cost effective, plus they allow patients to remain in control and decrease the likelihood of rebound of acid secretion. 54,55 Most studies evaluated the value of on-demand and intermittent PPI treatment in patients with nonerosive reflux disease However, these therapeutic strategies also may be considered in patients with mild erosive esophagitis (Los Angeles grades A and B). 60 Studies in patients receiving on-demand standard-dose PPI versus placebo for a period of 6 months have shown a significant decrease in discontinuation of treatment as a result of insufficient heartburn control, lower average consumption of antacids (per week), better quality of life, and overall higher level of satisfaction. 56,57 Similar results have been documented in studies evaluating the value of maintenance intermittent therapy with a standarddose PPI once daily for 1 to 2 weeks at a time. 58,59 Importantly, initial therapy with a PPI followed by on-demand therapy was found to be the most cost-effective approach when compared with other therapeutic strategies, such as step-up (H 2 RA-PPI), stepdown (PPI-H 2 RA), step-in (PPI continuous), as well as others, using a decision-analysis model. 61 Thus far, studies have not compared the type and frequency of adverse events between daily and on-demand/intermittent PPI therapy. However, it is highly likely that these noncontinuous PPI treatment strategies are safer than daily PPI therapy for the long run. Endoscopic Treatment Another therapeutic strategy that may attract our attention once again is intraluminal treatment through endoscopic techniques. The mechanism of action of the endoscopic techniques is detailed in Table 3. However, most of these techniques have failed, primarily because of unacceptable side effects, modest or lack of long-term efficacy, cost, time invested, and lack of reversibility. Presently, 2 of the endoscopic techniques for GERD are under evaluation: EsophyX (EndoGastro Solutions, Redmond, WA) and the Stretta procedure (Mederi Therapeutics, Inc, Greenwich, CT). The transoral incisionless fundoplication system (EsophyX) uses suction and transmural fasteners to affix tissue from the gastroesophageal junction to the fundus and create a neogastroesophageal valve. This potentially can reduce hiatal hernias. Table 3. Mechanisms of Action of Endoscopic Treatments for GERD Decrease proximal migration of acid reflux Decrease TLESR rate Mechanical obstruction of reflux Increase LES basal pressure Decrease esophageal sensitivity Studies have shown that EsophyX increases LES length and resting pressure and normalizes esophageal ph and cardia circumference in GERD patients. 62 In addition, the technique improves GERD-related symptoms, quality of life, and esophageal inflammation, as well as reduces PPI consumption. 62,63 Although follow-up evaluation has been limited to 2 years, few studies reported worrisome side effects. Thus, the technique may provide a longterm solution for patients who elect not to receive chronic PPI treatment. 64 The Stretta procedure uses an endoluminal approach to deliver low-power, temperature-controlled, radiofrequency energy into the gastroesophageal junction. In animal models, LES thickening was observed after radiofrequency application and was associated with a reduction in the frequency of TLESRs, gastroesophageal reflux episodes, esophageal acid exposure, 65 and acid sensitivity. 66 Clinical studies also have shown that the Stretta procedure was effective in improving GERD-related symptoms and quality-of-life assessment as well as reducing the use of antireflux medications over a period of 4 years. 67 Concerns have been raised about neurolysis resulting from the Stretta energy application, lack of reversibility of the technique, and, in some studies, lack of normalization of esophageal acid exposure. However, as with EsophyX, the Stretta procedure, in experienced hands, might serve as an alternative therapeutic strategy to chronic PPI treatment. In general, the potential risks of endoscopic therapies for GERD require careful patient selection and a high level of expertise of those performing these procedures. Antireflux Surgery Antireflux surgery is an effective, long-term therapeutic strategy for GERD that is comparable with medical therapy with a PPI. 68 Antireflux surgery prevents both acid and nonacid reflux, as documented by combined impedance and a phmonitoring technique. 69 There are several proposed mechanisms that explain the efficacy of antireflux surgery in preventing gastroesophageal reflux: (1) reduction of hiatal hernia, (2) restoration of the intra-abdominal portion of the esophagus and consequently the angle of His and the lower esophageal sphincter flap valve, (3) improvement of sphincteric function of the crural diaphragm, (4) enhancement of the basal LES pressure, and (5) reduction in the rate of TLESRs. 70 Interest in antireflux surgery has declined over the years because of concerns about short- and long-term complications, risk of insufficient symptom relief, reoperation (up to 15%), and recurrence of GERD-related symptoms in up to 62% of the patients undergoing surgery (11 13 years after surgery). 71,72 Predictors for success of antireflux surgery include careful preoperative assessment of the patient, expertise of the surgeon, and symptom relief while on antireflux treatment. 73 A resurgence of interest in antireflux surgery, with a more proactive approach, is highly likely in the near future because of

6 April 2012 ALTERNATIVE APPROACHES TO CHRONIC PPI 343 concerns about long-term PPI treatment. Antireflux surgery is a therapeutic modality that can reduce long-term reliance on PPI treatment. Proper candidates, those who meet the clinical criteria for successful antireflux surgery, should entertain antireflux surgery as an alternative therapeutic strategy for chronic PPI treatment. However, in each individual candidate for antireflux surgery, the benefit of the procedure should outweigh the risk from potential short- or long-term complications. Laparoscopic Sphincter Augmentation Device The Magnetic Sphincter Augmentation device (LINX Reflux Management System; Thorax Medical, Shoreview, MN) was developed to augment the LES barrier. 74 The device comprises a miniature spring of interlinked titanium beads with magnetic cores that are placed around the gastroesophageal junction. The magnetic bond between adjacent beads augments sphincter competence. The beads temporarily separate to accommodate a swallowed bolus and allow belching or vomiting, and reapproximate to augment the LES in the closed position. LINX is inserted by a simple standardized laparoscopic procedure that does not alter the anatomy of the cardia. In a feasibility study, 77% and 90% of 44 patients assessed had normal esophageal acid exposure at 1- and 2-year follow-up evaluations, respectively. 75 The GERD health-related quality-of-life scores improved by 85% and 90%, at 1 and 2 years, respectively. Complete cessation of PPI use was reported by 90% of patients at year 1 and by 86% of patients at year 2. Postprocedural dysphagia was present in 43% of the patients, but it disappeared within 3 months of surgery. The LINX represents a novel and highly innovative technique to treat GERD. Although more long-term studies are needed and the safety profile of the device needs to be evaluated further, the LINX could be an alternative solution for GERD patients who require chronic PPI treatment. Acupuncture and Acupressure The role and value of complementary medicine techniques such as acupuncture, Reiki, and Johrei in the treatment of GERD patients is likely to continue to grow in the future. These techniques can be used instead of, or in addition to, chronic antireflux treatment. Results of early studies have been encouraging and suggest a therapeutic potential for GERD patients. In a placebo-controlled study performed in 14 healthy volunteers, electroacupuncture at the neiguan (pericardial meridian) decreased the rate of TLERSs by approximately 40% without a significant effect on LES basal pressure, residual LES pressure during TLESR, and duration of a TLESR. 76 The value of acupuncture also has been evaluated in GERD patients who failed once-daily PPI. 77 When compared with doubling the PPI dose (standard of care), adding acupuncture was significantly better in controlling regurgitation and both daytime and nighttime heartburn. Psychological Therapy The presence of psychological comorbidities increases patients propensity to report GERD-related symptoms. In addition, psychological comorbidity may contribute to patients failure to respond to PPI treatment. 78 In patients with NERD, Table 4. Proton Pump Inhibitor Therapy in 2012 Reassess if patient needs PPI treatment Ensure that patient receives the lowest dose that controls his/her symptoms Consider switching the patient to another PPI or combination with other antireflux modalities instead of doubling the dose Consider alternative approaches if the patient needs chronic PPI treatment Discuss long-term PPI treatment with your patient, including potential adverse events psychological comorbidity plays an important role in disease presentation as compared with patients with erosive esophagitis Various psychological interventions such as cognitive behavioral therapy, muscle relaxation technique, and hypnotherapy should be entertained in these patients, especially those who do not respond to antireflux treatment. It has not yet been determined if psychological intervention should be pursued solely or in combination with antireflux treatment. Regardless, various psychological techniques may help in the future to reduce reliance on high-dose or long-term PPI treatment. Conclusions Because we know that duration and dose of PPI administration increase the likelihood of adverse events, avoiding unnecessary use of this class of drugs should be our first goal. PPIs should be given in the lowest dose that controls the patient s symptoms (Table 4). Escalating PPI dose beyond once daily should be avoided. However, in patients who failed oncedaily PPI, adding antacids, Gaviscon, sucralfate, H 2 RAs, TLESR reducers, or prokinetics should be considered, but only after compliance and lifestyle modifications have been implemented. In patients who require long-term treatment with a PPI to control their symptoms, on-demand or intermittent treatment should be entertained. If possible, other antireflux modalities should be considered as sole treatment including H 2 RAs, antireflux surgery, and even endoscopic treatment for GERD. Overall, in patients who failed PPI treatment, attempts to obtain complete symptom relief with any of the therapeutic modalities available for GERD may not be achievable. It should be recognized that many patients are content with a limited level of symptoms breakthrough. The role of complementary medicine and psychological treatment in reducing reliance on PPI treatment likely will attract more attention in the future. References 1. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastrooesophageal reflux disease: a systematic review. Gut 2005;54: Locke GR 3rd, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112: Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976;21: Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. 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Erosive esophagitis and nonerosive reflux disease (NERD): comparison of epidemiologic, physiologic, and therapeutic characteristics. J Clin Gastroenterol 2007;41: Lee YC, Wang HP, Chiu HM, et al. Comparative analysis between psychological and endoscopic profiles in patients with gastroesophageal reflux disease: a prospective study based on screening endoscopy. J Gastroenterol Hepatol 2006;21: Reprint requests Address requests for reprints to: Ronnie Fass, MD, The Neuroenteric Clinical Research Group, Southern Arizona VA Health Care System, GI Section (111G-1), 3601 S. 6th Avenue, Tucson, Arizona ronnie.fass@va.gov; fax: (520) Conflicts of interest The author discloses the following: Ronnie Fass is a consultant for Takeda, Vecta, Shire, and Xenoport; and a speaker for Takeda and Nycomed. Funding AstraZeneca and Reckitt Benckiser provided research support.