Drugs 2011; 71 (18): 2381-2389 0012-6667/11/0018-2381/$55.55/0
CURRENT OPINION
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Gastro-Oesophageal Reflux Disease Beyond Proton Pump Inhibitor Therapy Tiberiu Hershcovici and Ronnie Fass The Neuroenteric Clinical Research Group, Southern Arizona VA Health Care System, Tucson, AZ, USA Department of Medicine, Section of Gastroenterology, University of Arizona, Tucson, AZ, USA
Abstract
Gastro-oesophageal reflux disease (GORD or GERD) is a very common disorder, and advancement in drug development over the years has markedly improved disease management. Proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD due to their profound and consistent inhibitory effect on acid secretion. However, PPIs do not reduce the number of reflux events and do not provide long-term cure for GERD. In addition, although the safety profile of PPIs is excellent, recent populationbased studies have suggested that long-term PPI use may be associated with a variety of adverse events. They include osteoporosis-related hip and spine fractures, community-acquired and nosocomial pneumonia, various enteric and non-enteric infections, fundic gland polyps and many others. Consequently, there is growing interest by patients and physicians alike in current, as well as future, non-PPI-related therapeutic strategies for GERD. This includes repositioning histamine H2 receptor antagonists and prokinetics in our current GERD therapeutic algorithms and a resurgence of non-medical therapeutic modalities for GERD, such as anti-reflux surgery, endoscopic treatment, alternative and complementary medicine and psychological interventions. Furthermore, there will be renewed efforts in further developing new medical and non-medical therapeutic modalities for GERD.
1. Introduction Gastro-oesophageal reflux disease (GORD or GERD) is the most common outpatient gastroenterological diagnosis in the US, with a prevalence rate of 10–30% and an annual incidence of 0.38– 0.45% in the Western world.[1] In the US, 20% of the adult population experience GERD-related symptoms weekly[2] and 7% daily.[3] GERD significantly reduces health-related quality of life and results in marked economic burden on the healthcare system.[4]
Medical anti-reflux treatment, most notably proton pump inhibitors (PPIs), is the current mainstay of therapy for GERD. The introduction of the PPI class of drugs during the late 1980s revolutionized the management of GERD. Presently, PPIs are the most effective class of drugs in relieving GERD-related symptoms, healing and maintaining remission of erosive oesophagitis, and improving health-related quality of life. Despite the success that PPIs have achieved in treating GERD and GERD-related complications, unmet needs and significant challenges remain.
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Specifically, approximately 10–15% of adult patients with erosive oesophagitis fail to achieve complete healing after 8 weeks of treatment.[5] Moreover, even when continuing the initial healing dose, 15–23% of adult patients with Los Angeles grades A and B, and 24–41% with grades C and D, relapse within 6 months while on treatment. In addition, up to 40% of non-erosive reflux disease (NERD) adult patients remain symptomatic while on standard dose (once daily) PPI therapy.[6] Treatment of extra-oesophageal manifestations of GERD has been a very disappointing clinical experience.[7] Most randomized controlled trials in patients with pharyngeal, laryngeal or pulmonary symptoms suspected to be related to GERD demonstrated lack of or modest benefit of PPI treatment over placebo. Other unmet needs include faster and more effective control of postprandial heartburn, control of volume reflux and acid regurgitation, improvement of heartburn relief during sleep for both erosive oesophagitis and NERD patients, improvement of acid control in Barrett’s oesophagus patients and a more flexible schedule of PPI treatment. Although the safety profile of PPIs is considered to be excellent, recent population-based studies have suggested that long-term PPI use may be associated with a variety of adverse effects. These include increased risk of Clostridium difficile infection; nosocomial and communityacquired pneumonia; enteric and nonenteric infections; hip, wrist and spine fracture; and vitamin and mineral deficiencies, as well as others. Furthermore, there is ongoing controversy about the safety of combining PPIs with antiplatelet agents such as clopidrogel (see section 2). As concerns mount about the safety of chronic acid suppression with PPIs, there is renewed interest in other medical and non-medical therapeutic strategies for GERD. Patients and physicians alike are becoming more interested in non-PPI management of GERD, especially when maintenance treatment is needed. 2. Proton Pump Inhibitor Complications Chronic PPI treatment has been associated with a variety of adverse effects. However, most studª 2011 Adis Data Information BV. All rights reserved.
ies conducted have revealed a modest risk, at best. The reports about PPI-related adverse effects are further compounded by the scarcity of highquality prospective trials. Several recent studies have suggested an association between long-term PPI treatment and nosocomial and communityacquired pneumonia,[8] Clostridium difficile colitis,[9] microscopic colitis[10] and bacterial overgrowth.[11] In addition, several population-based studies have demonstrated an association between long-term PPI consumption and increased risk for osteoporosisrelated spine, wrist and hip fracture. It is likely that, by reducing gastric acid, PPIs interfere with calcium extraction from insoluble compounds that contain calcium, such as calcium carbonate or calcium phosphate.[12] That leads to secondary hyperparathyroidism, which may result in osteoporosis. In addition, it has been suggested that vitamins, minerals and electrolyte deficiencies, rebound acid secretion and gastric polyps may all result from chronic PPI treatment.[12-16] Almost all the existing data regarding the long-term adverse effects of PPI are based on observational, population-based studies that are susceptible to bias and various confounding factors.[12] Consequently, patients who are likely to benefit from PPIs should not be denied them because of concerns about putative adverse effects. However, PPIs should only be prescribed when there is an appropriate clinical indication. Recently, concerns have been raised about the potential for PPIs to reduce the anti-platelet effect of clopidogrel.[17] 3. Medical Therapies 3.1 Histamine H2 Receptor Antagonists
Histamine H2 receptor antagonists (H2RAs) are widely used for the treatment of GERD. H2RAs reduce gastric acid output by competitive inhibition of histamine H2 receptors on the parietal cells. H2RAs reduce pepsin output by an unknown mechanism and also reduce gastric acid volume.[18] As a class, the different H2RAs are considered equivalent in suppressing gastric acid output when administered in equipotent doses. The pharmacokinetic differences among the agents appear to be clinically insignificant.[19] Although H2RAs are effective in Drugs 2011; 71 (18)
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controlling basal acid secretion, they are less effective in suppressing postprandial acid secretion. Standard doses have been proven effective in controlling symptoms and healing mild to moderate erosive oesophagitis. In a meta-analysis, the efficacy of 8-week H2RA treatment in healing erosive oesophagitis was 64% and 55.5% for grade I and II, respectively.[20] The more severe forms of erosive oesophagitis require greater acid suppression, which the H2RAs are less likely to provide. Clinical trials that attempted to address this concern with higher doses of H2RAs have yielded conflicting results.[21,22] The potential effect of H2RAs on the nighttime histamine-driven surge of gastric acid secretion led to the popular use of these drugs at bedtime by patients who continued to be symptomatic on standard- or double-dose PPI therapy.[23] However, tachyphylaxis develops quickly with H2RAs, limiting their regular use in clinical practice.[24] The main appeal of H2RAs is their use as an on-demand therapy. Their rapid effect on GERD symptoms, unsurpassed by any of the currently available PPIs, makes this class of drugs a very popular over-the-counter (OTC) remedy for many GERD sufferers who never seek medical attention. 3.2 Potassium-Competitive Acid Blockers
Potassium-competitive acid blockers (P-CABs), or acid pump antagonists, inhibit gastric H+/K+ATPase in a K+-competitive and reversible manner. These compounds exhibit a fast onset of acidsecretion inhibition by achieving a rapid peak plasma concentration. Moreover, the full effect of gastric acid inhibition is already observed on the first day of administration. Given the pharmacokinetic and pharmacodynamic profile of P-CABs, this class of drug is more likely to be beneficial as an on-demand drug for symptomatic GERD. However, the only compound from this class (AZD8065) that progressed to phase III development demonstrated similar efficacy to esomeprazole in healing and controlling symptoms of patients with erosive oesophagitis.[25] Similarly, there was no difference in heartburn control in NERD patients between AZD8065 and esomeprazole. Several ª 2011 Adis Data Information BV. All rights reserved.
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other P-CABs were associated with severe liver toxicity and so further development was discontinued. Presently, the future of this class of drugs remains unknown. 3.3 Transient Lower Oesophageal Sphincter Relaxation Reducers
Baclofen, a GABAB receptor agonist, reduces the transient lower oesophageal sphincter relaxation (TLESR) rate (by 40–60%) and reflux episodes (by up to 48%), increases lower oesophageal sphincter (LES) basal pressure and accelerates gastric emptying.[26] Baclofen has been shown to significantly reduce both weakly acidic and duodenogastro-oesophageal reflux (DGER) as well as DGER-related symptoms.[27,28] The main limitations of baclofen include a short half-life and a variety of CNS-related adverse effects. Several TLESR reducers are presently under development, including GABAB receptor agonists, metabotropic glutamate receptor 5 (mGluR5) antagonists, cannabinoid receptor agonists and serotonin 5-HT4 receptor agonists. TLESR reducers have been primarily niched as an add-on treatment for patients who failed PPI once-daily therapy. Table I depicts different anti-reflux medications with an effect on TLESR. Arbaclofen placarbil is an actively transported pro-drug of the pharmacologically active R-isomer of baclofen. Arbaclofen significantly reduced the total number of reflux episodes over 12 hours in 44 patients with GERD.[29] The most efficacious dose of arbaclofen (60 mg) significantly reduced acid reflux episodes by 35% and heartburn episodes associated with reflux by 49%. Arbaclofen had a favourable tolerability and safety profile across the evaluated doses, with no significant difference compared with placebo. Recently, the makers of arbaclofen placarbil halted further development due to lack of clinical efficacy in a phase 2B trial. Lesogaberan, a GABAB-receptor agonist that does not cross the blood-brain barrier, was developed with the hope of reducing CNS-related adverse events. Lesogaberan decreased TLESRs by 25%, increased basal LES pressure by 28% and decreased reflux episodes (mostly acidic) by Drugs 2011; 71 (18)
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Table I. Anti-reflux medications that affect lower oesophageal sphincter (LES) function Agents by class
Receptor action
LESP
TLESR
Status
Baclofen
GABAB receptor agonist
Increase
Decrease
Commercially available
R-baclofen
GABAB receptor agonist
Increase
Decrease
Development halted
Lesogaberan
GABAB receptor agonist
Increase
Decrease
Development halted
mGluR5 receptor negative allosteric modulator
No effect
Decrease
Development halted
CB1/CB2 receptor agonist
Increase
Decrease
Investigational
D2 receptor antagonist, cholinomimetic
Increase
Unknown
Commercially available with a ‘black box’ warning due to side effects
Domperidone
D2 receptor antagonist
Increase
Unknown
Commercially available outside the US
Itopride
D2 receptor antagonist and acetylcholine esterase inhibitor
No effect
Decrease
Commercially available outside the US
Mosapride
5-HT4 receptor agonist and 5-HT3 receptor antagonist
Increase
Unknown
Commercially available outside the US
Pumosetrag (DDP733)
5-HT3 receptor agonist
Increase
Decrease
Investigational
CCK-A receptor antagonist
No effect
Decrease
Investigational
GABAB receptor agonists
mGluR5 antagonist ADX10059 Cannabinoids Delta 9-tetrahydrocannabinol (Dronabinol) Dopaminergic agents Metoclopramide
Serotonergic agents
CCK antagonists Loxiglumide
CCK = cholecystokinin; LESP = LES basal pressure; mGluR5 = metabotropic glutamate receptor 5; TLESR = transient LES relaxation.
47%.[30] The clinical value of lesogaberan as an add-on therapy for GERD patients who failed PPI therapy was further investigated in a larger, randomized, double-blind, placebo-controlled trial.[31] After 4 weeks of treatment, the proportion of symptomatic responders (defined as, at most, one 24-hour period with heartburn or regurgitation of not more than mild intensity during the last week of treatment) was significantly higher in the lesogaberan (16%) than in the placebo (8%) group. The proportion of all symptom-free days was 19% in the lesogaberan group versus 10% in the placebo group. Lesogaberan appeared to be safe and well tolerated. Adverse events were similar in both the placebo and the lesogaberan arm. Overall, lesogaberan demonstrated a relatively modest therapeutic effect. Consequently, on 28 October 2010, AstraZeneca terminated further development of this compound. Glutamate is the primary neurotransmitter involved in signalling from visceral primary afferents to the CNS. Peripherally located mGluR5 ª 2011 Adis Data Information BV. All rights reserved.
receptors have been associated with control of TLESRs, making it a potential target for the treatment of GERD.[32] The only mGluR5 antagonist that reached clinical assessment was ADX10059, a potent, selective, negative allosteric modulator. ADX10059 significantly reduced TLESRs and decreased oesophageal acid exposure and the duration of symptomatic reflux episodes.[33] However, the drug was associated with a predictable rise in liver function tests, cases of hepatic failure and CNSrelated adverse events. Consequently, ADX10059 drug development was recently halted. The cannabinoid CB1 receptor has been localized to the neuronal areas involved in triggering TLESRs, and animal studies have confirmed their potential role in the control of TLESRs.[34] Delta 9-tetrahydrocannabinol (dronabinol), a mixed CB1/ CB2 receptor agonist, reduced the occurrence of meal-induced TLESRs and significantly reduced LES basal pressure in healthy subjects but was associated with central side effects, including nausea and vomiting.[35] Rimonabant, a CB1 receptor Drugs 2011; 71 (18)
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antagonist, was also shown to increase LES basal pressure, decrease the rate of postprandial TLESRs and, as a result, decrease postprandial reflux events in healthy volunteers. However, the drug has also been associated with central side effects.[36] Overall, the development of the TLESRreducing class of drugs has hit many obstacles, including undesirable adverse effect profiles and modest clinical efficacy.[37] However, the fate of these compounds has not yet been sealed and further development of other TLESR reducers, using lessons from the aforementioned compounds, is likely to proceed with better chance of success. 3.4 Prokinetics
Prokinetic drugs have been presumed to improve GERD by increasing LES basal pressure, improving oesophageal peristalsis, accelerating oesophageal acid clearance and facilitating gastric emptying. However, the benefit of these compounds in controlling heartburn and healing erosive oesophagitis has been relatively modest, primarily due to lack of effect on the rate or duration of TLESRs. Moreover, the current use of prokinetic agents is hampered by adverse effects that limit their utilization in GERD. Metoclopramide, a dopamine D2 receptor antagonist and a cholinomimetic, has been shown to increase LES basal pressure without significant effect on oesophageal peristalsis and acid clearance. It improves GERD-related symptoms and has a modest effect, if any, on erosive oesophageal healing. Its usage in GERD has been limited by various neurological and psychological adverse effects, some of which may not be reversible after drug cessation.[38] Domperidone is a peripheral dopamine receptor antagonist that does not cross the blood-brain barrier and is better tolerated than metoclopramide. The drug has been shown to be comparable to H2RAs in relieving GERD-related symptoms and healing erosive oesophagitis.[39] Domperidone increases LES basal pressure but has no consistent effect on oesophageal peristalsis. Although its effect on TLESRs has not been investigated, it has been shown to decrease postprandial gastric volume. ª 2011 Adis Data Information BV. All rights reserved.
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Itopride is a new prokinetic agent that acts through inhibition of acetylcholine esterase and as a D2 receptor antagonist. Itopride has been shown to improve GERD-related symptoms and decrease 24-hour oesophageal acid exposure in patients with mild erosive oesophagitis.[40] A recent study in healthy subjects suggested that itopride inhibits the meal-induced rise in TLESRs without significantly affecting oesophageal peristaltic function or LES basal pressure.[41] Although its mechanism of action is not completely understood, itopride probably inhibits the triggering of TLESR by reducing the distention of the proximal stomach. Further studies are needed to elucidate the physiological and clinical effects of itopride in patients with GERD. Mosapride citrate has both 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties. The compound has been shown to improve oesophageal and gastric motility in human subjects and to reduce visceral hypersensitivity in rats.[42] However, basal LES pressure and the number of TLESRs in healthy subjects did not change after treatment with mosapride as compared with placebo.[43] 3.5 Drugs in the Pipeline
Previous experimental studies in animal models have suggested that cholecystokinin (CCK) is involved in triggering TLESRs via stimulation of peripheral CCK-A receptors.[44] Loxiglumide, a CCK-A receptor antagonist, significantly reduced postprandial TLESRs without significantly affecting LES pressure and fundic tone as compared with placebo in healthy volunteers.[45] Pumosetrag (DDP733) is a partial 5-HT3 receptor agonist with gastrointestinal prokinetic activities. Pumosetrag increased LES basal pressure in experimental animal models. In addition, pumosetrag significantly reduced the rate of reflux events and increased the mean amplitude of the distal oesophageal contractions without changing the LES basal pressure in healthy volunteers.[46] Antagonists of transient receptor potential vanilloid 1 (TRPV1) have been a target for drug development as pain modulators in patients with GERD who demonstrate oesophageal hypersensitivity, such as those with NERD or Drugs 2011; 71 (18)
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refractory GERD. AZD1386, a new TRPV1 antagonist, was demonstrated to reduce the threshold of oesophageal pain perception in healthy men.[47] However, AZD1386 had an effect on pain that was due to heat and not due to distension, acid or electrical current. 4. Surgical and Endoscopic Therapies 4.1 Anti-Reflux Surgery
Anti-reflux surgery prevents both acid and nonacid reflux as documented by a combined impedance and pH-monitoring technique.[48] There are several proposed mechanisms that explain the efficacy of anti-reflux surgery in preventing gastrooesophageal reflux: (i) reduction of hiatus hernia; (ii) restoration of the intra-abdominal portion of the oesophagus and consequently of the angle of His and the lower oesophageal sphincter flap valve; (iii) improvement of the sphincteric function of the crural diaphragm; (iv) enhancement of the basal LES pressure; and (v) reduction of the rate of TLESRs.[49] Anti-reflux surgery is an effective long-term therapeutic strategy for GERD and has been shown to be equivalent to medical therapy with a PPI in studies using data that originated from high-volume centres with highly experienced surgeons.[50] However, interest in anti-reflux surgery has declined due to concerns about short- and long-term complications (table II).[51] In addition, one study demonstrated that GERD symptoms recurred in the majority of patients 11–13 years post-anti-reflux surgery.[52] However, interest in anti-reflux surgery will likely rise again due to concerns about the long-term use of PPIs. Table II. Limitations of anti-reflux surgery (reproduced from Schwartz and Smout[51] with permission) Invasive, hospital stay, absenteeism from work
4.2 Endoscopic Treatment
In the last 10 years, various anti-reflux endoscopic procedures have been developed. Overall, these procedures demonstrated only modest, if any, improvement in objective reflux measures. Several of these procedures were abandoned due to lack of efficacy or post-procedural complications, or due to bankruptcy of the company developing the product.[53] Two procedures are currently commercially available: the transoral incisionless fundoplication system (EsophyX) and the radiofrequency application (Stretta procedure). EsophyX uses suction and transmural fasteners to affix tissue from the gastro-oesophageal junction (GEJ) to the fundus and create a neogastrooesophageal valve. This can potentially reduce the size of hiatal hernias. Recent uncontrolled studies demonstrated conflicting results. One study demonstrated that EsophyX increased LES length and resting pressure, improved GERD-related symptoms and reduced PPI use after 12 months followup.[54] However, in another study, a high rate of major complications (16%), patient dissatisfaction (53%) and conversion to laparoscopic Nissen fundoplication (53%) during follow-up were reported in 19 patients with refractory GERD and abnormal pH testing who were treated with EsophyX.[55] The Stretta procedure uses an endoluminal approach to deliver low-power, temperature-controlled radiofrequency energy into the GEJ. In animal models, LES thickening was observed after radiofrequency application and was associated with a reduction in the frequency of TLESRs, gastrooesophageal reflux episodes, oesophageal acid exposure[56] and acid sensitivity.[57] The Stretta procedure proved to be superior to placebo in reducing GERD symptoms and improving quality of life at 6-month follow-up.[58] However, it was not associated with reduction in oesophageal acid exposure or a reduction in PPI use at 6-month follow-up.
Risk of severe early complications: 2–5%; mortality: 0–0.8% Risk of insufficient symptom relief: 10–13% Risk of developing new symptoms (e.g. gas bloating, severe dysphagia, diarrhoea): up to 67% Risk of re-operation: 3–15% Restart of anti-reflux medication: 11–62% High cost
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4.3 Laparoscopic Sphincter Augmentation Device (LINX)
The magnetic sphincter augmentation device (LINX Reflux Management System; Torax Medical, Shoreview, MN, USA) has been developed to augment the LES barrier.[59] The device comprises Drugs 2011; 71 (18)
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a miniature string of interlinked titanium beads with magnetic cores placed around the GEJ. The magnetic bond between adjacent beads augments sphincter competence. The beads temporarily separate to accommodate a swallowed bolus, allow belching or vomiting, and re-approximate 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 the 44 patients assessed had a normal oesophageal acid exposure at 1 and 2 years’ follow-up, respectively.[60] 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. Post-procedural dysphagia was present in 43% of the patients, but it disappeared within 3 months of the surgery. 5. Other Therapies 5.1 Acupuncture and Acupressure
There are limited data to support the value of non-traditional methods, such as acupuncture, in treating patients with GERD. In a placebocontrolled study performed in 14 healthy volunteers, electro-acupuncture at the Neiguan (pericardial meridian) decreased the rate of TLESRs by approximately 40% without significant effect on LES basal pressure, residual LES pressure during TLESR and duration of a TLESR.[61] The value of acupuncture has also been evaluated in GERD patients who failed PPI once daily.[62] When compared with doubling the PPI dose (standard of care), adding acupuncture was significantly better at controlling regurgitation and daytime as well as night-time heartburn. 5.2 Psychological Therapy
Anxiety and depression have been shown to increase reporting of GERD-related symptoms in population-based studies. In addition, response to PPI treatment may be dependent on the level of psychological distress.[63] Thus, psychosocial co-morbidity may play an important role in patients who failed treatment with a PPI. In these patients, ª 2011 Adis Data Information BV. All rights reserved.
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treatment directed towards the underlying psychological abnormality may improve patients’ response to PPI therapy. 6. Conclusions Given the growing concerns regarding safety of chronic acid suppression with PPIs for the treatment of GERD, focus will shift in the future to other medical or non-medical therapeutic strategies. The role of H2RAs, prokinetics, endoscopic treatment and anti-reflux surgery in therapeutic algorithms for GERD will likely be reassessed. The value of alternative treatment modalities for GERD-related symptoms will be reconsidered. In addition, development of new medical and nonmedical therapeutic strategies in lieu of chronic or high-dose PPI treatment may again become a high priority for pharmaceutical and device companies. Acknowledgements Dr Fass has received research support from AstraZeneca and Reckitt-Benckiser and served as a speaker for Takeda, and as a consultant for Shire, Takeda, Vecta and ReckittBenckiser. Dr Hershcovici has no conflicts of interest that are directly relevant to the content of this article. No sources of funding were used in the preparation of this article.
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Correspondence: Dr Ronnie Fass, MD, Professor of Medicine, University of Arizona, Chief of Gastroenterology, Head, The Neuroenteric Clinical Research Group, Southern Arizona VA Health Care System, GI Section (1-111G-1), 3601 S. 6th Avenue, Tucson, AZ 85723-0001, USA. E-mail:
[email protected]
Drugs 2011; 71 (18)
