Therapeutic options for refractory gastroesophageal reflux disease

doi:10.1111/j.1440-1746.2012.07064.x REVIEW Therapeutic options for refractory gastroesophageal reflux disease Ronnie Fass*,† *The Neuroenteric Clinical Research Group, Southern Arizona VA Health Care System, and †Health Sciences Center, University of Arizona, Tucson, Arizona, USA Key words gastroesophageal reflux disease (GERD), heartburn, proton pump inhibitors (PPIs), refractory GERD. Accepted for publication 29 August 2011. Correspondence Ronnie Fass, The Neuro-Enteric Clinical Research Group, Southern Arizona VA Health Care System, GI Section (1-111G-1)3601 S. 6th Avenue, Tucson, AZ 85723-0001, USA. Email: [email protected] Abstract Refractory gastroesophageal reflux disease may affect up to one-third of the patients that consume proton pump inhibitor (PPI) once daily. Treatment in clinical practice has been primarily focused on doubling the PPI dose, despite lack of evidence of its value. In patients who failed PPI twice daily, medical treatment has been primarily focused on reducing transient lower esophageal sphincter relaxation rate or attenuating esophageal pain perception using visceral analgesics. In patients with evidence of reflux as the direct trigger of their symptoms, endoscopic treatment or antireflux surgery may be helpful in remitting symptoms. The role of psychological interventions, as well as non-traditional therapeutic strategies remains to be further elucidated. Conflicts of Interest Ronnie Fass serves as a consultant to Takeda, Vecta, Shire; Given Imaging. Fass has received research support from AstraZeneca and Reckitt Benckiser. The author also serves as a speaker to Takeda and Nycomed. Introduction Gastroesophageal reflux disease (GERD) is very common affecting 20% of the US adult population weekly and 7% daily.1,2 The mainstay of treatment remains proton pump inhibitors (PPIs), the most efficacious (class of drugs) in healing erosive esophagitis, controlling GERD-related symptoms and preventing GERDrelated complications.3,4 However, studies have demonstrated that up to 40% of the heartburn patients reported either partial or complete lack of response to PPI once daily.5–7 The main underlying mechanisms for PPI failure are poor compliance, residual reflux (non-acidic, bile or acidic), functional heartburn and comorbidities (functional bowel disorders, gastroparesis, etc.).8–10 Management of refractory GERD patients remains a very challenging task. Medical and non-medical therapeutic strategies should be considered and tailored, each one to the proper patient population (see Table 1). Utilization of various diagnostic techniques, such as intra-luminal impedance +pH sensor, wireless pH capsule and others may better direct treatment. Lifestyle modifications The specific value of lifestyle modifications in GERD patients who failed PPI treatment has yet to be elucidated. In a recent systematic review of all publications that evaluated the value of lifestyle modifications in GERD patients, the authors determined that only Table 1 Therapeutic options for patients who failed standard dose proton pump inhibitor • Lifestyle modifications • Antireflux medications — Histamin 2 receptor antagonist — Proton pump inhibitor • Transient lower esophageal sphincter reducers — Baclofen • Visceral pain modulators — Tricyclics — Trazadone — Selective serotonin re-uptake inhibitors • Antireflux surgery • Endoscopic treatment for gastroesophageal reflux disease • Alternative and complimentary medicine — Acupuncture • Psychological intervention weight loss and elevation of head of the bed are effective in improving GERD.11 There were no sufficient data to support any of the other commonly practiced lifestyle modifications. Recently, food sensitivity has been suggested to drive some of the refractory GERD cases.12 A diet that excludes identified sensitizing food products led to symptom improvement in a subset of patients. Overall, in patients with persistent heartburn despite PPI Journal of Gastroenterology and Hepatology 27 (2012) Suppl. 3; 3–7 © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd 3 Refractory GERD R Fass treatment, it is reasonable to recommend avoidance of specific lifestyle activities that have been identified by patients or physicians to trigger GERD-related symptoms. Histamine 2 receptor antagonist (H2RA) The potential effect of H2RAs on the night-time histamine-driven surge in gastric acid secretion led to the popular use of these drugs at bedtime by patients who continued to be symptomatic on a standard or double-dose PPI.13 Early studies have shown that the addition of H2RA at bedtime significantly reduced the duration of nocturnal acid breakthrough (NAB) and the number of GERD patients on PPI twice daily who demonstrated NAB.13 The effect on NAB was not different between standard dose and double-dose H2RA. Despite lack of any clinical correlation between the presence of NAB and nocturnal GERD symptoms, the addition of H2RA at bedtime has become common practice in GERD patients who failed PPIs regardless of dosing. However, concerns were raised about the development of rapid tolerance (within 1 week) in patients taking daily H2RA.14 In a study that evaluated 100 patients (58 on twice daily PPI and 42 on twice daily PPI + H2RA at bedtime for at least 1 month), the authors demonstrated that the addition of a bedtime H2RA significantly reduced the percentage time with intragastric pH < 4 during upright, recumbent, and the entire period.15 Unfortunately, the authors failed to provide any evidence for similar effects on clinical end-points. Rackoff et al. evaluated 56 GERD patients on PPI twice daily who were receiving H2RA at bedtime for variable periods of time.16 The authors demonstrated that 72% of the patients reported improvement in overall symptoms, 74% in night-time reflux symptoms, and 67% in GERD-associated sleep disturbances. Proton pump inhibitors Currently, PPIs are the most efficacious treatment for both healing erosive esophagitis and for symptom relief of GERD patients. In those who failed PPI once a day, there are two potential therapeutic strategies that could be utilized in clinical practice. These include switching to another PPI or doubling the PPI dose. However, doubling the PPI dose is by far the most common therapeutic strategy that is used by practicing physicians when managing patients who failed PPI once daily as also recommended by the 2008 American Gastroenterological Association guidelines for GERD.16 The Cochrane review also suggests that doubling the PPI dose is associated with greater healing of erosive esophagitis with the number needed to treat of 25. However, there is no clear dose—response relationship for heartburn resolution in either erosive esophagitis or nonerosive reflux disease (NERD).17 Switching to another PPI is an attractive therapeutic strategy that could be utilized in the management of patients who failed PPI once daily. In several studies, switching patients who failed a PPI to esomeprazole, resulted in a significant symptom improvement.18,19 Switching refractory GERD patients to other PPIs beside esomeprazole has yet to be evaluated, but it would be of great interest. While doubling the PPI dose has become the standard of care, there is no evidence to support further escalation of the PPI dose beyond PPI twice daily either in symptom control or healing of erosive esophagitis. When doubling the PPI dose, one PPI should be given before breakfast and the other before dinner. The support 4 for splitting the dose originates primarily from pharmacodynamics studies demonstrating an improved control of intragastric pH when one PPI is given in the AM and the other in the PM as compared with both PPIs being given before breakfast.20 A recent study suggested that a minority of GERD patients may lose PPI efficacy after 2 years of continuous and unmodified treatment with one or two PPIs per day.21 The sole parameter evaluated in this study was the level of esophageal acid exposure as assessed by pH testing. The authors failed to provide any clinical data to support their physiological findings. In another study, the authors demonstrated that infection with Helicobacter pylori in healthy subjects, who are CYP2C19 extensive metabolizers, eliminated the differences in intragastric pH control between standard and double-dose PPI.22 As with the previous study, the authors did not provide any clinical end-points to support their conclusion. The value of utilizing Dexlansoprazole MR, an R-enantiomer of lansoprazole that also contains the dual delayed release technology, in patients who failed PPI remains to be elucidated.23,24 Potentially, the dual release of the drug that is separated by 4–5 h may be helpful in reducing the number of patients who failed PPI once daily. Transient lower esophageal sphincter relaxation (TLESR) reducers A wide range of receptors have been shown to be involved in triggering TLESR providing us with the opportunity to develop novel reflux inhibitors.25 The most promising among these appear to be the gamma-aminobutyric acid B (GABAB) receptor agonists and metabotropic glutamate receptor 5 (mGluR5) antagonists which can achieve high level of TLESR’s inhibition.25,26 Baclofen, a GABAB agonist, was introduced into the clinical arena as a potential add-on treatment for patients who failed PPI treatment (once or twice daily).27,28 The drug reduced TLESR rate by 40–60%, reflux episodes by 43%, increased lower esophageal sphincter basal pressure, and accelerated gastric emptying.27–29 Baclofen has been shown to significantly reduce duodenogastroesophageal reflux (DGER) and weakly acidic reflux as well as DGER-related symptoms.30,31 In subjects with persistent heartburn despite PPI treatment, doses of up to 20 mg trice daily have been used.31 In addition to its effect on TLESR rate, baclofen appears to be also effective in attenuating pain-associated responses using an experimental rodent model.32 This effect, which appears to be mediated by central mechanisms, could be also used in treating refractory GERD patients, where esophageal hypersensitivity is the leading underlying mechanism. Because the drug crosses the blood–brain barrier, a variety of central nervous system (CNS)related side-effects have been reported. They primarily include somnolence, confusion, dizziness, lightheadedness, drowsiness, weakness, and trembling. The side-effects are likely an important limiting factor in the routine usage of baclofen in clinical practice. Arbaclofen placarbil (also known as XP19986) is a novel transported pro-drug of the pharmacologically active R-isomer of baclofen. The drug is currently in clinical development for the treatment of refractory GERD. Arbaclofen placarbil was designed to be efficiently absorbed in the gastrointestinal tract and rapidly metabolized to release R-baclofen after absorption. Unlike baclofen, arbaclofen placarbil is well absorbed from the colon, allowing the drug to be delivered in a sustained release formulation that may allow less frequent dosing and thus reduced fluctuations Journal of Gastroenterology and Hepatology 27 (2012) Suppl. 3; 3–7 © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd R Fass in plasma exposure. This in turn may lead to potentially improved efficacy through a combination of greater duration of action, subject’s convenience, and better safety profile compared with baclofen.33,34 A recent study demonstrated that arbaclofen significantly reduced the total number of reflux episodes over 12 h in 44 patients with GERD.34 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 favorable 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 new GABAB agonist, with a better CNS safety profile was developed in order to overcome the side-effects of baclofen. The physiological effects of lesogaberan were evaluated in a small group of patients with persistent GERD-related symptoms despite PPI therapy.35 In this placebo-controlled, cross-over study, lesogaberan significantly decreased the rate of TLESRs, increased basal Lower Esophageal Sphincter (LES) pressure, decreased esophageal acid exposure and decreased the number of postprandial reflux episodes. Furthermore, a decrease in the proximal extent of gastroesophageal reflux events was also demonstrated. However, there was no difference in the number of reflux symptom episodes between the two arms of the study. The results of a larger clinical (232 patients), double-blind, placebo-controlled trial that examined the efficacy of lesogaberan as add-on therapy to PPI once or twice daily for refractory GERD patients were recently published in a abstract form.36 The proportion of responders increased from 8% to 16% and the proportion of symptom-free days increased from 21% to 36% after 4 weeks of treatment in the lesogaberan versus placebo group. Overall, lesogaberan was safe and well tolerated. While lesogaberan appear to be a promising future treatment for PPI failure, the aforementioned studies demonstrated only modest effect. Last year, AstraZeneca terminated further development of this compound. Glutamate is the primary neurotransmitter involved in signaling from visceral primary afferents to the CNS. Peripherally located mGluR5 receptors have been associated with control of TLESRs, making it a potential target for the treatment of GERD.26 The only mGluR5 antagonist that reached clinical assessment was ADX10059, a potent, selective, negative allosteric modulator. ADX10059 significantly decreased TLESRs and reduced esophageal acid exposure and improved symptomatic reflux episodes.37,38 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. Visceral pain modulators Thus far, there are no studies that specifically evaluated the value of visceral pain modulators in refractory GERD patients. However, given the fact that most of the patients who fail PPI treatment originate from the NERD group and more than 50% of the PPI failure (twice daily) subjects demonstrate lack of either weakly or acidic reflux, the usage of these agents is highly attractive.39,40 Additionally, it could be argued that even for weakly acidic reflux that has not been shown to be associated with esophageal mucosal damage, visceral pain modulators could be helpful. Pain modula- Refractory GERD tors such as tricyclic antidepressants, trazodone (a tetracyclic antidepressants), and selective serotonin reuptake inhibitors have all been shown to improve esophageal pain in patients with noncardiac chest pain.40–42 It is believed that these agents confer their visceral analgesic effect by acting at the CNS and/or peripherally at the sensory afferent level. The pain modulators are used in non-mood-altering doses, and they presently provide a therapeutic alternative until more novel esophageal-specific compounds are available. In addition, sideeffects are relatively common, and may limit their usage in certain patient populations, like the elderly or those with multiple comorbidities. Other medical therapies The addition of antacids, alginate-based formulations, such as Gavison, and sucralfate to once daily PPI in patients with refractory GERD has yet to be studied.5,6 Similarly, the value of cholestyramine, a bile-acid binder, in improving symptoms of refractory GERD patients has never been assessed.7,8 Botulinum toxin injection In one recent study, botulinum toxin was administered by pyloric injection to 11 patients with refractory GERD and associated gastroparesis.43 Marked improvement in GERD-related symptoms was demonstrated that correlated with improvement in gastroparesis-related symptoms and gastric-emptying scintigraphy. The mean duration of response is approximately 5 months.44 Antireflux surgery A recent surgical study reported that refractory GERD was the most common (88%) indication for antireflux surgery.45 Interestingly, the most common preoperative symptom reported under failure of medical antireflux treatment was regurgitation (54%). Overall, 82% of the patients reported that the preoperative reflux symptom completely resolved, and 94% were satisfied with the results of the surgery. In another study that included only 30 subjects with refractory GERD who were followed for a period of 12 months, the main preoperative symptoms were regurgitation (93%) and heartburn (60%). At the end of 1 year follow up post surgery, all patients reported complete heartburn relief and 86% reported resolution of the regurgitation symptom. Patients’ satisfaction rate with surgery was 87%. Several studies suggested that a positive symptom index (SI) during impedance–pH monitoring in patients on PPI can predict a favorable response to medical or surgical therapy.46–49 The first study by Mainie et al. followed 19 patients who were refractory to a double-dose PPI and underwent a successful laparoscopic Nissen fundoplication.48 Prior to surgery, 18 of the 19 patients were found to have a positive SI on Multichannel Intraluminal Impedance (MII)–pH monitoring (14 with non-acid and 4 with acid reflux). After a mean follow up of 14 months, 16 of the patients with a positive SI were asymptomatic. The second study by Becker et al. assessed 56 patients with persistent symptoms on a single dose of PPI and an abnormal MII–pH monitoring.46 Most of these patients had a positive SI and later demonstrated a significantly higher response rate to doubling the PPI dose as compared to subjects with Journal of Gastroenterology and Hepatology 27 (2012) Suppl. 3; 3–7 © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd 5 Refractory GERD R Fass normal MII–pH monitoring. In a third study, a group of Italian investigators prospectively assessed the outcomes of laparoscopic Nissen fundoplication in 62 patients who were PPI non-responsive or non-compliant.47 All surgically treated patients had a positive MII–pH monitoring. The overall patient satisfaction rate was 98.3% and no differences were found in clinical outcomes based on their preoperative MII–pH or manometry results. It was concluded that MII–pH provide useful information for better selection of patients for antireflux surgery and that laparoscopic Nissen fundoplication results in excellent outcomes primarily in patients with positive MII–pH monitoring or SI. Unfortunately, all the aforementioned studies were uncontrolled and did not clearly describe whether symptoms were due to residual reflux. In addition, follow up was relatively short and in some, number of participants was small. Endoscopic treatment The transoral incisionless fundoplication system (Esophyx) uses suction and transmural fasteners to affix tissue from the Gastroesophageal Junction (GEJ) to the fundus and create a neogastroesophageal valve. This can potentially reduce hiatal hernia. Recent uncontrolled studies demonstrated increase in LES length and LES resting pressure after this procedure.50 However, there are no studies specifically investigating the effect of this technique on TLESR. Alternative medicine The value of acupuncture has been recently evaluated in GERD patients who failed PPI once daily. When compared to doubling the PPI dose (standard of care), adding acupuncture was significantly better in controlling regurgitation and daytime as well as night-time heartburn. This is the first study to suggest that alternative approaches for treating visceral pain may have a role in GERD patients with persistent heartburn despite PPI therapy.51 Psychological treatment Patients with poor correlation of symptoms with acid reflux events display a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid-reflux events.52 Anxiety and depression have been shown to increase GERD-related symptoms report in population-based studies. Nojkov et al. provided the first evidence that response to PPI treatment may be dependent on the level of psychological distress.53 Thus, it has been proposed that a subset of patients who did not respond to PPI therapy are more likely to have a psychosocial comorbidity than those who were successfully treated with a PPI. In these patients, treatment directed toward underlying psychosocial abnormality may improve patients response to PPI therapy. Summary The main focus for drug development in refractory GERD patients is TLESR reduction and more potent, early and consistent acid suppression. However, due to the diverse causes of PPI failure, one therapeutic strategy may not be the solution for all patients. It is likely that individually tailored therapy would be the most proper therapeutic approach. 6 References 1 Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112: 1448–56. 2 Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am. J. Dig. Dis. 1976; 21: 953–6. 3 Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112: 1798–810. 4 Hershcovici T, Fass R. Nonerosive reflux disease (NERD)—an update. J. Neurogastroenterol. Motil. 2010; 16: 8–21. 5 Hershcovici T, Fass R. Management of gastroesophageal reflux disease that does not respond well to proton pump inhibitors. Curr. Opin. Gastroenterol. 2010; 26: 367–78. 6 Hershcovici T, Fass R. An algorithm for diagnosis and treatment of refractory GERD. Best Pract. Res. Clin. Gastroenterol. 2010; 24: 923–36. 7 Fass R. Proton pump inhibitor failure—what are the therapeutic options? Am. J. Gastroenterol. 2009; 104 (Suppl. 2): S33–8. 8 Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009; 58: 295–309. 9 Fass R, Gasiorowska A. Refractory GERD: what is it? Curr. Gastroenterol. Rep. 2008; 10: 252–7. 10 Fass R. Persistent heartburn in a patient on proton-pump inhibitor. Clin. Gastroenterol. Hepatol. 2008; 6: 393–400. 11 Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch. Intern. Med. 2006; 166: 965–71. 12 Pomiecinski F, Yang AC, Navarro-Rodrigues T, Kalil J, Castro FF. Sensitization to foods in gastroesophageal reflux disease and its relation to eosinophils in the esophagus: is it of clinical importance? Ann. Allergy Asthma Immunol. 2010; 105: 359–63. 13 Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998; 115: 1335–9. 14 Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002; 122: 625–32. 15 Mainie I, Tutuian R, Castell DO. Addition of a H2 receptor antagonist to PPI improves acid control and decreases nocturnal acid breakthrough. J. Clin. Gastroenterol. 2008; 42: 676–9. 16 Rackoff A, Agrawal A, Hila A, Mainie I, Tutuian R, Castell DO. Histamine-2 receptor antagonists at night improve gastroesophageal reflux disease symptoms for patients on proton pump inhibitor therapy. Dis. Esophagus 2005; 18: 370–3. 17 Kahrilas PJ, Shaheen NJ, Vaezi MF et al. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 2008; 135: 1383–91, 91 e1–5. 18 Fass R, Sontag SJ, Traxler B, Sostek M. Treatment of patients with persistent heartburn symptoms: a double-blind, randomized trial. Clin. Gastroenterol. Hepatol. 2006; 4: 40–56. 19 Moayyedi P, Armstrong D, Hunt RH, Lei Y, Bukoski M, White RJ. The gain in quality-adjusted life months by switching to esomeprazole in those with continued reflux symptoms in primary care: encomPASS—a cluster-randomized trial. Am. J. Gastroenterol. 2010; 105: 2341–6. 20 Hatlebakk J, Katz P, Kuo B, Castell DO. Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily. Aliment. Pharmacol. Ther. 1998; 12: 1235–40. 21 Frazzoni M, Manno M, De Micheli E, Savarino V. Efficacy in intra-oesophageal acid suppression may decrease after 2-year Journal of Gastroenterology and Hepatology 27 (2012) Suppl. 3; 3–7 © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd R Fass 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 continuous treatment with proton pump inhibitors. Dig. Liver Dis. 2007; 39: 415–21. Shimatani T, Moriwaki M, Xu J, Tazuma S, Inoue M. Acidsuppressive effects of rabeprazole: comparing 10 mg and 20 mg twice daily in Japanese Helicobacter pylori-negative and -positive CYP2C19 extensive metabolisers. Dig. Liver Dis. 2006; 38: 802–8. Sharma P, Shaheen NJ, Perez MC et al. Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation—results from two randomized controlled studies. Aliment. Pharmacol. Ther. 2009; 29: 731–41. Fass R, Chey WD, Zakko SF et al. Clinical trial: the effects of the proton pump inhibitor dexlansoprazole MR on daytime and nighttime heartburn in patients with non-erosive reflux disease. Aliment. Pharmacol. Ther. 2009; 29: 1261–72. Blackshaw LA. Receptors and transmission in the brain-gut axis: potential for novel therapies. IV. GABA(B) receptors in the brain-gastroesophageal axis. Am. J. Physiol. Heart Circ. Physiol. 2001; 281: G311–15. Frisby CL, Mattsson JP, Jensen JM, Lehmann A, Dent J, Blackshaw LA. Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands. Gastroenterology 2005; 129: 995–1004. Zhang Q, Lehmann A, Ridga R, Dent J, Holloway RH. Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease. Gut 2002; 50: 19–24. Lidums I, Lehmann A, Checklin H, Dent J, Holloway RH. Control of transient lower esophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in normal subjects. Gastroenterology 2000; 118: 7–13. Omari TI, Benninga MA, Sansom L, Butler RN, Dent J, Davidson GP. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trial. J. Pediatr. 2006; 149: 436–8. Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment. Pharmacol. Ther. 2003; 17: 243–51. Koek GH, Sifrim D, Lerut T, Janssens J, Tack J. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 2003; 52: 1397–402. Liu LS, Shenoy M, Pasricha PJ. The analgesic effects of the GABA(B) receptor agonist, baclofen, in a rodent model of functional dyspepsia. Neurogastroenterol. Motil. 2011; 23: 356–61. Lal R, Sukbuntherng J, Tai EH et al. Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J. Pharmacol. Exp. Ther. 2009; 330: 911–21. Gerson LB, Huff FJ, Hila A et al. Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease. Am. J. Gastroenterol. 2010; 1266–75. Boeckxstaens GE, Beaumont H, Mertens V et al. Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease. Gastroenterology 2010; 139: 409–17. Boeckxstaens GE, Beaumont H, Hatlebakk JG, Silberg DG, Adler J, Denison H. Efficacy and tolerability of the novel reflux inhibitor, AZD3355, As add-on treatment in GERD patients with symptoms despite proton pump inhibitor therapy. Gastroenterology 2009; 136: A436-A. Keywood C, Wakefield M, Tack J. A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate Refractory GERD 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease. Gut 2009; 58: 1192–9. Zerbib F, Bruley des Varannes S, Roman S et al. Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 2011; 33: 911–21. Fass R, Shapiro M, Dekel R, Sewell J. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease—where next? Aliment. Pharmacol. Ther. 2005; 22: 79–94. Mainie I, Tutuian R, Shay S et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut 2006; 55: 1398–402. Handa M, Mine K, Yamamoto H et al. Antidepressant treatment of patients with diffuse esophageal spasm: a psychosomatic approach. J. Clin. Gastroenterol. 1999; 28: 228–32. Clouse RE, Lustman PJ, Eckert TC, Ferney DM, Griffith LS. Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities. A double-blind, placebo-controlled trial. Gastroenterology 1987; 92: 1027–36. Mirbagheri SA, Sadeghi A, Amouie M et al. Pyloric injection of botulinum toxin for the treatment of refractory GERD accompanied with gastroparesis: a preliminary report. Dig. Dis. Sci. 2008; 53: 2621–6. Bromer MQ, Friedenberg F, Miller LS, Fisher RS, Swartz K, Parkman HP. Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest. Endosc. 2005; 61: 833–9. Rosenthal R, Peterli R, Guenin MO, van Flüe M, Ackermann C. Laparoscopic antireflux surgery: long-term outcomes and quality of life. J. Laparoendosc. Adv. Surg. Tech. A 2006; 16: 557–61. Becker V, Bajbouj M, Waller K, Schmid RM, Meining A. Clinical trial: persistent gastro-oesophageal reflux symptoms despite standard therapy with proton pump inhibitors—a follow-up study of intraluminal-impedance guided therapy. Aliment. Pharmacol. Ther. 2007; 26: 1355–60. del Genio G, Tolone S, del Genio F et al. Prospective assessment of patient selection for antireflux surgery by combined multichannel intraluminal impedance pH monitoring. J. Gastrointest. Surg. 2008; 12: 1491–6. Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br. J. Surg. 2006; 93: 1483–7. Frazzoni M, Conigliaro R, Melotti G. Reflux parameters as modified by laparoscopic fundoplication in 40 patients with heartburn/regurgitation persisting despite PPI therapy: a study using impedance-pH monitoring. Dig. Dis. Sci. 2011; 56: 1099–106. Cadiere GB, Buset M, Muls V et al. Antireflux transoral incisionless fundoplication using EsophyX: 12-month results of a prospective multicenter study. World J. Surg. 2008; 32: 1676–88. Dickman R, Schiff E, Holland A et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment. Pharmacol. Ther. 2007; 26: 1333–44. Rubenstein JH, Nojkov B, Korsnes S et al. Oesophageal hypersensitivity is associated with features of psychiatric disorders and the irritable bowel syndrome. Aliment. Pharmacol. Ther. 2007; 26: 443–53. Nojkov B, Rubenstein JH, Adlis SA et al. The influence of co-morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 2008; 27: 473–82. Journal of Gastroenterology and Hepatology 27 (2012) Suppl. 3; 3–7 © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd 7