Algoritma Gerd

Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936

Contents lists available at ScienceDirect

Best Practice & Research ClinicalGastroenterology

14

An algorithm for diagnosis and treatment of refractoryGERD

Tiberiu Hershcovici, MD, Research Fellowa,b, Ronnie Fass, MD, Professorof Medicine, Chief of Gastroenterology, and Head, Neuroenteric ClinicalResearch Group a,b,*

a The Neuroenteric Clinical Research Group, Southern Arizona VA Health Care System, GI Section (1-111G-1) 3601 S. 6th Avenue,Tucson, AZ 85723-0001, USAbUniversity of Arizona Health Sciences Center, Tucson, AZ, USA

Keywords:Gastro-esophageal reflux disease (GERD)HeartburnProton pump Inhibitors (PPIs)Refractory GERD

Abbreviations: GERD, gastro-esophageal refluxassociation probability; NAB, nocturnal acid breakthro*Corresponding author. TheNeuroenteric Clinical R

3601 S. 6th Avenue, Tucson, AZ 85723-0001, USA. TeE-mail address: [email protected] (R. Fass).

1521-6918/$ – see front matter Published by Elsevdoi:10.1016/j.bpg.2010.10.004

Downloaded from ClinicalKeFor personal use only. No other uses witho

Patients with gastro-esophageal reflux disease (GERD) who are notresponding toprotonpump inhibitors (PPIs) givenoncedailyareverycommon. These therapy-resistant patients have become the newface of GERD in clinical practice in the last decade. Upper endoscopyappears to have a limited diagnostic value. In contrast, esophagealimpedance with pH testing on therapy appears to provide the mostinsightful information about the subsequent management of thesepatients. Commonly, doubling the PPI dose or switching to anotherPPI will be offered to patients who failed PPI once daily. Failure ofsuch therapeutic strategies is commonly followed by assessment forweakly or residual acidic reflux. There is growing information aboutthe potential value of compounds that can reduce transient loweresophageal sphincter relaxation rate. Esophageal pain modulatorsare commonly offered to patients with functional heartburnalthough supportive clinical studies are still missing.

Published by Elsevier Ltd.

Introduction

It has been estimated that between 10% and 40% of patients with GERD fail to respond symptom-atically, either partially or completely, to a standard dose PPI [1,2]. During a period of only seven years

disease; DIS, dilated intercellular spaces; SI, symptom index; SAP, symptomugh; NERD, nonerosive reflux disease; DGER, duodenogastro-esophageal reflux.esearchGroup, SouthernArizonaVAHealth Care System,GI Section (1-111G-1)l.: þ1 520 792 1450x5139; fax: þ1 520 629 4737.

ier Ltd.

y.com.au at University of Melbourne March 31, 2016.ut permission. Copyright ©2016. Elsevier Inc. All rights reserved.

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T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936924

(1997–2004), there was an increase by almost 50% in the usage of at least double-dose PPI in patientswith GERD [3]. 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 as-needed basis [4]. Approximately 42.1% of all patientssupplemented their prescription PPIs with other antireflux therapies, including over-the-counter anti-acids and H2-receptor antagonists (H2RA). Over 85% of the patients still experienced GERD-relatedsymptoms, but, 72.8% of all patients were satisfied or very satisfied with their PPI treatment.

In the 2000 Gallup Study of Consumers’ Use of Stomach Relief Products, 36% reported takingnonprescription medication in addition to a prescriptionmedication for GERD (Fig. 1) [2]. Of those, 56%stated that they used their prescription medication daily but still needed to supplement withnonprescription medication for breakthrough symptoms. Interestingly, 28% stated that only thecombination of prescription and nonprescription medications relieved their symptoms, and 24%reported that prescription medication worked better in the long run but nonprescription medicationwas faster acting.

Failure of PPI treatment to resolve GERD-related symptoms has become the most commonpresentation of GERD in GI practice. Whilst cost analysis of PPI failure has yet to be carried out, it islikely an expensive clinical problem due to repeated utilisation of healthcare resources such as clinicvisits, diagnostic tests, and prescription medications.

Most of the GERD patients who are not responsive to PPIs originate from the nonerosive refluxdisease (NERD) and functional heartburn (FH) groups, primarily due to their relative large size amongthe heartburn patient population (up to 70%) and their low response rate to PPI once daily [3,5]. Incontrast, patients with erosive oesophagitis (EE) which account for 30–40% of the GERD population,have a symptoms response rate significantly higher thanwhat has been reported in patients with NERD(pooled symptomatic response rate to PPI once daily at 4 weeks is 56%) [3,6].

The Rome III Committee for Functional Esophageal Disorders redefined the FH group, and conse-quently NERD, by primarily incorporating the hypersensitive oesophagus group and those patientswith negative symptom association who are responsive to PPI treatment back into the NERD group(Fig. 2) [7]. Presently, FH is recognised as one of themost important groups that contribute to PPI failureamong patients with heartburn.

Definition

What constitutes refractory GERD remains an area of controversy. Most investigators believe thatonly GERD patients who exhibit partial or lack of response to PPI twice daily should be considered as

Fig. 1. Reported type of medications used in the past 30 days in 1009 subjects that were surveyed. The box shows the commonexplanations given by patients with GORD for adding a nonprescription drug to a prescription drug (Adapted from [2]).

Downloaded from ClinicalKey.com.au at University of Melbourne March 31, 2016.For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.

Fig. 2. A diagnostic algorithm of NERD and functional heartburn based on Rome III criteria (Adapted from [7]).

T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936 925

PPI failures. Others suggest that lack of satisfactory symptomatic response to PPI once a day is sufficientto consider patients as PPI failures. The latter definition is much more relevant to pharmaceuticalcompanies and third-party payers, because there is no GERD-related indication for PPI twice a day.Furthermore, it is unclear what symptom burden during PPI consumption fulfils the definition ofrefractory GERD. This is likely to vary from one individual patient to another. Because refractory GERDis a patient-driven phenomenon, PPI failure patients who seek medical attention will exhibit differentfrequency and/or severity of GERD-related symptoms. Consequently, any attempt to narrow thedefinition of refractory GERD might exclude many true sufferers [8].

Diagnostic tests

Management of a patient with refractory GERD requires a high level of certainty about the initialdiagnosis of GERD that prompted the PPI therapy. It should be determined if the diagnosis of GERDwasbased solely on symptoms (subjective findings) or if other objective tests, such as upper endoscopy orpH testing, were utilised. A management algorithm of GERD patients who failed PPI once daily ispresented in Fig. 3.

Various underlying mechanisms have been shown to contribute to the failure of PPI treatment. Atpresent, much of the research conducted in this area is focused on weakly acid reflux and esophagealhypersensitivity [9].

Compliance to treatment and proper dosing are important. Several surveys have demonstrated thatpoor compliance with PPI treatment is not uncommon among patients with GERD. In a large, pop-ulation-based study, it was demonstrated that the main factors influencing compliance were thepresence or absence of symptoms, the severity of symptoms, and a personal preference about when totake treatment [10]. In addition to compliance, timing and frequency of dosing are critical formaximum efficacy of the medication. In a study of 100 patients with persistent GERD symptoms, only46% dosed optimally the PPIs [11]. Of those who dosed suboptimally, 39% consumed their PPI >60 minbefore meals, 30% after meals, 28% at bedtime and 4% as-needed. Thus far, there is still no clearevidence that by restoring adequate PPI dosing time, patients with refractory GERD report improve-ment in symptom control.

Weakly acidic and alkaline reflux was recently implicated as the cause for refractory GERD-relatedsymptoms. The mechanism by which weakly acidic reflux causes GERD-related symptoms remainspoorly understood. Some authorities have proposed thatmechanical distension of the oesophagus and/or esophageal hypersensitivity is the culprit. Thus far, there is no evidence that weakly acidic reflux is


PIP once daily (2 months)

Review proper PPI dosing time and compliance

PPI twice daily (AM & PM)for 2 months

Switch to another PPI (2 months)

Esophageal impedance + pH Empirical therapy

Pain Modulators

TricyclicsSSRIs

Trazodone

Regurgitation and/or sour/bitter taste in mouth

H2RA at bedtime

Antireflux surgery

Review Again

PPI dosing timeand compliance

TLESR Reducers

Pain Modulators

Antireflux surgery

Failure *

Negative

H2RA at bedtime

Pain Modulators

TricyclicsSSRIs

Trazodone

Heartburn

Failure *

Failure *

Failure *

Failure *

No access to esophageal impedance

Predominant

symptomPositive

for

acid reflux

Positive

for weakly

acidic reflux

* Partial or incomplete relief of symptoms

Failure *

Alarm

symptoms Upper endoscopy

Treat mucosal findings

Negative

Fig. 3. Management algorithm of GERD patient who failed PPI once daily (*complete or partial) (Adapted from [8]).


more commonly associated with increased volume of the refluxate than acidic reflux. Although thisassociation has been proposed, esophageal impedance is unable to measure volume and thussubstantiates this claim.

Several studies have demonstrated that proximal extent of weakly acidic reflux (a possible surro-gate of volume reflux) was the most important determinant of symptomatic reflux events in patientswho failed PPI treatment [12,13]. However, these studies also demonstrated a considerable overlap inthe proximal extent between symptomatic and asymptomatic weakly acidic reflux episodes. In addi-tion to proximal extent, symptomatic reflux episodes in patients who failed PPI twice daily wereprimarily composed of both gas and liquid [12]. There are several potential explanations for theassociation between proximal migration of a reflux event and symptoms. These include increasedsensitivity of the proximal oesophagus as compared with the distal oesophagus and/or ‘summation



effect’ due to greater recruitment of sensitised pain receptors along the oesophagus. Recently it wasdemonstrated that the transition zone between the striated and smooth muscle of the oesophagus ismore sensitive to mechanical stimulation than the distal oesophagus, which is composed solely ofsmooth muscle [14].

Diagnostic tests in refractory GERD are primarily utilised to identify residual reflux (acidic, non-acidic or bile), anatomical and histological abnormalities of the upper GI tract and functionalheartburn.

Upper gastrointestinal endoscopy

Upper endoscopy is commonly used in clinical practice to evaluate patients with GERD who failedPPI treatment. This clinical strategy has been endorsed by the American Society of GastrointestinalEndoscopy (ASGE) [15]. The hope is to identify anatomical and histological abnormalities that canexplain patients’ refractoriness to potent and adequate antireflux treatment. However, a recent studyevaluated GERD-related endoscopic and histological findings in patients with refractory GERD (failureto once daily PPI therapy) versus those not receiving antireflux treatment [16]. A total of 105 subjects(mean age 54.7 years; 71 men, 34 women) were enrolled into the refractory GERD group and 91 (meanage 53.4 years; 68 men, 23 women) into the no-treatment group. Anatomical findings during upperendoscopy were significantly more common in the no-treatment group compared with the refractoryGERD group (55.2% vs. 40.7%, P <0.05). GERD-related findings were significantly more common in theno-treatment group compared with the refractory GERD group (erosive oesophagitis: 30.8% vs. 6.7%,respectively; P < 0.05). Refractory GERD was associated with a significantly decreased odds ratio oferosive oesophagitis as compared with no treatment when adjusted for age, sex, and body mass index(adjusted OR, 0.11; 95% CI, 0.04–0.30). Eosinophilic oesophagitis was found in only 0.9% of refractoryGERD patients.

In general, the value of endoscopy in discovering GERD-related findings in patients with refractoryGERD is very low. This is primarily due to the predominance of NERD and functional heartburn patientsamong this group of patients and the high efficacy of PPIs in healing erosive oesophagitis. Studies havedemonstrated that the healing rates of erosive oesophagitis in patients receiving standard dose PPI arehigh and range from 75% to 95% [17,18]. Endoscopic healing of erosive oesophagitis is commonlyaccompanied, albeit not always, by symptom improvement. Persistence of symptoms despite PPItreatment may reflect failure in healing esophageal mucosal injury, almost always in those with moresevere grades of erosive oesophagitis (C and D).

In very rare cases, endoscopy in heartburn patients who failed PPI treatment may reveal a non-GERD-related cause, which could explain the patient’s symptoms (ulcers due to Zollinger–Ellisonsyndrome, pill-induced oesophagitis, achalasia, gastroparesis and skin diseases with esophagealinvolvement) [19]. In addition, eosinophilic oesophagitis or other causes of persistent gastric orduodenal ulcer could be identified.

Dilated intercellular spaces (DIS) of the esophageal mucosa can be identified in all GERD patients[20]. The presence of DIS can be assessed quantitatively with electron microscopy. Since electronmicroscopy is expensive and difficult to perform, assessing the presence of DIS in a busy general GIpractice may be time consuming and costly. However, at the same time it may provide the clue thatclinicians are seeking to confirm that reflux is still the cause of the patient’s symptoms.

Ambulatory 24-h esophageal pH monitoring

Both catheter and wireless esophageal pH monitoring allow the quantification of esophageal acidexposure and the assessment of the temporal relationship between symptoms and acid reflux events[21,22]. Esophageal pH monitoring is commonly used in the evaluation of patients with refractoryGERD. In the assessment of such patients, pH monitoring can be performed off PPI to test if the initialdiagnosis was correct (i.e., heartburn was due to acid reflux) or on PPI to test whether the symptomsare due to residual acid reflux. Inclusion of a symptom–reflux correlation measure such as symptomindex (SI) and/or symptom association probability (SAP) helps to determine the relationship betweenheartburn episodes and acid reflux events, regardless if the pH test is normal or abnormal. Some



authorities have suggested that the threshold for abnormal pH test should be lowered in patientsundergoing pH testing on PPI therapy. Kuo and Castell proposed a cutoff of 1.6% based on a study inhealthy subjects treated with omeprazole 40 mg once daily [23]. However, most GI motility labora-tories use the classic DeMeester and Johnson criteria regardless if patients are on or off PPI treatment.

A positive pH testing on PPI suggests that patients’ persistent heartburnmight be related to ongoingacid reflux. If the pH test is normal on PPI treatment but the symptom index is abnormal, thenheartburn induced by physiological levels of acid exposure could be the explanation. A normal pH teston PPI and a negative symptom index suggests that the patient’s heartburn is unlikely to be related toongoing acid reflux. However, one has to recall that a negative pH test may occur due to poor toler-ability of the pH probe that can result in a significant impact on reflux-provoking activities [24].

Residual acid reflux has been documented in GERD patients with persistent heartburn despitetreatment with PPI once or twice daily. In one study, 38.6% of the GERD patients undergoing pH testingfor persistent symptoms while on PPI once a day, were found to have an abnormal pH test [21]. Therewas no correlation between a negative pH test and age, gender, or brand of PPI. In another study, 31%and 4% of the GERD patients with refractory symptoms on PPI once daily and PPI twice daily,respectively, had an abnormal pH test [25]. Recently, Karamanolis et al demonstrated that 16% and 32%of the symptomatic subjects on double-dose and standard dose PPI, respectively, had an abnormal pHtest [26]. Overall, positive symptom index was documented in 40% and 7–11% of the patients whoremained symptomatic on PPI once or twice daily, respectively [27–29].

Extending the usage of the wireless pHmonitoring to 4 days has been suggested to provide a bettercomparison of esophageal acid exposure and symptom reflux association between off and on PPItreatment periods [30]. However, studies evaluating this diagnostic strategy in refractory GERDpatients are still missing.

Esophageal multichannel intraluminal impedance-pH monitoring (MII-pH)

MII-pH monitoring allows the detection of most reflux events and the distinction between acidic,weakly acidic, and weakly alkaline reflux [31]. Studies have suggested that persistent typical as well asatypical GERD-related symptoms while on PPI treatment might be due to non-acidic reflux (weaklyacid or alkaline).

The first stationary, postprandial impedance-pH study in patients who failed PPI twice daily, atbaseline and during therapy, documented a shift from primarily acidic reflux to mostly weakly acidicreflux. Unlike untreated patients, regurgitation became the predominant symptom in patients whofailed PPI twice daily [32]. Further studies using ambulatory MII-pH monitoring in patients who failedPPI twice daily, demonstrated that acidic reflux was associated with 7–28% of the persistent GERD-related symptoms. In contrast, weakly acidic reflux preceded 30–40% of the symptoms. Between 30%and 60% of the symptoms were not preceded by any reflux [28,33,34].

A recent MII-pH study in refractory GERD patients while on PPI therapy showed that up to 68% ofheartburn episodes were associated with weakly acidic reflux [13]. High esophageal proximal extentwas the only important factor associated with reflux perception. Furthermore, as compared withregurgitation, weakly acidic reflux episodes resulting in heartburn were more frequently pure liquid,slightly more acidic, had a lower nadir pH (4.8 vs. 5.5), and were more commonly associated withpreceding acid reflux episodes.

An important controversy in patients with refractory GERD is whether to conduct testing on or offPPI therapy. Zerbib et al reported the results of MII-pH monitoring in a group of patients off versusthose on twice a day PPI treatment. In patients off PPI, MII-pH monitoring added very little value topatients’ diagnosis when compared with pH monitoring alone (5–10%). In patients on PPI therapy,however, adding impedance to pH monitoring improved the diagnostic yield by 15–20%, resulting inbetter symptom correlation analysis than during the pH test alone [34].

Esophageal Bilitec

Bilitec detects bilirubin in the refluxate that is used as a surrogate marker for bile reflux. One has torecall that non-acidic and bile reflux are two distinct phenomena. A recent study evaluated 20 patients



with refractory GERD with both Bilitec and MII-pH monitoring [35]. The authors demonstratedabnormal duodenogastro-esophageal reflux (DGER) in 9 cases, 6 of them had normal values of non-acidic reflux. There was no correlation between the two types of reflux.

There is evidence that esophageal exposure to bile acids can result in heartburn symptoms.Perfusion of bile salts with non-acidic pH has been shown to provoke heartburn [36]. In addition,exposure of rabbit esophageal mucosa to weakly acidic solutions containing bile acids resulted in anincreased mucosal permeability and also induced DIS [37].

Tack et al suggested a possible role for DGER in a subset of patients with difficult to manage,symptomatic reflux [38]. In a study that included 65 patients with persistent heartburn and regurgi-tation while on single or double-dose PPI therapy, the authors demonstrated that 64% of patientsexperienced symptoms that were associated with bile reflux alone or bile reflux concomitantly withacid reflux. The role of adding Bilitec to conventional pH monitoring was also assessed in 347 patients(157 men, mean age 49.4 years) who underwent pH studies on PPI therapy (28% half, 67% full, and 5%double-dose PPI) for persistent typical (53%) or atypical (75%) GERD-related symptoms [26]. Theaddition of Bilitec increased the number of abnormal results over pH monitoring alone, from 38% to69% on half-dose, from 27% to 69% on full-dose, and from 0% to 38% on double-dose PPI.

Most studies evaluating patients with refractory GERD tend to compare reflux patterns at baselineand during treatment in the PPI failure group. However, these studies do not provide the answer to the‘burning’ query if residual reflux (acidic, non-acidic or bile) is a unique PPI failure phenomenon ora general PPI phenomenon, regardless if the patient is responsive or non responsive to treatment. Toanswer this question, the reflux pattern of responders and non-responders to the same dose of PPIshould be compared. Recently, a study evaluated 24 patients who failed PPI once daily and 23 patientswho fully responded to PPI once a day with both 24-h esophageal Bilitec and pH monitoring while ontreatment [39]. The authors demonstrated that abnormal DGER was documented in 82% of theresponders vs. 67% of the non-responders (P ¼ NS). All pH testing and Bilitec parameters were similarbetween the two groups. GERD symptoms in the PPI failure group were more commonly associatedwith acid reflux than with DGER. This study demonstrated for the first time that the level of bile andacid exposure is similar among patients who failed and those who were successfully treated with PPIonce daily. In addition, in patients who failed to respond to PPI once daily, acidic reflux still plays animportant role in symptom generation.

Although PPI therapy reduces the occurrence of both acid as well as bile reflux [40,41], it has beenshown that complete acid suppression does not guarantee elimination of DGER [42,43].

Treatment

Overall, evaluation for proper compliance and adequate dosing time should be the first manage-ment stepwhen assessing patients with heartburnwho are not responding to PPI before instituting anyother intervention [44]. Emphasising the need to consume PPIs half an hour before a meal should beprovided to all patients.

Lifestyle modifications

The specific value of lifestyle modifications in GERD patients who failed PPI treatment has yet to beelucidated. In a recent systematic review of all publications that evaluated the value of lifestylemodifications in GERD patients, the authors determined that only weight loss and elevation of head ofthe bed are effective in improving GERD [45]. There were no sufficient data to support any of the othercommonly practiced lifestyle modifications. Regardless, in patients with persistent heartburn despitePPI treatment, it is reasonable to recommend avoidance of specific lifestyle activities that have beenidentified by patients or physicians to trigger GERD-related symptoms.

Histamine 2 receptor antagonist (H2RA)

Early studies have shown that the addition of H2RA at bedtime significantly reduced the duration ofnocturnal acid breakthrough (NAB) and the number of GERD patients on PPI twice daily who



demonstrated NAB [46]. The effect on NAB was not different between standard dose and double-doseH2RA. Despite lack of any clinical correlation between the presence of NAB and nocturnal GERDsymptoms, the addition of H2RA at bedtime has become common practice in GERD patients who failedPPIs regardless of dosing. However, concerns were raised about the development of rapid tolerance(within 1 week) in patients taking daily H2RA [47].

In a study that evaluated 100 patients (58 on twice daily PPI and 42 on twice daily PPI þ H2RA atbedtime for at least 1 month), the authors demonstrated that the addition of a bedtime H2RAsignificantly reduced the percentage time with intragastric pH <4 during upright, recumbent, and theentire period [48]. Unfortunately, the authors failed to provide any evidence for similar effects onclinical end points. Rackoff et al evaluated 56 GERD patients on PPI twice daily who were receivingH2RA at bedtime for variable periods of time [49]. The authors demonstrated that 72% of the patientsreported improvement in overall symptoms, 74% in nighttime reflux symptoms, and 67% in GERD-associated sleep disturbances.

Proton pump inhibitors

Currently, PPIs are the most efficacious treatment for both healing erosive oesophagitis and forsymptom relief in GERD patients. In those who failed PPI once a day, there are two potential thera-peutic strategies that could be utilised in clinical practice. These include switching to another PPI ordoubling the PPI dose. However, doubling the PPI dose is by far the most common therapeutic strategythat is used by practicing physicians when managing patients that failed PPI once daily as also rec-ommended by the 2008 American Gastroenterological Association guidelines for GERD [50]. TheCochrane review also suggests that doubling the PPI dose is associated with greater healing of erosiveoesophagitis with the number needed to treat of 25. However there is no clear dose–response rela-tionship for heartburn resolution in either erosive oesophagitis or NERD [51].

Switching to another PPI is an attractive therapeutic strategy that could be utilised in themanagement of patients who failed PPI once daily. In one study, patients who failed lansoprazole30 mg once daily were randomised to either double-dose lansoprazole or 40 mg once daily esome-prazole. Single-dose esomeprazole was as effective as double-dose lansoprazole in percentage ofheartburn-free days as well as symptom score for heartburn, acid regurgitation, and epigastric pain[52].

While doubling the PPI dose has became the standard of care, there is no evidence to supportfurther escalation of the PPI dose beyond PPI twice daily either in symptom control or healing of erosiveoesophagitis. When doubling the PPI dose, one PPI should be given before breakfast and the otherbefore dinner. The support for splitting the dose originates primarily from physiological studiesdemonstrating an improved control of intragastric pH when one PPI is given in the AM and the other inthe PM as compared with both PPIs being given before breakfast [53].

A recent study suggested that a minority of GERD patients may lose PPI efficacy after two years ofcontinuous and unmodified treatment with one or two PPIs per day [54]. The sole parameter evaluatedin this study was the level of esophageal acid exposure as assessed by pH testing. The authors failed toprovide any clinical data to support their physiological findings. In another study, the authorsdemonstrated that infection with Helicobacter pylori in healthy subjects, who are CYP2C19 extensivemetabolizers, eliminated the differences in intragastric pH control between standard and double-dosePPI [55]. As with the previous study, the authors did not provide any clinical end points to support theirconclusion.

The value of utilising Dexlansoprazole MR, an R-enantiomer of lansoprazole that also contains thedual delayed release (DDR) technology, in patients who failed PPI remains to be elucidated [56,57].Potentially, the dual release of the drug that is separated by 4–5 h, may be helpful in patients who failedPPI once daily.

Transient lower esophageal sphincter relaxation (TLESR) reducers

Awide range of receptors have been shown to be involved in triggering TLESR providing us with theopportunity to develop novel reflux inhibitors [58]. 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 [58,59].

Baclofen, a GABAB agonist, was introduced into the clinical arena as a potential add-on treatment forpatients who failed PPI treatment (once or twice daily) [60,61]. The drug reduced TLESR rate by 40–60%, reflux episodes by 43%, increased lower esophageal sphincter basal pressure, and acceleratedgastric emptying [60–62]. Baclofen has been shown to significantly reduce DGER and weakly acidicreflux as well as DGER-related symptoms [43,63]. In subjects with persistent heartburn despite PPItreatment, doses of up to 20 mg trice daily have been used [43]. Because the drug crosses the blood–brain barrier, a variety of central nervous system (CNS)-related side effects have been reported. Theyprimarily include somnolence, confusion, dizziness, lightheadedness, drowsiness, weakness, andtrembling. The side effects are likely an important limiting factor in the routine usage of baclofen inclinical practice.

Arbaclofen placarbil (also known as XP19986) is a novel transported pro-drug of the pharmaco-logically active R-isomer of baclofen. The drug is currently in clinical development for the treatment ofrefractory GERD. Arbaclofen placarbil was designed to be efficiently absorbed in the gastrointestinaltract and rapidly metabolised to release R-baclofen after absorption. Unlike baclofen, arbaclofenplacarbil is well absorbed from the colon, allowing the drug to be delivered in a sustained releaseformulation that may allow less frequent dosing and thus reduced fluctuations in plasma exposure.This in turn may lead to potentially improved efficacy through a combination of greater duration ofaction, subject’s convenience, and better safety profile compared with baclofen [64,65].

Lesogaberan, a new GABAB agonist, with a better CNS safety profile was developed in order toovercome the side effects of baclofen. The physiological effects of lesogaberanwere evaluated in a smallgroup of patients with persistent GERD-related symptoms despite PPI therapy [66]. In this placebo-controlled, cross-over study, lesogaberan significantly decreased the rate of TLESRs, increased basal LESpressure, decreased esophageal acid exposure and decreased the number of postprandial refluxepisodes. Furthermore, a decrease in the proximal extent of gastro-esophageal reflux events was alsodemonstrated. However, there was no difference in the number of reflux symptom episodes betweenthe 2 arms of the study. The results of a larger clinical (232 patients), double blind, placebo-controlledtrial that examined the efficacy of lesogaberan as add-on therapy to PPI once or twice daily forrefractory GERD patients were recently published in a abstract form [67]. The proportion of respondersincreased from 8% to 16% and the proportion of symptom-free days increased from 21% to 36% after 4weeks of treatment in the lesogaberan versus placebo group. Overall, lesogaberan was safe and welltolerated. While lesogaberan appear to be a promising future treatment for PPI failure, the afore-mentioned studies demonstrated only modest effect.

The effect of ADX10059, a potent, selective, negative allosteric modulator (NAM) of mGluR5, onesophageal acid exposure and symptoms has been recently evaluated in GERD patients. ADX10059 ata dose of 250 mg trice daily significantly reduced the percentage of time pH<4 and the duration ofsymptomatic reflux episodes. In this study, ADX10059 was generally well tolerated. Based on thesepreliminary data, the mGluR5 NAM ADX10059 appears to have a potential role in the clinicalmanagement of GERD [68]. However on December 14, 2009 Addex Pharmaceuticals Ltd. endeddevelopment of ADX10059 because of a possible link to severe hepatic side effects. The adverse eventsoccurred regardless of the dose and appeared to be related to the duration of drug administration.

Visceral pain modulators

Thus far, there are no studies that specifically evaluated the value of visceral pain modulators inrefractory GERD patients. However, given the fact that most of the patients who fail PPI treatmentoriginate from the NERD group andmore than 50% of the PPI failure (twice daily) subjects demonstratelack of either weakly or acidic reflux, the usage of these agents is highly attractive [28,69]. Additionally,it could be argued that even for weakly acidic reflux that has not been shown to be associated withesophageal mucosal damage, visceral pain modulators could be helpful. Pain modulators such astricyclic antidepressants, trazodone (a tetracyclic antidepressants), and selective serotonin reuptakeinhibitors (SSRIs) have all been shown to improve esophageal pain in patients with noncardiac chest



pain [28,70,71]. It is believed that these agents confer their visceral analgesic effect by acting at thecentral nervous system and/or peripherally at the sensory afferent level.

The painmodulators are used in non-mood-altering doses, and they presently provide a therapeuticalternative until more novel esophageal-specific compounds are available. In addition, side effects arerelatively common, and may limit their usage in certain patient populations, like the elderly or thosewith multiple comorbidities.

Botulinum toxin injection

In one recent study, botulinum toxin was administered by pyloric injection to 11 patients withrefractory GERD and associated gastroparesis [72]. Marked improvement in GERD-related symptomswas demonstrated that correlated with improvement in gastroparesis related symptoms and gastricemptying scintigraphy. The mean duration of response is approximately 5 months [73].

Antireflux surgery

A recent surgical study reported that refractory GERD was the most common (88%) indication forantireflux surgery [74]. Interestingly, the most common preoperative symptom reported under failureof medical antireflux treatment was regurgitation (54%). Overall, 82% of the patients reported that thepreoperative reflux symptom completely resolved, and 94% were satisfied with the results of thesurgery. In another study that included only 30 subjects with refractory GERD who were followed fora period of 12months, themain preoperative symptomswere regurgitation (93%) and heartburn (60%).At the end of one 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%.

Three recent studies suggested that a positive SI during impedance-pH monitoring in patients onPPI can predict a favourable response to medical or surgical therapy. The first study by Mainie et alfollowed 19 patients who were refractory to a double-dose PPI and underwent a successful laparo-scopic Nissen fundoplication [75]. Prior to surgery,18 of the 19 patients were found to have a positive SIon 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 56patients with persistent symptoms on a single-dose of PPI and an abnormal MII-pH monitoring [76].Most of these patients had a positive SI and later demonstrated a significantly higher response rate todoubling the PPI dose as compared to subjects with normal MII-pH monitoring. In a third study,a group of Italian investigators prospectively assessed the outcomes of laparoscopic Nissen fundopli-cation in 62 patients whowere PPI non responsive or noncompliant [77]. All surgically treated patientshad a positive MII-pH monitoring. The overall patient satisfaction rate was 98.3% and no differenceswere found in clinical outcomes based on their preoperative MII-pH or manometry results. It wasconcluded that MII-pH provide useful information for better selection of patients for antireflux surgeryand that laparoscopic Nissen fundoplication results in excellent outcomes primarily in patients withpositive MII-pHmonitoring or SI. Unfortunately, all the aforementioned studies were uncontrolled anddid not clearly describe whether symptoms were due to residual reflux.

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 significantlybetter in controlling regurgitation and daytime and nighttime heartburn. This is the first study tosuggest that alternative approaches for treating visceral pain may have a role in GERD patients withpersistent heartburn despite PPI therapy [78].

Psychological treatment

Patients with poor correlation of symptoms with acid reflux events display a high level of anxietyand hysteria as compared with patients who demonstrate a close correlation between symptoms and



acid reflux events [79]. Anxiety and depression have been shown to increase GERD-related symptomsreport in population-based studies. Nojkov et al provided the first evidence that response to PPItreatment may be dependent on the level of psychological distress [80]. Thus, it has been proposed thata subset of patients who did not respond to PPI therapy are more likely to have a psychosocialcomorbidity than those who were successfully treated with a PPI. In these patients, treatment directedtowards 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 morepotent, early and consistent acid suppression. However, due to the diverse causes of PPI failure, onetherapeutic strategy may not be the solution for all patients. It is likely that individually tailoredtherapy would be the most proper management approach.

Practice points

� Evaluation for proper compliance and adequate dosing time should be the initial manage-ment of patients with heartburn who are not responsive to PPI.

� In patients who failed PPI once daily, doubling the PPI dose or switching to another PPI arepotential therapeutic strategies.

� Upper endoscopy has very limited value in patients who failed PPI treatment and lack alarmsymptoms.

� Esophageal multichannel intraluminal impedance-pH monitoring provides the best diag-nostic tool to stratify GERD patients who failed PPI treatment.

� In patients with non-acidic reflux, TLESR reducers, pain modulators and antireflux surgeryshould be considered.

� In patient with functional heartburn, pain modulators are the cornerstone of therapy.

Research agenda

� Themain focus for drug development in refractory GERD is TLESR reduction andmore potent,early and consistent acid suppression.

� Specific esophageal pain modulators for patients with functional heartburn or non-acidicacidic reflux.

� Complementary and alternative therapeutic modalities that can interferewith brain–gut axis.

Conflict of interest

Ronnie Fass, MD, has served as a speaker for Takeda, and served as a consultant toTakeda, GSK, Eisai,XenoPort and Vecta. He has received research funding from Takeda, Wyeth, and AstraZeneca.

Tiberiu Hershcovici, MD, has no conflicts of interest to declare.

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