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

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

14

An algorithm for diagnosis and treatment of refractory

GERD
Tiberiu Hershcovici, MD, Research Fellow a, b, Ronnie Fass, MD, Professor
of Medicine, Chief of Gastroenterology, and Head, Neuroenteric Clinical
Research 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, USA
b
University of Arizona Health Sciences Center, Tucson, AZ, USA

Keywords:
Patients with gastro-esophageal reflux disease (GERD) who are not
Gastro-esophageal reflux disease (GERD) responding to proton pump inhibitors (PPIs) given once daily are very
Heartburn common. These therapy-resistant patients have become the new
Proton pump Inhibitors (PPIs) face of GERD in clinical practice in the last decade. Upper endoscopy
Refractory GERD appears to have a limited diagnostic value. In contrast, esophageal
impedance with pH testing on therapy appears to provide the most
insightful information about the subsequent management of these
patients. Commonly, doubling the PPI dose or switching to another
PPI will be offered to patients who failed PPI once daily. Failure of
such therapeutic strategies is commonly followed by assessment for
weakly or residual acidic reflux. There is growing information about
the potential value of compounds that can reduce transient lower
esophageal sphincter relaxation rate. Esophageal pain modulators
are commonly offered to patients with functional heartburn
although 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

Abbreviations: GERD, gastro-esophageal reflux disease; DIS, dilated intercellular spaces; SI, symptom index; SAP, symptom
association probability; NAB, nocturnal acid breakthrough; NERD, nonerosive reflux disease; DGER, duodenogastro-esophageal reflux.
*Corresponding author. 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. Tel.: þ1 520 792 1450x5139; fax: þ1 520 629 4737.
E-mail address: Ronnie.Fass@va.gov (R. Fass).

1521-6918/$ – see front matter Published by Elsevier Ltd.

doi:10.1016/j.bpg.2010.10.004
924 T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936

(1997–2004), there was an increase by almost 50% in the usage of at least double-dose PPI in patients
with 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 patients
supplemented 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-related
symptoms, 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 taking
nonprescription medication in addition to a prescription medication for GERD (Fig. 1) [2]. Of those, 56%
stated that they used their prescription medication daily but still needed to supplement with
nonprescription medication for breakthrough symptoms. Interestingly, 28% stated that only the
combination of prescription and nonprescription medications relieved their symptoms, and 24%
reported that prescription medication worked better in the long run but nonprescription medication
was faster acting.
Failure of PPI treatment to resolve GERD-related symptoms has become the most common
presentation of GERD in GI practice. Whilst cost analysis of PPI failure has yet to be carried out, it is
likely an expensive clinical problem due to repeated utilisation of healthcare resources such as clinic
visits, diagnostic tests, and prescription medications.
Most of the GERD patients who are not responsive to PPIs originate from the nonerosive reflux
disease (NERD) and functional heartburn (FH) groups, primarily due to their relative large size among
the heartburn patient population (up to 70%) and their low response rate to PPI once daily [3,5]. In
contrast, patients with erosive oesophagitis (EE) which account for 30–40% of the GERD population,
have a symptoms response rate significantly higher than what 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 patients
with negative symptom association who are responsive to PPI treatment back into the NERD group
(Fig. 2) [7]. Presently, FH is recognised as one of the most important groups that contribute to PPI failure
among patients with heartburn.

Definition

What constitutes refractory GERD remains an area of controversy. Most investigators believe that
only 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 common
explanations given by patients with GORD for adding a nonprescription drug to a prescription drug (Adapted from [2]).
 T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936 925

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

PPI failures. Others suggest that lack of satisfactory symptomatic response to PPI once a day is sufficient
to consider patients as PPI failures. The latter definition is much more relevant to pharmaceutical
companies 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 of
refractory GERD. This is likely to vary from one individual patient to another. Because refractory GERD
is a patient-driven phenomenon, PPI failure patients who seek medical attention will exhibit different
frequency and/or severity of GERD-related symptoms. Consequently, any attempt to narrow the
definition 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 initial
diagnosis of GERD that prompted the PPI therapy. It should be determined if the diagnosis of GERD was
based solely on symptoms (subjective findings) or if other objective tests, such as upper endoscopy or
pH testing, were utilised. A management algorithm of GERD patients who failed PPI once daily is
presented in Fig. 3.
Various underlying mechanisms have been shown to contribute to the failure of PPI treatment. At
present, much of the research conducted in this area is focused on weakly acid reflux and esophageal
hypersensitivity [9].
Compliance to treatment and proper dosing are important. Several surveys have demonstrated that
poor 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 the
presence or absence of symptoms, the severity of symptoms, and a personal preference about when to
take treatment [10]. In addition to compliance, timing and frequency of dosing are critical for
maximum efficacy of the medication. In a study of 100 patients with persistent GERD symptoms, only
46% dosed optimally the PPIs [11]. Of those who dosed suboptimally, 39% consumed their PPI >60 min
before meals, 30% after meals, 28% at bedtime and 4% as-needed. Thus far, there is still no clear
evidence 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-related
symptoms. The mechanism by which weakly acidic reflux causes GERD-related symptoms remains
poorly understood. Some authorities have proposed that mechanical distension of the oesophagus and/
or esophageal hypersensitivity is the culprit. Thus far, there is no evidence that weakly acidic reflux is
926 T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936

Alarm
symptoms Upper endoscopy
PIP once daily (2 months)

Failure *
Treat mucosal findings
Review proper PPI dosing
Failure * time and compliance

Failure *
Switch to another
PPI (2 months)

Failure *
PPI twice daily (AM & PM)
for 2 months

Failure * No access to esophageal impedance

Esophageal
Empirical therapy
impedance + pH

Regurgitation and/or Predominant

Heartburn
sour/bitter taste in mouth symptom
Negative Positive Positive
for for weakly
acid reflux acidic reflux

Pain Modulators Review Again TLESR Reducers H2RA at bedtime

Tricyclics PPI dosing time Pain Modulators
SSRIs and compliance Antireflux surgery
Trazodone
Failure *
Negative

Pain Modulators
H2RA at bedtime Tricyclics
Antireflux surgery SSRIs
Trazodone

* Partial or incomplete relief of symptoms

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 this
association has been proposed, esophageal impedance is unable to measure volume and thus
substantiates 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 patients
who failed PPI treatment [12,13]. However, these studies also demonstrated a considerable overlap in
the 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 were
primarily composed of both gas and liquid [12]. There are several potential explanations for the
association between proximal migration of a reflux event and symptoms. These include increased
sensitivity of the proximal oesophagus as compared with the distal oesophagus and/or ‘summation
 T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936 927

effect’ due to greater recruitment of sensitised pain receptors along the oesophagus. Recently it was
demonstrated that the transition zone between the striated and smooth muscle of the oesophagus is
more sensitive to mechanical stimulation than the distal oesophagus, which is composed solely of
smooth 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 functional
heartburn.

Upper gastrointestinal endoscopy

Upper endoscopy is commonly used in clinical practice to evaluate patients with GERD who failed
PPI treatment. This clinical strategy has been endorsed by the American Society of Gastrointestinal
Endoscopy (ASGE) [15]. The hope is to identify anatomical and histological abnormalities that can
explain patients’ refractoriness to potent and adequate antireflux treatment. However, a recent study
evaluated GERD-related endoscopic and histological findings in patients with refractory GERD (failure
to 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 (mean
age 53.4 years; 68 men, 23 women) into the no-treatment group. Anatomical findings during upper
endoscopy were significantly more common in the no-treatment group compared with the refractory
GERD group (55.2% vs. 40.7%, P <0.05). GERD-related findings were significantly more common in the
no-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 of
erosive 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 refractory
GERD patients.
In general, the value of endoscopy in discovering GERD-related findings in patients with refractory
GERD is very low. This is primarily due to the predominance of NERD and functional heartburn patients
among this group of patients and the high efficacy of PPIs in healing erosive oesophagitis. Studies have
demonstrated that the healing rates of erosive oesophagitis in patients receiving standard dose PPI are
high and range from 75% to 95% [17,18]. Endoscopic healing of erosive oesophagitis is commonly
accompanied, albeit not always, by symptom improvement. Persistence of symptoms despite PPI
treatment may reflect failure in healing esophageal mucosal injury, almost always in those with more
severe 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–Ellison
syndrome, pill-induced oesophagitis, achalasia, gastroparesis and skin diseases with esophageal
involvement) [19]. In addition, eosinophilic oesophagitis or other causes of persistent gastric or
duodenal 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 electron
microscopy is expensive and difficult to perform, assessing the presence of DIS in a busy general GI
practice may be time consuming and costly. However, at the same time it may provide the clue that
clinicians 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 acid
exposure 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 refractory
GERD. In the assessment of such patients, pH monitoring can be performed off PPI to test if the initial
diagnosis was correct (i.e., heartburn was due to acid reflux) or on PPI to test whether the symptoms
are due to residual acid reflux. Inclusion of a symptom–reflux correlation measure such as symptom
index (SI) and/or symptom association probability (SAP) helps to determine the relationship between
heartburn episodes and acid reflux events, regardless if the pH test is normal or abnormal. Some
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authorities have suggested that the threshold for abnormal pH test should be lowered in patients
undergoing pH testing on PPI therapy. Kuo and Castell proposed a cutoff of 1.6% based on a study in
healthy 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 heartburn might be related to ongoing
acid reflux. If the pH test is normal on PPI treatment but the symptom index is abnormal, then
heartburn induced by physiological levels of acid exposure could be the explanation. A normal pH test
on PPI and a negative symptom index suggests that the patient’s heartburn is unlikely to be related to
ongoing 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 despite
treatment with PPI once or twice daily. In one study, 38.6% of the GERD patients undergoing pH testing
for persistent symptoms while on PPI once a day, were found to have an abnormal pH test [21]. There
was 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 pH
test [26]. Overall, positive symptom index was documented in 40% and 7–11% of the patients who
remained symptomatic on PPI once or twice daily, respectively [27–29].
Extending the usage of the wireless pH monitoring to 4 days has been suggested to provide a better
comparison of esophageal acid exposure and symptom reflux association between off and on PPI
treatment periods [30]. However, studies evaluating this diagnostic strategy in refractory GERD
patients 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 as
atypical GERD-related symptoms while on PPI treatment might be due to non-acidic reflux (weakly
acid or alkaline).
The first stationary, postprandial impedance-pH study in patients who failed PPI twice daily, at
baseline and during therapy, documented a shift from primarily acidic reflux to mostly weakly acidic
reflux. Unlike untreated patients, regurgitation became the predominant symptom in patients who
failed PPI twice daily [32]. Further studies using ambulatory MII-pH monitoring in patients who failed
PPI 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% of
heartburn episodes were associated with weakly acidic reflux [13]. High esophageal proximal extent
was the only important factor associated with reflux perception. Furthermore, as compared with
regurgitation, 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 with
preceding acid reflux episodes.
An important controversy in patients with refractory GERD is whether to conduct testing on or off
PPI therapy. Zerbib et al reported the results of MII-pH monitoring in a group of patients off versus
those on twice a day PPI treatment. In patients off PPI, MII-pH monitoring added very little value to
patients’ 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 in
better 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 to
recall that non-acidic and bile reflux are two distinct phenomena. A recent study evaluated 20 patients
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with refractory GERD with both Bilitec and MII-pH monitoring [35]. The authors demonstrated
abnormal 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 an
increased 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 patients
experienced symptoms that were associated with bile reflux alone or bile reflux concomitantly with
acid 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]. The
addition of Bilitec increased the number of abnormal results over pH monitoring alone, from 38% to
69% 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 baseline
and 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 or
a general PPI phenomenon, regardless if the patient is responsive or non responsive to treatment. To
answer this question, the reflux pattern of responders and non-responders to the same dose of PPI
should be compared. Recently, a study evaluated 24 patients who failed PPI once daily and 23 patients
who fully responded to PPI once a day with both 24-h esophageal Bilitec and pH monitoring while on
treatment [39]. The authors demonstrated that abnormal DGER was documented in 82% of the
responders vs. 67% of the non-responders (P ¼ NS). All pH testing and Bilitec parameters were similar
between the two groups. GERD symptoms in the PPI failure group were more commonly associated
with acid reflux than with DGER. This study demonstrated for the first time that the level of bile and
acid exposure is similar among patients who failed and those who were successfully treated with PPI
once daily. In addition, in patients who failed to respond to PPI once daily, acidic reflux still plays an
important role in symptom generation.
Although PPI therapy reduces the occurrence of both acid as well as bile reflux [40,41], it has been
shown 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 step when assessing patients with heartburn who are not responding to PPI before instituting any
other intervention [44]. Emphasising the need to consume PPIs half an hour before a meal should be
provided to all patients.

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 weight loss and elevation of head of
the bed are effective in improving GERD [45]. There were no sufficient data to support any of the other
commonly practiced lifestyle modifications. Regardless, in patients with persistent heartburn despite
PPI 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)

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
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demonstrated NAB [46]. 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 [47].
In a study that evaluated 100 patients (58 on twice daily PPI and 42 on twice daily PPI þ 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 [48]. 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 [49]. The authors demonstrated that 72% of the patients
reported 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 for
symptom 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 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 that failed PPI once daily as also rec-
ommended by the 2008 American Gastroenterological Association guidelines for GERD [50]. The
Cochrane review also suggests that doubling the PPI dose is associated with greater healing of erosive
oesophagitis 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 the
management of patients who failed PPI once daily. In one study, patients who failed lansoprazole
30 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 of
heartburn-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 support
further escalation of the PPI dose beyond PPI twice daily either in symptom control or healing of erosive
oesophagitis. When doubling the PPI dose, one PPI should be given before breakfast and the other
before dinner. The support for splitting the dose originates primarily from physiological 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 [53].
A recent study suggested that a minority of GERD patients may lose PPI efficacy after two years of
continuous and unmodified treatment with one or two PPIs per day [54]. 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 [55]. As with the previous study, the authors did not provide any clinical end points to support their
conclusion.
The value of utilising Dexlansoprazole MR, an R-enantiomer of lansoprazole that also contains the
dual 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 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 [58]. The most promising among these appear to be the
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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 for
patients 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 accelerated
gastric emptying [60–62]. Baclofen has been shown to significantly reduce DGER and weakly acidic
reflux as well as DGER-related symptoms [43,63]. In subjects with persistent heartburn despite PPI
treatment, 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. 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 pharmaco-
logically 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 metabolised 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 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 [64,65].
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 [66]. In this placebo-
controlled, cross-over study, lesogaberan significantly decreased the rate of TLESRs, increased basal LES
pressure, decreased esophageal acid exposure and decreased the number of postprandial reflux
episodes. Furthermore, a decrease in the proximal extent of gastro-esophageal reflux events was also
demonstrated. However, there was no difference in the number of reflux symptom episodes between
the 2 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 [67]. 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 afore-
mentioned studies demonstrated only modest effect.
The effect of ADX10059, a potent, selective, negative allosteric modulator (NAM) of mGluR5, on
esophageal acid exposure and symptoms has been recently evaluated in GERD patients. ADX10059 at
a dose of 250 mg trice daily significantly reduced the percentage of time pH<4 and the duration of
symptomatic reflux episodes. In this study, ADX10059 was generally well tolerated. Based on these
preliminary data, the mGluR5 NAM ADX10059 appears to have a potential role in the clinical
management of GERD [68]. However on December 14, 2009 Addex Pharmaceuticals Ltd. ended
development of ADX10059 because of a possible link to severe hepatic side effects. The adverse events
occurred 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 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 [28,69]. 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 modulators such as
tricyclic antidepressants, trazodone (a tetracyclic antidepressants), and selective serotonin reuptake
inhibitors (SSRIs) have all been shown to improve esophageal pain in patients with noncardiac chest
932 T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936

pain [28,70,71]. It is believed that these agents confer their visceral analgesic effect by acting at the
central nervous system 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, side effects are
relatively common, and may limit their usage in certain patient populations, like the elderly or those
with multiple comorbidities.

Botulinum toxin injection

In one recent study, botulinum toxin was administered by pyloric injection to 11 patients with
refractory GERD and associated gastroparesis [72]. 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 [73].

Antireflux surgery

A recent surgical study reported that refractory GERD was the most common (88%) indication for
antireflux surgery [74]. 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 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 on
PPI can predict a favourable response to medical or surgical therapy. The first study by Mainie et al
followed 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 SI
on 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 [76].
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 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 who were PPI non responsive or noncompliant [77]. 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.

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 and nighttime 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 [78].

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
 T. Hershcovici, R. Fass / Best Practice & Research Clinical Gastroenterology 24 (2010) 923–936 933

acid reflux events [79]. 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 [80]. 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
towards 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 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 are
potential therapeutic strategies.
 Upper endoscopy has very limited value in patients who failed PPI treatment and lack alarm
symptoms.
 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 surgery
should be considered.
 In patient with functional heartburn, pain modulators are the cornerstone of therapy.

Research agenda

 The main focus for drug development in refractory GERD is TLESR reduction and more potent,
early and consistent acid suppression.
 Specific esophageal pain modulators for patients with functional heartburn or non-acidic
acidic reflux.
 Complementary and alternative therapeutic modalities that can interfere with brain–gut axis.

Conflict of interest

Ronnie Fass, MD, has served as a speaker for Takeda, and served as a consultant to Takeda, 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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