Current Diagnosis and Management of

Suspected Reflux Symptoms Refractory

to Proton Pump Inhibitor Therapy
Joel E. Richter, MD

Dr Richter is a professor of medicine,

the Hugh F. Culverhouse Chair for
Esophagology, director of the Division
of Digestive Diseases and Nutrition, and
director of the Joy McCann Culverhouse
Center for Swallowing Disorders at the
University of South Florida Morsani
College of Medicine in Tampa, Florida.
Address correspondence to:
Dr Joel E. Richter
Division of Digestive Diseases and
Nutrition
University of South Florida
Morsani College of Medicine
12901 Bruce B. Downs Blvd
Tampa, FL 33612
Tel: 813-625-3992
E-mail: jrichte1@health.usf.edu

Abstract: Suspected reflux symptoms that are refractory to proton

pump inhibitors (PPIs) are rapidly becoming the most common
presentation of gastroesophageal reflux disease (GERD) in patients
seen in gastroenterology clinics. These patients are a heterogeneous group, differing in symptom frequency and severity, PPI
dosing regimens, and responses to therapy (from partial to absent).
Before testing, the physician needs to question the patient carefully
about PPI compliance and the timing of drug intake in relation to
meals. Switching PPIs or doubling the dose is the next step, but
only 20% to 25% of the group refractory to PPIs will respond. The
first diagnostic test should be upper gastrointestinal endoscopy. In
more than 90% of cases, the results will be normal, but persistent
esophagitis may suggest pill esophagitis, eosinophilic esophagitis,
or rarer diseases, such as lichen planus, Zollinger-Ellison syndrome,
or genotype variants of PPI metabolism. If the endoscopy results are
normal, esophageal manometry and especially reflux testing should
follow. Whether patients should be tested on or off PPI therapy
is controversial. Most physicians prefer to test patients off PPIs to
identify whether abnormal acid reflux is even present; if it is not,
PPIs can be stopped and other diagnoses sought. Testing patients on
PPI therapy allows nonacid reflux to be identified, but more than
50% of patients have a normal test result, leaving the clinician with
a conundrumwhether to stop PPIs or continue them because
the GERD is being treated adequately. Alternative diagnoses in
patients with refractory GERD and normal reflux testing include
achalasia, eosinophilic esophagitis, gastroparesis, rumination, and
aerophagia. However, more than 50% will be given the diagnosis of
functional heartburn, a visceral hypersensitivity syndrome. Treating
patients with PPI-refractory GERDlike symptoms can be difficult
and frustrating. Any of the following may help: a histamine-2
receptor antagonist at night, baclofen to decrease transient lower

Keywords
Refractory gastroesophageal reflux disease, proton
pump inhibitorresistant gastroesophageal reflux
disease, proton pump inhibitors, baclofen, pain
modulators, antireflux surgery

esophageal sphincter relaxations, pain modulators, acupuncture,

or hypnotherapy. At this time, antireflux surgery should be limited
to patients with abnormal acid reflux defined by pH testing and a
good correlation of symptoms with acid reflux.

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RICHTER

cid suppression with proton pump inhibitors

(PPIs) is the mainstay of therapy for gastroesophageal reflux disease (GERD). Although
success rates for healing esophagitis approach 80% to
90%, a large percentage of patients (10%-40%) fail to
respond symptomatically, either partially or completely,
to standard doses of PPIs.1,2 These patients are said to
have refractory GERD, which is one of the most common presentations of the GERD syndrome in general
gastroenterology practices.2 The patients are a heterogeneous group, differing in symptom frequency and
severity, PPI dosing regimens, and responses to therapy
(from partial to absent). Although studies often define
a poor response to PPIs as less than a 50% reduction in
the chief complaint over 8 to 12 weeks of therapy, the
distinction in clinical practice is difficult. The symptoms
often are not classic for reflux, tools for measuring the
disease are imperfect, and each patients perception of
the remaining symptoms is subjective and depends on
his or her expectations of the therapy.3 For example, a
large study in a family practice setting found that only
49% of patients with GERD had either heartburn or
acid regurgitation as their most troublesome symptom,
and symptom response to esomeprazole was neither sensitive nor specific for the diagnosis of GERD.4
The PPI regimen used to define refractory GERD
is controversial. Some experts suggest that the lack of a
symptomatic response to once-daily PPI dosing is sufficient to consider a patients response to PPI therapy a
failure. This definition is relevant to drug companies
and third-party payors because the US Food and Drug
Administrations approval for PPI dosing does not extend
to twice-daily therapy.2 However, physicians in clinical
practice usually double the PPI dose, hoping for symptom
resolution. Nonetheless, the majority of patients (75%)
continue to experience reflux symptoms despite increased
doses of PPIs.2 These patients are a major factor in the
50% increase in twice-daily PPI use being reported in the
United States and Canada, now exceeding 20% in the
province of Manitoba.5
Refractory GERD is a patient-driven phenomenon.1
The vast majority of patients have normal findings on
endoscopy, and true GERD-related complications are
rare. However, these persistent symptoms have a significant impact on quality of life. A recent systematic review
of 9 studies found that refractory symptoms in patients
on PPIs are associated with reductions in both physical
and mental health-related quality of life.6 Because not all
patients failing to respond to PPIs have GERD, the most
important goal of the diagnostic evaluation is to differentiate those with persistent reflux as the cause of their
ongoing symptoms from those with non-GERD causes,
both organic and functional.

Evaluation of Symptoms and Proton Pump

Inhibitor Compliance
Clarification of the characteristics of the persistent
symptoms and the factors that aggravate them is crucial.
Heartburn is characterized by pain or discomfort of a
burning quality beginning in the epigastrium and often
radiating into the chest. Aggravating factors are usually
foods, exercise, and the reclining position. In clinical practice, many patients with refractory heartburn
experience an atypical burning sensation beginning
in the upper chest or throat that is often unrelated to
meals and associated with dyspepsia, belching, bloating,
and throat symptoms.4 Regurgitation is an important
factor in some patients with refractory symptoms.
In clinical trials, PPIs have been less effective for the
relief of regurgitation than of heartburn.7 As a result, a
patients heartburn may be relieved by PPIs, but persistent regurgitation becomes the driving complaint. The
patient should be carefully assessed for the presence of
associated functional disorders because of their negative
impact on the treatment of reflux symptoms.3,8 In fact,
a recent study found that 3 clinical featuresa body
mass index below 25 kg/m2, normal endoscopy results,
and/or associated irritable bowel syndrome or functional
dyspepsiawere superior to 24-hour pH-impedance
parameters with the patient off antacids as predictors of
a poor response to PPI therapy.9
As part of the clinical evaluation, physicians should
carefully check the patients compliance and ensure that
PPI dosing is appropriate before ordering additional and
expensive testing. Compliance with once-daily PPIs in
patients who have GERD has been reported to be lower
in those with refractory symptoms (46%-55%) than in
those experiencing adequate relief (84%).10 The efficacy
of PPIs is generally maximized when they are taken before
a meal.11 A survey of 491 physicians in the United States
found that nearly 70% of primary care physicians and
20% of gastroenterologists advised patients to take their
PPI dose at bedtime or did not believe that the timing of
dosing in relation to meals was important.12
Once compliance and appropriate dosing have been
confirmed, a single trial of a different PPI can be considered. The efficacy of this approach was supported in
a multicenter study of patients who had persistent heartburn while taking 30 mg of lansoprazole before breakfast.
A switch to a single morning dose of 40 g of esomeprazole
was as helpful as 30 mg of lansoprazole twice daily for
relieving heartburn symptoms over 8 weeks.13 Another
randomized multicenter trial showed that either increasing PPI dosing to twice daily or switching to another PPI
resulted in symptomatic relief in 20% of patients, without
a clear advantage for either strategy.14

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Refractory GERD

Optimize PPI therapy

No response
Exclude other etiologies

Typical symptoms

Atypical symptoms

Upper gastrointestinal endoscopy

Referral to ENT, pulmonary, and allergy specialists

Normal

Abnormal (eosinophilic
esophagitis, erosive
esophagitis, or other)

Abnormal
(ENT, pulmonary, or
allergic disorder)

Specific treatment

Specific treatment
Reflux monitoring

Low pretest
probability of GERD

High pretest
probability of GERD

Test off medication with pH

or impedance-pH

Test on medication with

impedance-pH

Figure. An algorithm for the evaluation of refractory GERD as suggested by the recent guidelines from the ACG.
ACG, American College of Gastroenterology; ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.
Reproduced with permission from Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease.
Am J Gastroenterol. 2013;108(3):308-328, quiz 329.

Further Investigation of Reflux Symptoms

Refractory to Proton Pump Inhibitors
Upper Gastrointestinal Endoscopy
Patients with persistent symptoms despite the optimization of PPI therapy require further work-up. A suggested
algorithm was recently published by the American College
of Gastroenterology (Figure).15 It recommends that patients
with typical esophageal symptoms undergo upper gastrointestinal endoscopy primarily to exclude nonreflux esophageal
disorders. Those with primarily extraesophageal symptoms
persisting despite twice-daily PPIs should be referred to other
specialists for thorough pulmonary, otolaryngology, and

allergy evaluations. However, in the gastroenterology world,

all of these patients first undergo upper gastrointestinal
endoscopy, and, at the present time, the procedure is nearly
always performed while the patients are on PPIs.
In my experience, more than 90% of patients with
refractory symptoms while on twice-daily PPI therapy
have generally normal endoscopy findings. This observation was recently confirmed in a Veterans Affairs study of
100 patients, each of whom had reflux symptoms while
off PPIs or were PPI failures. Endoscopy findings were
completely normal in 54% of the PPI failures, compared
with 41% of the patients off PPIs. In the refractory group,
the most common abnormal finding was a hiatal hernia,

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Table 1. Differential Diagnosis for Patients With Refractory

Gastroesophageal Reflux Disease and Esophagitis

Eosinophilic esophagitis
Pill esophagitis
Skin diseases with esophagitis, especially lichen planus
Acid hypersecretory state: Zollinger-Ellison syndrome
Genotypic differences in cytochrome P450 2C19
metabolism

but 7% had esophagitis (all Los Angeles [LA] grade A

or B), 4% had Barrett esophagus, 1% had eosinophilic
esophagitis, and 1% had ulcer disease. There were no
upper gastrointestinal cancers.16
Several diagnoses should be considered in patients
with refractory GERD and esophagitis (Table 1). In my
experience, the most common are eosinophilic esophagitis and pill-induced esophagitis. The prevalence of eosinophilic esophagitis in patients with refractory GERD is
poorly studied but likely approximately 5%17; however,
the prevalence is much higher if dysphagia is a major
complaint. Even patients with classic LA esophagitis and
Schatzki rings can have eosinophilic esophagitis18; therefore, at least 6 biopsy specimens should be obtained from
the distal and proximal esophagus. Pill-induced esophagitis should be suspected in young and elderly patients
with atypical esophagitis or ulcers in the proximal or distal esophagus, but not adjacent to the squamocolumnar
junction. Usually, odynophagia is a major complaint, but
it may be interpreted as heartburn by the patient.19
Other, less common diseases are esophageal presentations of autoimmune skin diseases, acid hypersecretory
states, and genotypic differences. Patients with autoimmune skin diseases are primarily middle-aged to elderly
women who usually have associated dysphagia resulting
from proximal strictures and who may have lesions on
their skin, oral mucosa, and anogenital region.20 The most
common diagnosis is lichen planus,21 but epidermolysis
bullosa, pemphigus vulgaris, and cicatricial pemphigoid have also been reported. Endoscopy reveals diffuse
erythema, blistered mucosa that is easily peeled away
from the submucosa, whitish nodules, and proximal
strictures.22 Acid hypersecretory states, such as ZollingerEllison syndrome, may be associated with esophagitis and
difficult-to-manage strictures in 30% to 45% of patients.22
Associated symptoms include gastric and duodenal ulcers
and diarrhea. The esophagitis may be difficult to manage,
and intravenous PPIs are sometimes required to reduce
acid production to less than 1 mEq/h.22 Genotypic differences in cytochrome P450 2C19 enzymes, especially
in the Asian population, are associated with the rapid
metabolism of PPIs in 12% to 20% of these patients. This
may result in persistent esophagitis, usually at once-daily,
rather than twice-daily, PPI dosing.23

Refractory Gastroesophageal Reflux Disease With

Normal Endoscopy: Role of Esophageal Function Tests
If the results of endoscopy are negative, the next step is to
perform esophageal function tests, especially reflux monitoring, to quantify the presence and type of abnormal
reflux and its relationship to the patients symptoms.
Esophageal Manometry When transnasal reflux catheters are used, esophageal manometry must be performed
to define the proximal border of the lower esophageal
sphincter (LES) for proper placement of the pH catheter.
In the United States, transnasal catheters are increasingly
being replaced by wireless pH capsules, which are positioned endoscopically and do not require manometry for
placement.24 Nevertheless, achalasia and severe esophageal
motor disorders must be excluded in patients with refractory symptoms because heartburn is a common symptom
in up to 35% of patients with achalasia.25
Ambulatory Reflux Monitoring Refractory reflux symptoms are one of the most common indications for reflux
testing.2 Any of the available systems (pH alone, wireless pH
capsule, or impedance-pH) is sufficiently accurate to test
patients off PPI therapy to confirm or exclude the presence of abnormal acid reflux and define its relationship to
symptoms. Impedance-pH testing is the only technology
sufficiently accurate to measure weak and nonacid reflux
in patients on PPI therapy for assessment of adequate acid
control but ongoing symptomatic nonacid reflux.26
Clinical Questions
My approach is to address the 4 clinical questions below,
tailoring my testing to the patients PPI status to outline
further treatment.
Is the proton pump inhibitor dose insufficient to control acid reflux? As previously discussed, this is rarely the
case with double-dose PPIs. A retrospective study from
the Cleveland Clinic found that only 7% of 175 patients
with typical GERD symptoms still had abnormal acid
reflux values while on twice-daily PPIs, as did none of 145
patients with extraesophageal symptoms while on twicedaily dosing.27 Other studies suggest that up to 15% of
patients may still have abnormal acid reflux.2 Therefore,
the results of traditional pH testing are most likely to be
normal in patients on twice-daily PPIs, which would not
exclude ongoing weak or nonacid reflux. On the other
hand, studying patients with refractory symptoms while
off PPI therapy for at least 1 week has the important
advantage of defining whether the patients have abnormal acid reflux at all. This is critical if antireflux surgery is
being planned because the best predictor of surgical success is an abnormal result of a 24- to 48-hour pH test.28

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Table 2. Alternative Diagnoses in Patients With Refractory

Reflux Symptoms and Normal Endoscopic Findings

Achalasia
Gastroparesis
Eosinophilic esophagitis
Rumination
Aerophagia
Functional heartburn
Acid-sensitive esophagus
Functional heartburn with no symptom relationship

In fact, most US surgeons will not operate on a patient

who has refractory GERD without this documentation.29
Does the patient have uncontrolled weak or nonacid
reflux on twice-daily proton pump inhibitors? This
can be accurately measured only with impedance-pH
testing because PPIs do not change the number of reflux
episodes, but rather shift the pH of the refluxate from
an acidic (pH <4) to a less acidic (pH 4-6) value.30 Antimony pH electrodes cannot accurately measure weak
acid, and impedance is required to identify these episodes
of retrograde reflux.26 In both of 2 large studies from the
United States31 and Europe32 examining patients on PPI
therapy (usually twice daily), nonacid reflux accounted
for 37% of the abnormal study results, although the
number of episodes of weak or nonacid reflux was usually not increased in these studies (ie, >73 episodes per
24 hours). Rather, the abnormal association was usually
defined by a positive symptom relationshipeither the
symptom index (SI) in the United States or the symptom
association probability (SAP) in Europe. However, these
symptom analyses have been validated only for acid reflux
and the symptoms of heartburn, regurgitation, and chest
pain33,34; the analyses have not been adequately studied
for extraesophageal symptoms and weak or nonacid
reflux.2 Therapies based on these nonvalidated measurements are not predictable, which helps to explain the
lack of high-quality studies addressing the treatment of
nonacid reflux. Most commonly, impedance-pH testing
found that 50% to 60% of patients did not have reflux
to account for their symptoms.31,32 Although this finding
is encouraging for the gastroenterologist, most patients
will then ask what they should do with their PPIs. This is
a difficult question because testing while patients are on
PPIs does not allow the gastroenterologist to distinguish
those with acid reflux disease and adequate control on
their current PPI dose from the many patients who do
not have acid reflux, in whom another diagnosis needs to
be considered and the PPIs discontinued.
What is the cause of the refractory symptoms? This
question is best answered if we know the true probability of

the patient having acid reflux disease. Patients with typical

heartburn and regurgitation partially responding to PPIs
and those with endoscopic findings strongly suggestive of
acid reflux disease (persistent esophagitis, Barrett esophagus,
and large [>3 cm] hiatal hernia) have a high probability of
having GERD and are best evaluated to address this question with impedance-pH testing while on PPI therapy. On
the other hand, the vast majority of patients with refractory
symptoms have atypical heartburn complaints, extraesophageal symptoms, and normal endoscopic findings, with little
to no response to a multitude of different PPIs. Therefore,
these patients have a low probability of having GERD and
can be studied with any of the 3 pH tests while off PPIs for
at least 1 week. Only 2 studies have compared the yield of
reflux monitoring while the same patients with refractory
GERD were off and on PPI therapy. Hemmink and colleagues35 concluded that patients should be tested while off
PPIs because this approach gave a higher yield of abnormal
acid reflux exposure (12 subjects off therapy vs 10 subjects on
therapy) and a positive SAP correlation (15 vs 11 subjects).
In contrast, Pritchett and colleagues36 found that reflux monitoring with patients on therapy might be the best approach.
Does the patient have abnormal acid reflux at all? I
believe that this is the most important question to answer
in my practice, as most of my patients (70%) have a low
probability of having GERD. If third-party payors allow,
I prefer to perform 48-hour and sometimes 92-hour
wireless pH capsule studies to increase the likelihood of
detecting abnormal acid reflux values and a correlation
of symptoms with episodes of acid reflux.37 In the experience of many large esophageal centers, the majority of
these patients have no acid reflux and a poor correlation
between symptoms and acid reflux. In this setting, other
gastrointestinal diagnoses need to be considered (Table
2). Patients with primarily extraesophageal complaints
can be referred back to otolaryngology, lung, or cardiac
specialists with great confidence that GERD is not causing their symptoms and that other etiologies must be
considered. Lastly, and perhaps most importantly, these
patients can be encouraged to stop their PPIs and use
other medications to relieve their symptoms. However,
a recent retrospective study suggests that this may be
more easily said than done. After a negative evaluation
for refractory GERD that included normal endoscopic
findings and negative results of reflux testing, 42% of 90
patients on chart review 2 years later reported continued
use of PPIs despite the negative test results.38 This study
emphasizes the importance of a face-to-face conversation
to educate patients about the need to stop PPIs once
GERD has been ruled out. On the other hand, if patients
are found to have abnormal acid reflux parameters with a
strong relationship to symptoms, then these patients have

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GERD, the timing of PPI medication can be adjusted,

and antireflux surgery becomes a viable option.

Treatment of Proton Pump Inhibitor

Nonresponders

Alternative Diagnoses in Patients With Refractory Reflux

Symptoms
Table 2 outlines the important diseases that I attempt to
identify after GERD has been ruled out. Achalasia is often
misdiagnosed if heartburn is a predominant complaint
and the esophagus is not dilated.39 The dysphagia of these
patients does not decrease with esophageal dilation, as would
be expected with a peptic stricture. Esophageal manometry
and high-quality barium studies will confirm the diagnosis
of achalasia. Mild to moderate gastroparesis is likely the most
common alternative organic disease that I find in patients
with PPI-refractory symptoms. Helpful clues include the
associated symptoms of pain, belching and bloating after
meals, more regurgitation than heartburn, and a normal
LES pressure on esophageal manometry. Most of these
patients are women with idiopathic gastroparesis, confirmed
by a 4-hour gastric emptying study. Eosinophilic esophagitis
must be considered because heartburn can be a dominant
symptom, and approximately 10% of patients will have normal endoscopic results but positive findings on esophageal
biopsy.40 Other, less common syndromes include rumination
and aerophagia, which respond well to behavioral modification. Rumination should be suspected primarily in women
with effortless regurgitation within the first 2 hours after a
meal.41 Their reflux material is usually not acidic. A recent
study that used impedance-pH monitoring found that 26
patients with PPI-refractory symptoms swallowed more air
during meals and had more episodes of reflux containing gas
than 18 patients with PPI-responsive symptoms.42
After testing, up to 58% of patients will have a final
diagnosis of functional heartburn.2 This comes in 2
forms: acid-hypersensitive esophagus and functional
heartburn. Patients with the former condition have a
positive association of symptoms with acid reflux, but
the esophageal acid reflux parameters are normal.43 These
patients usually have a normal esophagus on endoscopic
examination, frequently have dyspeptic symptoms, and
are less responsive to PPIs and fundoplication than those
with abnormal acid exposure, although prospective data
are lacking.2 Functional heartburn is defined by the Rome
III criteria as heartburn refractory to PPIs in patients
with normal endoscopic findings, normal esophageal acid
reflux exposure, and a negative association of symptoms
and reflux.44 The current diagnosis is based on acid reflux
monitoring only, but the addition of impedance to pH
testing may increase the diagnostic yield from 29% with
pH testing alone to 39%.44 In overall studies performed
with 24-hour pH-impedance testing, 21% to 40% of
patients with PPI-refractory reflux symptoms are reported
as having functional heartburn.2,44,45

As discussed, the key to successful treatment is a better

understanding of the physiology causing the symptoms.
In this context, one might even argue that patients who
fail to obtain symptom relief after a single-dose PPI
should undergo endoscopy and reflux testing before progressing to expensive and potentially dangerous doubledose PPI treatment. However, this is not realistic in a busy
gastroenterology clinic, and doubling the PPI dose will
always be the first next step. However, we know that only
approximately 20% to 25% of this refractory group will
respond.14 What else do we have to offer these patients?
The options are not great, which underscores the need to
test early and then attempt to resolve the symptom issues.
Acid Suppression
In practice, patients are frequently switched to another
PPI, although there are no strong scientific data to support this approach. To date, 2 studies, one controlled46
and the other randomized,47 support switching from a
first-generation PPI to esomeprazole. This may even be
cost-effective.47 Doubling the dose of the same PPI is usually done first, but the 2 available studies13,14 show only
a 20% to 30% success rate, with 25% of subjects still
experiencing refractory symptoms.
If acid is the driving factor behind persistent symptoms, logic suggests that a faster onset of action or a
greater degree of acid inhibition should help. However,
the results of studies with dexlansoprazole (Dexilant,
Takeda) or potassium-competitive acid blockers have
been disappointing. Dexlansoprazole, with its 2-stage
releasing process, failed to produce any clinically significant improvement in either healing rates or esophagitis
and symptom control.48 Despite a more rapid onset of
action and nearly complete acid inhibition, AZD0865
(revaprazan), a potassium-competitive acid blocker,
failed to achieve any significant improvement in esophagitis healing rates or symptom relief compared with
esomeprazole in 2 large clinical trials.49,50 The development of this class of compounds has been discontinued.
Nocturnal breakthrough of gastric acid occurs in
more than 75% of patients on twice-daily PPIs, and
adding a histamine-2 receptor antagonist (H2RA) at
bedtime can improve nighttime acid control.51 Whether
this results in symptom relief has yet to be established.
The only clinical data come from a retrospective,
uncontrolled case series that reported overall symptom
relief in 72% of patients.52 Furthermore, tachyphylaxis
with daily H2RA use may blunt its effectiveness over 4
weeks.53 The addition of an H2RA at night is inexpensive and safe and can help some patients with nocturnal

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symptoms. It may be best if an H2RA is taken intermittently, such as before going to bed after a late or heavy
meal, rather than daily.
Reflux Inhibitors
Because transient LES relaxation is the main mechanism underlying all forms of reflux, directed therapy to
decrease these events appears to be the next logical step
when PPIs and H2RAs fail. However, despite aggressive
pharmaceutical testing over the past 10 years, the only
compound available is baclofen, a -aminobutyric acid
type B (GABAB) agonist used for many years to treat
spastic muscle disorders. Baclofen decreases the number
of postprandial acid and nonacid reflux events via inhibition of transient LES relaxation and reduces reflux symptoms.54,55 The dosage of 20 mg 3 times daily has been
proposed in refractory GERD. However, no controlled
trials of baclofen have been conducted in PPI nonresponders, and side effects are a major issue. Baclofen
crosses the blood-brain barrier, and despite progressive
titration of the drug from 5 mg to 20 mg over 1 to 2
weeks, many patients experience somnolence, dizziness,
and drowsiness. A number of GABAB agonists with
better tolerability were developed (arbaclofen placarbil
and lesogaberan), but all have been abandoned, mainly
because of limited clinical efficacy.2 I have had some success with baclofen in patients who had increased episodes
of nonacid reflux (>72 per day) and related symptoms
and, more recently, in 2 patients with rumination.
Pain Modulators
As already discussed, many patients with persistent
symptoms despite PPI therapy have normal esophageal
acid exposure and a form of visceral hypersensitivity.
This appears to be the case both for patients with acidhypersensitive esophagus and for the larger group with
functional heartburn. In this situation, the use of pain
modulators, such as tricyclic antidepressants, trazodone,
and selective serotonin reuptake inhibitors (SSRIs), offers
the best opportunity for symptom relief. They have been
shown to relieve esophageal pain in patients with noncardiac chest pain,56 but the data for refractory GERD are
limited. In a recent randomized, placebo-controlled trial,
the SSRI citalopram (20 mg at bedtime for 6 months) was
shown to be effective in patients with acid-hypersensitive
esophagus and refractory reflux symptoms.57
Other approaches to address visceral hypersensitivity
include acupuncture and hypnotherapy. In a small series
of 30 patients with refractory heartburn, acupuncture in
combination with a single-dose PPI was more effective
than double-dose PPIs.58 High levels of anxiety are seen
in patients with a poor correlation between symptoms
and episodes of reflux.59 In patients with noncardiac chest

pain, hypnotherapy improved pain relief and decreased

medication use.60 I have used hypnotherapy in several
patients with good outcome. Further studies are needed
because the therapy is time-consuming and expensive.
Endoscopic Therapy
Currently, only 2 antireflux endoscopic devices are on
the market: radiofrequency energy delivery at the gastroesophageal junction (Stretta, Mederi Therapeutics) and
transnasal incisionless fundoplication (EsophyX, EndoGastric Solutions). The former procedure may decrease
esophageal sensitivity to acid but does not decrease acid
reflux.61 Although current guidelines do not support its
use in patients with GERD,15 it may have a role as a pain
modulator technique in certain patients and warrants
further testing in patients with a hypersensitive esophagus or functional heartburn.2 Small studies with transnasal incisionless fundoplication show relief of symptoms
and 50% normalization of acid reflux parameters, but the
long-term durability of the procedure is suspect.62
Antireflux Surgery
There is no doubt that laparoscopic fundoplication is a
very effective therapy for controlling acid and nonacid
reflux.63 The best candidates are patients who (1) have
abnormal reflux parameters while off PPIs, (2) have
typical symptoms, and (3) show some response to
PPIs.28 However, some data suggest favorable outcomes
in patients who have an inadequate PPI response. For
example, one study reported similar 5-year postoperative
outcomes in patients with abnormal acid exposure times
regardless of whether their SI or SAP was positive or
negative.64 Patients with a positive SAP (acid-hypersensitive esophagus) and normal acid reflux values are also
reported to do well with surgery.65 Whether a decision
for antireflux surgery can be based on abnormal nonacid
reflux and symptom correlation alone is not known. The
results of 2 studies66,67 with limited follow-up have suggested that typical symptoms (heartburn and regurgitation, not extraesophageal complaints) decrease, and one
of these studies67 documented postoperative decreases
in episodes of nonacid reflux. A recent medical-surgical
advisory board recommends documenting abnormal
acid reflux in all patients before surgery.29 Some patients
who have an acid-hypersensitive esophagus with normal
reflux values may do well surgically, but their SI or SAP
should be highly positive and the patients warned that
the outcome is not guaranteed.2 Currently, the added
value of impedance-pH monitoring remains to be determined by prospective studies. These caveats are primarily
for patients with typical reflux symptoms; all bets are
off for those with primarily extraesophageal symptoms,
especially those with no heartburn or regurgitation.68,69

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Conclusions
Suspected reflux symptoms refractory to PPI therapy
are common and can be a frustrating problem. Before
testing, patient compliance to PPIs should be investigated, and switching PPIs or doubling the dose for 6 to 8
weeks should be considered. For nonresponders, the first
diagnostic test should be upper endoscopy, but in 90%
of cases, the results will be normal. Next, esophageal
manometry and pH testing should be performed, usually
in patients off PPIs for at least 1 week. In my experience,
over 70% of these refractory GERD patients will be
found to have normal reflux testing, and other diagnoses
will need to be considered, including achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. However, more than 50% will have functional
heartburn, a visceral hypersensitivity syndrome. Treating
patients with PPI-refractory GERDlike symptoms can
be difficult, as no medical, endoscopic, or surgical treatments have proven efficacy.
Dr Richter has no relevant conflicts of interest to disclose.
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