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GERD, defined as the occurrence of symptoms orlesions as a consequence of retrograde flow of gastriccontents into the oesophagus1, is one of the most preva-lent gastrointestinal disorders worldwide2. Heartburnand regurgitation are the typical symptoms of GERD,but GERD can also manifest itself through non-cardiacchest pain, pulmonary or ear, nose and throat symp-toms and dental erosion1. Acid-suppressive therapy,especially PPI therapy, is the first-line approach forGERD treatment. PPIs in general have a favourableadverse effect profile, are highly effective at healingoesophagitis and provide symptom control in the

majority of patients2. However, a substantial subgroupof up to 30% of patients with GERD will continue toexperience reflux symptoms despite adequately dosedPPI therapy 3,4. GERD in these patients is termedrefractory GERD (rGERD)4,5.

Current guidelines recommend starting acid-suppressive therapy, and especially PPIs, in patientspresenting with typical GERD symptoms withoutdiagnostic testing3–5. Upper gastrointestinal endoscopycan be performed in individuals with additional riskfactors for GERD (including increasing age, intake ofNSAIDs, smoking, alcohol and family history of uppergastrointestinal cancers) and in those who have failed

to respond to initial PPI therapy. Early endoscopy alsohas to be considered to exclude other more seriousconditions (such as oesophageal carcinoma) in thosepresenting with atypical or alarm symptoms (such asweight loss, anaemia or dysphagia) and in those at riskof Barrett oesophagus (FIG. 1). In the past, histamine H2 receptor antagonists, which reduce gastric acid secretion,were proposed as adjunctive treatments to PPI therapyin individuals with incomplete PPI response6, but thisapproach has been abandoned as a long-term strat-egy because patients rapidly develop tolerance againstthe acid-suppressive effects of these drugs7. Currently,

increasing the dose of the PPI to twice a day is thestandard clinical approach for patients with insufficientsymptom control on a standard once a day PPI dose.PPI dosing escalation is based upon indirect evidencefrom studies monitoring oesphogeal pH in patients withGERD on low-dose or high-dose PPI regimens, whichshow better control of oesophageal acid exposure withhigher PPI doses (TABLE 1). In addition, dose escalation isalso supported by results from a small number of clinicaltrials comparing the effects of once a day PPI doubledosing and of twice a day PPI standard dosing comparedwith standard once a day PPI dosing on acid reflux or onsymptom control3,8–12. On the basis of these studies and

1Translational Research in

Gastrointestinal Disorders

(TARGID), University ofLeuven, Herestraat 49,

B-3000 Leuven, Belgium.2Division Gastroenterology,

Sapienza University of Rome,

Viale del Policlinico 155,

00100, Rome, Italy.3Division of Gastroenterology,

Changi General Hospital,

2 Simei Street 3,

Singapore 529889.

Correspondence to J.T.

[email protected]

doi:10.1038/nrgastro.2016.50

Published online 14 April 2016

Management of refractory typicalGERD symptomsEmidio Scarpellini 1,2, Daphne Ang 3, Ans Pauwels1, Adriano De Santis3, Tim Vanuytsel 1

and Jan Tack1

Abstract | The management of patients with refractory GERD (rGERD) is a major clinical

challenge for gastroenterologists. In up to 30% of patients with typical GERD symptoms

(heartburn and/or regurgitation), acid-suppressive therapy does not provide clinical benefit.

In this Review, we discuss the current management algorithm for GERD and the features and

management of patients who do not respond to treatment (such as those individuals with anincorrect diagnosis of GERD, inadequate PPI intake, persisting acid reflux and persisting

weakly acidic reflux). Symptom response to existing surgical techniques, novel antireflux

procedures, and the value of add-on medical therapies (including prokinetics and reflux

inhibitors) for rGERD symptoms are discussed. Pharmaceutical agents targeting oesophageal

sensitivity, a condition that can contribute to symptom generation in rGERD, are also

discussed. Finally, on the basis of available published data and our expert opinion, we present

an outline of a current, usable algorithm for management of patients with rGERD that

considers the timing and diagnostic use of pH–impedance monitoring on or off PPI, additional

diagnostic tests, the clinical use of baclofen and the use of add-on neuromodulators

(tricyclic agents and selective serotonin reuptake inhibitors).

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on clinical practice experience, it has been proposed thatrGERD is defined as the persistence of typical symptoms(heartburn and/or regurgitation) that do not respond toa stable double dose of a PPI during a treatment periodof at least 12 weeks4,5.

The 30% of patients with GERD remaining symp-tomatic in spite of double PPI dosing constitute a largeproportion of gastroenterology clinical practice, owingto the high prevalence of GERD symptoms in this popu-lation5. As the progress in establishing effective manage-ment approaches for patients with rGERD has been slow,this patient population poses considerable challengesto practicing clinicians5. This Review summarizes thecurrent management of patients with refractory typicalGERD symptoms (heartburn and regurgitation) anddiscusses advances made in the past few years.

Mechanisms underlying rGERD symptoms

A range of underlying mechanisms can contributeto persistent GERD symptoms, including poor com-pliance to prescribed PPI use, weakly acidic reflux(pH >4), persistent regurgitation of large volumes ofnon-acid refluxate and oesophageal hypersensitivity 4,5,13.Additional factors have been proposed as potential con-tributors to rGERD pathogenesis: lower oesophagealsphincter (LES) dysfunction; poor oesophageal clear-ance; decreased resistance of the oesophageal mucosato reflux-induced damage; persistence of an acidpocket at the gastro-oesophagal junction; and slowgastric emptying4,5,13,14.

Performing an upper gastrointestinal endoscopyis usually recommended in patients with GERD not

responding sufficiently to PPI if this procedure wasnot done at the start of treatment, but the diagnosticyield of endoscopy on high-dose PPI regimens is low 15.Multichannel intraluminal impedance–pH (MII–pH)monitoring, which enables the detection of all types ofreflux independent of their acidity, can be combinedwith an analysis of symptom occurrence reported bythe patient during the measurement to determine theassociation of reflux events with GERD symptoms. TheMII–pH monitoring technique, in combination withstatistical analysis of the relationship between symptomsand reflux events (symptom index or symptom associ-ation probability, SAP) has contributed to improved

understanding of some of the mechanisms underlyingrGERD4,5 (FIG. 1). Approximately 16% of patients withGERD symptoms that persist in spite of PPI therapy haveongoing abnormal acid exposure, and a positive symp-tom index or SAP for acid reflux is found in 13–16% ofthose with PPI-refractory symptoms (TABLE 1). In bothof these patient groups, ongoing acid reflux seems totrigger rGERD symptoms. The prevalence of a positivesymptom index or SAP for non-acid reflux (defined asweakly acidic (pH 4–7) or alkaline reflux) is 25–27%4,5 (TABLE 1) and, in these patients, non-acid reflux seems totrigger rGERD symptoms. In the majority of patients,however, ongoing symptoms cannot be attributed to acidor non-acid reflux events based on symptom index orSAP analysis4,5,9,14,16–37.

Patients with persisting acid reflux

In those patients with persisting acid reflux on MII–pH monitoring, compliance with PPI intake needs tobe assessed, both in terms of dose and timing, as theseare key factors underlying poor PPI response38. Ideally,

PPIs are taken 0.5–1 h before a meal, typically breakfastand/or dinner. In some individuals, acid exposure canoccur in spite of adequate PPI dosing and intake4–7,10. Oneapproach to inadequate acid suppression might be tofurther increase the PPI dose, but very little informationis available on the therapeutic benefit of doses greaterthan the standard twice a day intake recommended forpatients with rGERD; in addition, the optimal dosingfrequency or the tolerance and safety of higher PPI doseshave not been established. Acid-suppressive drugs thatare stronger or longer acting than currently availablepharmaceuticals have a theoretical potential to providebetter symptom relief in patients with a poor responseto adequately dosed PPIs.

Patients with persisting non-acid reflux

For patients with persisting non-acid reflux as thecause of symptoms during adequate acid suppression,reinforcement of the antireflux barrier seems to be themost logical approach to prevent non-acidic materialrising into the oesophagus. This reinforcement can beachieved by increasing resting LES pressure, reducingthe occurrence of transient lower oesophageal sphinc-ter relaxations (TLESRs) or repairing hiatal herniasand related mechanical defects. Antireflux surgery is anoption but, in theory, drugs that enhance LES functioncould also be considered for patients with persisting

non-acid reflux5,38. Indirect approaches, such as pro-kinetic therapy to enhance oesophageal clearance andspeed up gastric emptying, could also result in thera-peutic benefit to patients with persisting non-acid oracid reflux5. Patients whose symptoms occur indepen-dently from reflux events, (that is, those with a nega-tive symptom index or SAP) seem less likely to respondto reflux-inhibitory approaches, although the availabledata are limited5,38. In this group, which are defined ashaving functional heartburn according to the Rome IIIcriteria39, visceral hypersensitivity is thought to con-tribute to symptom generation38–40. Visceral hypersen-sitivity is also implicated in patients with symptomatic

Key points

• Patients with refractory GERD (rGERD) are those individuals whose symptoms

do not respond to a stable double dose of a PPI during a treatment period of at least

12 weeks

• Weakly acidic reflux episodes have been implicated in symptom generation in

patients with rGERD

• Several reflux inhibitors have been studied for rGERD treatment, but development

was discontinued because of limited clinical efficacy and poor tolerance profiles

• Antidepressant drugs are emerging as potentially efficacious neuromodulatory

therapies for patients with rGERD

• Data suggests that antireflux surgery has lower efficacy in rGERD than in GERD

• The experience with novel endoscopic or surgical techniques is limited and their

application requires large-scale studies

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non-acid reflux, as in this group the number and dur-ation of reflux events are usually in the normal range40,41.The outcomes of MII–pH testing and related measure-ments can suggest a number of different pathophysio-logical mechanisms responsible for rGERD symptomsand inform the use of therapeutic options, includingstronger acid suppression, motility-modifying or anti-reflux drugs, antireflux surgery and related approachesand drugs targeting visceral hypersensitivity.

As the results of reflux monitoring can inform thera-peutic strategy selection, a major role for MII–pH

studies in the clinical management of patients withrGERD is expected (FIG. 1). However, an importantproblem in determining the pathophysiological mech-anisms underlying rGERD symptoms from the analysisof MII–pH data is the major dependence on the use ofsymptom markers and quantification of their relation-ship with reflux events. Although these analyses, usingsymptom index or SAP, are decisive in categorizingpatients’ symptoms as related or unrelated to acid or non-acid reflux events, their relevance in determining treat-ment outcomes has never been adequately proven42–44.Moreover, outcome studies dedicated to studying thebenefit of MII–pH monitoring on long-term symptom

control in patients with rGERD are lacking 38. Hence,caution should be applied when using MII–pH data ina clinical setting to decide whether patients will receiveother medical therapeutic approaches or whether, forinstance, they will be referred for surgery.

Surgery for rGERD symptoms

Traditionally, antireflux surgery has been consid-ered as the logical option for treating patients withrGERD. Several peer-reviewed and controlled studiesinvestigating patients reporting a complete or at leastpartial response to PPI therapy before antireflux sur-gery showed a benefit of antireflux surgery for rGERDsymptoms45–48 (TABLE 2). Furthermore, a favourableresponse to PPI treatment (at least 50% symptomimprovement), good compliance with antireflux medi-cation, the presence of typical symptoms and objectivepreoperative evidence of acid reflux all predict goodoutcome in terms of symptom control49,50. By contrast,a poor response to PPI was identified as a risk factor forpersistent symptoms in a large case series of antireflux

surgery 50. Although some case series report favourablesymptomatic outcomes after antireflux surgery in poorresponders to PPIs51,52, a single study comparing the out-comes of antireflux surgery in patients with completePPI response with outcomes in patients with incom-plete PPI response showed a higher symptom burdenand lower physical health quality of life scores and atendency towards higher persisting PPI use in the lattergroup53.Taken together, these data suggest that rGERDis associated with an increased risk of unfavourableoutcomes after antireflux surgery, and that caution isneeded when selecting patients with rGERD for sur-gery 54. On the basis of these considerations, we proposethat the selection of patients with rGERD for classic(laparoscopic Nissen fundoplication) antireflux surgeryshould be guided by a rigorous patient evaluation thatincludes careful assessment of symptoms, particularlyheartburn and regurgitation, and reflux monitoring offPPI treatment.

Novel invasive procedures

As a result of the invasive nature of antireflux sur-gery and the potential for adverse effects, such as gasbloat syndrome, dysphagia and dyspepsia3,48,54, severalattempts have been made to develop endoscopic orminimally invasive approaches to restore the antirefluxbarrier55. A f irst generation of devices and procedures,

developed around the beginning of the millennium, werecharacterized by a lack of efficacy or durability 55, andonly radiofrequency ablation therapy (Stretta®, MederiTherapeutics, USA) is currently still used56. Case seriesof patients with rGERD treated with radiofrequencyablation therapy with long-term follow-up (for exam-ple, over several years) have reported sustained symptomcontrol in the majority of patients57, but controlled datain these patients are lacking.

In the past few years, a new generation of minimallyinvasive antireflux approaches have become available.A magnetic sphincter augmentation device (Linx™, ToraxMedical, UK), surgically positioned around the LES,

No alarm symptoms

Additional alarmsymptoms or risk factors

Endoscopy

Double-dose PPI therapy

Maintenance treatment

• Endoscopy

• Manometry

• MII-pH monitoring

Positive for acid reflux

• Optimize acid suppression

• Consider antireflux surgery

• Reflux inhibitor therapy

Positive fornon-acid reflux

• Consider antireflux surgery

• Reflux inhibitor therapy

Negative for rGERD

• Functional dyspepsia or functional heartburn probable

• Consider neuromodulator therapy

Symptom resolution rGERD symptoms*

Persisting symptoms

PPI therapy

Typical GERD symptoms (heartburn ± regurgitation)

Figure 1 | Current treatment algorithm for patients with typical GERD symptoms.

Investigation of patients with rGERD symptoms is centred around multichannel

intraluminal impedance (MII)–pH monitoring. *Before rGERD can be considered, one

should ensure that the PPI regimen is adequately dosed and timed, that patient

compliance with the regimen is confirmed, and that symptoms are typical of GERD

(heartburn and/or regurgitation) and are not located in the epigastrium (dyspepsia)

or in the throat area. rGERD, refractory GERD.

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was developed with the intent of generating an effec-tive antireflux barrier whilst preserving easy deglutitivebolus passage and ability to belch58. In a retrospectivecase series of patients with rGERD over 6 monthsfollow-up, the magnetic sphincter augmentation devicewas able to provide similar symptom and pH control,and improved belching and bloating symptoms, com-pared with a similar cohort undergoing Nissen fundo-plication59. However, controlled prospective series areneeded. Notably, the magnetic sphincter augmentationprocedure is often combined with surgical closure ofa hiatal hernia, if present, which might contributeto the antireflux efficacy of the technique but also tothe occurrence of dysphagia58. In one study, a subsetof patients receiving magnetic sphincter augment-ation required endoscopic dilation for dysphagia afterthe procedure59.

Transoral incisionless fundoplication is an endoscopy-based procedure that aims to reinforce the antirefluxbarrier function by wrapping part of the fundus aroundthe gastro-oesophageal junction60,61. In a randomizedtrial, transoral fundoplication was superior to high-dosePPI therapy in controlling symptoms of heartburn andregurgitation in 60 patients with rGERD at follow-up after6 months60. In a sham-controlled study in 129 patientswith rGERD and troublesome regurgitation receivingPPI treatment, those who were randomly assigned toreceive active transoral fundoplication and placebo weremore likely to report elimination of regurgitation after6 months of follow-up than those randomly assigned toreceive sham procedure and double-dose omeprazole(67% versus 45%, respectively). The group who under-went active surgery also showed a greater reductionin heartburn and regurgitation symptom scores than

Table 1 | Symptom association (SI and SAP) in patients with typical GERD symptoms on PPI

Study (n; total patients on

PPI therapy)

Assessment

method

Patients

withpathologicalacidexposure

Patients

withpositiveSI for acidreflux

Patients

withpositive SIfor non-acid reflux

Other patient

populations(positive SAPfor acid ornon-acid reflux)

Ref.

Katzka et al. (1996) n= 45 pH 4 – – – 16

Charbel et al. (2005) n= 250 pH 42 44 – – 9

Bautista et al. (2005) n= 69 pH 25 21 – – 17

Zerbib et al. (2006) n= 71 pH/impedance 5 6 23 12*19‡

18

Mainie et al. (2006) n= 168 pH/impedance – 16 53 – 19

Tutuian et al. (2006) n= 50 pH/impedance 1 – 13 – 20

Anandasabapathy et al. (2006)n= 33

pH/impedance – 3 4 – 21

Pace et al. (2007) n= 13 pH/impedanceBilitec®

2 – – – 22

Becker et al. (2007) n= 143 pH/impedance 20 – – – 23

Sharma et al. (2008) n= 200 pH/impedance – 14 77 – 24

Karamanolis et al. (2008) n= 347 pH/Bilitec® 105 18 – – 25

Hemmink et al. (2008) n= 30 pH/impedance 10 – – – 26

Tutuian et al. (2008) n= 120 pH/impedance – – – – 27

Blonski et al. (2009) n= 70 pH/impedance 10 – – – 28

Pritchett et al. (2009) n= 39 Bravo® pHimpedance

0 – – – 20

Khan, A. et al. (2010) n= 51 pH/impedance 13 – – – 30

Iwakiri et al. (2010) n= 10 pH/impedance – 3 7 – 31

Frazzoni et al. (2011) n= 20 pH/impedance – 4 – – 32

Karamanolis et al. (2011) n= 71 pH/impedance – 12 13 – 33

Kohata et al. (2012) n= 29 pH/impedance – 1 2 – 34

Kunsch et al. (2012) n= 47 pH/Bilitec® 9 – – – 35

Yamashita et al. (2012) n= 25 pH/impedance 2 4 5 – 36

Frazzoni et al. (2012) n= 80 pH/impedance 7 – – – 37

Overall n= 1,981 255/1,585(16%)

146/1,099(13%)

197/788(25%)

12/71 (17%)*19/71 (28%)‡

–, not available; SAP, symptom association probability; SI, symptom index. *Patients with positive SAP and acid reflux. ‡Patientswith positive SAP and non-acid reflux.

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patients undergoing the sham operation, and reducedoesophageal acid exposure during pH-monitoring offmedical therapy. No major complications as a result ofsurgery occurred61.

Intermittent electrical stimulation of the LES isanother novel invasive approach to GERD and rGERDtreatment, but the available literature to date is restrictedto case series; the longest follow-up in these studies was2 years in 23 patients with rGERD62. The number of stud-ies investigating novel invasive approaches to rGERDtreatment, the total number of patients included in thesestudies and the follow-up duration of these patients is stilllimited, and further usage of novel invasive GERD treat-ments should ideally occur in a research setting (TABLE 3).Longer follow-up and additional comparisons with tradi-tional antireflux surgery are needed to determine the placeof these novel procedures in the treatment of rGERD.

Add-on medical therapies for rGERD

Alginates

Alginates decrease gastro-oesophageal reflux by forminga pH-neutral raft localized near the gastro-oesophageal

junction, at the site of the postprandial acid pocket on topof the intragastric food63. In a small study in 16 patientswith rGERD with a hiatal hernia of >3 cm, an alginate–antacid combination was superior in reducing thenumber of acid reflux episodes, but not non-acid refluxepisodes, compared with a standard antacid formula-tion63. In a multicentre, randomized placebo-controlledstudy in 134 patients with rGERD symptoms in spiteof once-daily PPI treatment, alginate suspension as anadd-on therapy decreased the severity and frequencyof heartburn, the frequency of regurgitation and thenumber of days with night-time symptoms64. Alginateformulations differ between the USA and Europe, with

Table 2 | Surgical approaches to treat GERD

Study Procedure Number of patients Studydesign

Follow-upduration

Outcomes Ref.

Peterset al. (1998)

Nissenfundoplication

100 patients withGERD (30 with refluxoesophagitis)

Prospectivestudy

21 months • ↓ Symptoms in 96% of patients, no deaths; seriouscomplications in 4% of patients

• ↓ Erosive oesophagitis and 24 h oesophageal acidexposure (oesophagitis resolved in 93% of patients)

• ↑ LES pressure

45

Anvariet al. (2003)


181 patients with rGERD(64% with rGERD and36% of patients opting forsurgery in preference tolong-term PPI therapy)

Prospectivestudy

5 years • ↓ GERD symptoms at 5 years, 12% with symptomrecurrence and 6% with further surgery

• ↓ 24 h oesophageal acid exposure• ↑ LES pressure, although decreasing at 5 years

46

Gilles et al. (2008)


38 patients with rGERDon PPI

Retrospectivestudy

6 months • ↑ QOL• ↓ Gastrointestinal and reflux symptom scores

47

Lundell

et al. (2015)

Nissen

fundoplicationvs esomeprazole20 mg or 40 mg

116 patients with rGERD Prospective,

randomizedopen-labelstudy

5 years Similar↓ GERD symptoms and 24 h oesophageal

acid exposure at 5 years

48

Camposet al. (1999)


139 patients with rGERDwith small hiatal hernias(≤2 cm)

Prospectivemultivariateanalysis

15 months • 86% had good or excellent outcome• Positive predictive factors: abnormal 24 h pH

score (main); typical primary symptom;clinical PPI response

50

Wilkersonet al. (2005)


324 patients with GERD(good PPI responders(n = 233) vs poor PPIresponders (n = 91))

Prospectivestudy

Median1 year

• Similar↓ GERD symptoms (94% of goodresponders reported good or excellent outcomesvs 87% of poor responders)

• 8% of the patients had poor surgery outcomedespite↓ GERD symptoms (only 1.5% hadabnormal 24 h pH)

51

Hamdyet al.

(2014)


370 patients withGERD (good PPI

responders (n = 296) vspoor PPI responders(n = 74) (atypical refluxsymptoms))

Prospectivestudy

12 months • ↓ Heartburn and regurgitation and ↑ integrityof the surgical wrap (fundoplication) in good

PPI responders• Similar anatomical and functional parameters

between patient groups

52

Anvariet al. (2003)


Patients with rGERD(445 poor PPI respondersvs 274 good PPIresponders)

Prospectivestudy

5 years • Similar↓ GERD symptoms and 24 h oesophagealacid exposure at 5 years in both groups

• Poor responders had statistically significantimprovements in both the physical and mentalhealth components of the QOL questionnaire

53

Lundellet al. (2014)


2,852 patients withrGERD (partial PPIresponders)

Systematicreview

16 yearsliteraturereview

• ↓ Heartburn and regurgitation.• Progressive symptom recurrence over time• At 10 years after surgery, heatburn in 36%,

regurgitation in 29%, PPI use in 18%

54

LES, lower oesophageal sphincter; QOL, quality of life; rGERD, refractory GERD.

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European formulations having higher concentrations ofalginate, which might improve symptom control64.

Prokinetic agents

Prokinetic agents are a plausible approach for treatingrGERD as they can increase LES pressure, enhanceoesophageal clearance of refluxed material and stim-ulate gastric emptying rate65,66. Because PPIs areeffective at treating oesophagitis, safe and widely avail-able, prokinetics should mainly be considered as anadd-on treatment for rGERD (TABLE 4). Cisapride, a5-hydroxytryptamine receptor 4 (5-HTR 4) agonist, wasthe first prokinetic to be approved for GERD treatment(the drug was approved for treatment of nocturnalheartburn)67. The efficacy of cisapride, added to hista-mine H2 receptor antagonists or PPIs, was addressed intwo clinical trials68,69. In a study of patients with severeerosive oesophagitis, combined therapy with cimeti-

dine and cisapride was superior to either agent alone athealing or improving erosive oesophagitis and in con-trolling symptoms of heartburn68. In a 5-arm mainten-ance trial of therapies for the treatment of oesophagitiswith 30 patients per arm, ranitidine plus cisapride wassuperior to ranitidine alone in providing continuedremission and maintaining control of symptoms, butthe combination of omeprazole with cisapride was notsuperior to omeprazole alone69. However, cisapride wasshown to cause corrected QT prolongation and poten-tially fatal arrhythmias, through a mechanism independ-ent of 5-HTR 4, and was progressively removed from themarket after 2002 (REF. 67). A number of other selective

5-HTR 4 agonists have also been evaluated for GERDtreatment, including mosapride and revexepride (FIG. 2).

Mosapride is a selective 5-HTR 4 agonist, with abenzamide structure similar to cisapride, which stimu-lates oesophageal clearance and gastric emptying rate66.A randomized controlled study conducted in India foundthat a combination of pantoprazole and mosapride wasmore effective at providing symptom relief than panto-prazole alone for patients with erosive oesophagitis, butnot in those with nonerosive reflux disease (NERD)70.In a randomized controlled study conducted in Taiwan,mosapride 5 mg three times a day added to lansopra-zole 30 mg daily was not superior to placebo plus lanso-prazole 30 mg daily for the control of GERD symptoms71.In a subgroup with severe GERD symptoms before treat-ment, mosapride seemed to provide additional benefitat week 4, but not at week 8. In a study carried out inJapan, Miwa et al.72 compared NERD symptom response

in patients receiving omeprazole treatment either withor without mosapride, and found no difference in symp-tom response between both groups. Taken together, thesethree studies show that combining a PPI with mosaprideprovides insufficient additional benefit over the PPIalone in treating GERD. However, none of these studiesaddressed patients with rGERD. Three uncontrolled caseseries of patients with GERD with incomplete responseto PPI showed better GERD symptom control after add-ing mosapride73–75. In a randomized controlled studyof 60 patients, omeprazole alone was similarly effectiveas the combination of omeprazole and mosapride inimproving GERD symptoms76.

Table 3 | Novel invasive approaches to treat GERD

Study Procedure Patients Study design Follow-upduration

Outcomes Ref.

Perry et al. (2012)

Radiofrequencyablation therapy(Stretta®)

1,441 patientswith GERD

Meta-analysis of 18 RCT andcohort studies

Variable • ↓ Oesophageal acid exposure• ↑ GERD HRQOL• ↑ QOL in reflux and dyspepsia

scores

56

Ganz et al. (2013)

Magnetic sphincteraugmentation device(Linx®)

100 patients withrGERD

Uncontrolled prospective study 3 yearsand5 years

• ↓ Exposure to oesophageal acid• ↓ Reflux symptoms• ↓ PPI use

58

Louie et al. (2014)

Magnetic sphincteraugmentation device(Linx®)

66 patients withrGERD and hiatalhernia (


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In a dose-finding study, tegaserod, a nonbenzamideselective 5-HTR 4 agonist

67, showed the potential todecrease reflux events and TLESRs77. A number of add-on

trials evaluating tegaserod treatment in patients withrGERD were initiated (NCT00149851, NCT00171483and NCT00171418 on Clinicaltrials.gov ), but the resultsof these have not been published78–80.

Prucalopride is a benzofuran-class 5-hydroxy-tryptamine receptor 4 (5-HTR 4) agonist

67. A controlledtrial in healthy volunteers showed that a 4 mg dose ofprucalopride decreased oesophaegal acid exposure by50%81, but studies in patients with rGERD have notbeen conducted. Another 5-HTR 4 receptor agonist fromthe same chemical class, revexepride, failed to improvesymptoms at three different doses, as an add-on therapyto PPIs, in a controlled trial in patients with rGERD82.

An accompanying mechanistic study failed to show thatrevexepride was more effective than placebo at improv-ing reflux parameters (including the number of reflux

events, their proximal extent and bolus clearance times),as assessed by MII–pH monitoring, in patients withrGERD symptoms on a stable dose of PPI83.

Reflux inhibitors

Oesophageal clearance and gastric emptying are not theprimary mechanisms implicated in reflux events that per-sist during PPI therapy. As TLESRs are the main eventunderlying reflux events, both in healthy and diseasestates84, they are an attractive target when developingtherapies to inhibit reflux. TLESRs are reflexes mediatedby vagovagal pathways triggered by distention of theproximal stomach. Vagovagal signals are integrated in

Table 4 | Prokinetics and reflux inhibitors used in GERD and rGERD treatment

Study Drug used Patients Mucosalhealing(P value)

Reflux events (P value) Symptoms improvement(P value)

Ref.

Prokinetics

Galmicheet al. (1988)

Cisapride + cimetidine vscimetidine

Severe refluxoesophagitis (n = 73)

70% vs 46% (0.025)

– 87% vs 64% (


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the brain stem, leading to relaxation of the LES, presum-ably to enable venting of air, but at the same time allowingreflux to occur84. TLESRs can be modulated by severalneurotransmitters and receptors, all of which constitutepotential targets for therapy (TABLE 4). γ-aminobutyricacid type B (GABAB) receptors, present both in thecentral and enteric nervous systems, are the best-studiedpharmacological target for inhibiting TLESRs.

Baclofen. Proof-of-concept studies in healthy individ-uals and in patients with GERD and rGERD of baclofen,a GABAB receptor agonist used in the treatment ofspasticity, showed the potential of this modulator of theGABAB receptor pathway to inhibit acid and non-acidreflux events and improve GERD symptoms, both asa monotherapy and as an add-on therapy to PPIs85–89.Furthermore, baclofen also enhances postprandialLES pressure in healthy individuals and patients withGERD85,86. A meta-analysis that included nine random-ized controlled trials and a total of 283 patients withGERD and healthy individuals concluded that baclofen

is a potentially useful adjunctive therapy for the treat-ment of GERD90 as baclofen improved the number ofreflux events, reduced acid reflux exposure and TLESRrate compared with placebo. However, only one includedtrial studied baclofen as an add-on therapy to PPIs, sev-eral included studies evaluated only acute administra-tion of baclofen, and many of the studies included onlypatients that had been characterized by MII–pH to haveongoing weakly acidic reflux. The meta-analysis did notshow an increase in reported adverse events in patientstreated with baclofen compared with those given placebo,which is surprising given that clinical use of baclofen isoften associated with neurological disturbances (such as

dizziness, tiredness, sleepiness and accommodation dis-orders) and abdominal symptoms (such as discomfort,nausea, diarrhoea and flatulence), and these adverseeffects can interfere with add-on use84,85. The adverseeffect profile is less problematic when the drug is admin-istered at bedtime compared with daytime use. Orr et al.91 conducted a randomized crossover trial of baclofen 40 mg

versus placebo, administered at bedtime, in 21 patientswith GERD and night-time heartburn; sleep quality wasmeasured via polysomnography with concurrent MII–pH monitoring, and drug administration occurred atthe start of polysomnography. Baclofen reduced the totalnumber of reflux events related to sleep and markedlyincreased total sleep time by >50 min and sleep efficiencyby >10% on average, compared with placebo. The bene-fits to sleep variables might reflect the action of baclofenon GABA receptors in the brain involved in control ofarousal and sleep state92. The reduction in acid exposuretime in patients receiving baclofen did not reach statisti-cal significance91. Although the current evidence mightsupport the use of baclofen as an add-on therapy for

rGERD, the prevalence and severity of its adverse effectshave driven the development and evaluation of newerGABA-B receptor agonists with preference for peripheralreceptors (FIG. 3).

Lesogaberan. Lesogaberan is a novel GABAB receptoragonist that acts mainly through peripheral GABAB receptors, as the drug is sequestered by neurons andglial cells in the central nervous system by GABAtransporter-mediated uptake93. At a dose of 65 mgtwice a day, lesogaberan increased postprandial LESpressure and reduced TLESRs and reflux events in27 patients with GERD in a placebo-controlled parallelgroup study 94. In a pH-monitoring crossover study inpatients with rGERD on PPI, lesogaberan add-on treat-ment also resulted in a dose-dependent reduction inthe number of acid and weakly acidic reflux episodesin patients receiving 90 mg, 120 mg and 250 mg doses95.In a placebo-controlled clinical trial, 232 patients withrGERD treated for 4 weeks with lesogaberan 68 mg twicea day, in addition to existing PPI therapy, had a higherrate of treatment response (≤1 period of heartburn orregurgitation of not more than mild intensity duringthe last 7 days of treatment) than those patients receiv-ing placebo (16% versus 8%, respectively, P = 0.024)96.The subsequent randomized phase IIb trial involved661 patients with rGERD treated with either placebo,

60 mg, 120 mg, 180 mg or 240 mg lesogaberan, added totheir existing PPI treatment. The responder rate (pro-portion of patients experiencing 3 or more additionaldays per week with no more than mild overall symp-toms compared with baseline) was 17.9% for patientstaking placebo and increased dose-dependently to 26%for the highest 240 mg lesogaberan dose without reach-ing statistical significance, thus stopping drug develop-ment97; the improvement in heartburn, regurgitation andbelching scores was higher in patients taking one of thethree highest doses of lesogaberan (120 mg, 180 mg and240 mg) than with those taking placebo. Lesogaberanwas generally well tolerated in these trials.

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Galmicheet al.68

Miwaet al.72

Hsuet al.71

Madanet al.70Vigneri et al.69

Shaheenet al.82

H2R antagonist Treatment and add-on prokinetic PPI

* *

Figure 2 | Responder rates in studies investigating the effect of prokinetic drugs as

add-ons to acid-suppressive therapy for rGERD. Acid-suppressive therapy alone

(blue bars) is compared with acid-suppressive therapy and add-on prokinetic therapy

(yellow bars). *P


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Arbaclofen placarbil. A prodrug of baclofen, arbaclo-fen placarbil is designed to have better tolerance thanbaclofen through better absorption from the gastro-intestinal tract, resulting in less fluctuation in plasmalevels. A single-dose crossover trial of 10 mg, 20 mg,40 mg and 60 mg doses of arbaclofen placarbil in50 patients with GERD showed a dose-dependent inhib-ition of reflux events, heartburn and regurgitation over a12 h period, with the greatest effect in the 60 mg group98.In the subsequent phase II clinical trial, 156 patients withGERD who either had no history of taking PPIs (PPInaive, n= 58) or had at least partial symptom response toPPI treatment (PPI responders, n = 98) were randomlyassigned to receive arbaclofen placarbil 20 mg, 40 mg, or60 mg per day; 30 mg twice daily; or placebo for 4 weeks99.No change in weekly heartburn events, the primary out-come variable, occurred in any of the treatment groups.However, in a pre-planned secondary analysis, arbaclofentreatment in the PPI responder subgroup was superior toplacebo in reducing heartburn frequency, and the twicea day 30 mg dose was significantly better than placebo

in improving the severity of heartburn (P = 0.013) andin increasing the proportion of patients reaching com-plete relief of heartburn (50% versus 6%, P = 0.02)99. Thefollow-up trial comparing arbaclofen placarbil once daily(either 20 mg or 40 mg), twice daily (20 mg or 30 mg) orplacebo in 460 patients with rGERD taking PPIs failed toshow a benefit of the active drug on rGERD symptoms inthe primary end-point analysis100. However, in a post-hocanalysis that eliminated patients with only mild rGERDsymptoms from the analysis, all arbaclofen doses werestatistically significantly superior to placebo at reducingthe number of heartburn events with at least moderate

severity per week of treatment from baseline100. Despitethis promising post-hoc analysis, the development of thisdrug was discontinued.

mGlur5 inhibitors. Metabotropic glutamate recep-tors have been implicated in the pathways that controlTLESR occurrence101. In healthy volunteers, acute inhib-ition of metabotropic glutamate receptor 5 (mGluR5), byAZD2066 administration resulted in a dose-dependentreduction of TLESR frequency and the number of refluxepisodes compared with placebo102. Minor reversibleadverse effects were mostly related to central nervoussystem involvement (for example, dizziness and dis-turbances in attention), with no serious adverse eventsoccurring. In a single-blind, placebo-controlled 2-daystudy in patients with GERD, acute administration of250 mg of raseglurant (also known as ADX10059), a neg-ative allosteric modulator of the mGluR5 receptor, threetimes a day as monotherapy reduced oesophageal acidexposure and reflux-related symptoms103. A 120 mg, twicea day dose of modified-release formulation raseglurant

was investigated in a 2-week phase IIb double-blind,placebo-controlled, multicentre trial in PPI-responsivepatients with GERD after PPI washout (defined as inter-ruption of PPI therapy for at least 2 weeks). Treatmentwith raseglurant increased the number of days withoutGERD symptoms, the primary efficacy end-point, com-pared with patients receiving placebo104. Mavoglurant,another mGluR5 inhibitor, dose-dependently reducedTLESRs in a dog model of the disease; in patients withGERD, single doses of the drug dose-dependently inhib-ited TLESRs and reflux events similarly to baclofen (datapresented only in abstract form)105.

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Figure 3 | Responder rates in studies evaluating reflux inhibitors, either as monotherapy or as an add-on to acid

suppressive therapy, for rGERD. For Vakil et al.100 the left-hand yellow bars represent analysis of the entire population

and the right-hand green bars represent analysis of the patients excluding those with mild or very mild symptoms.

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None of these mGlur5 inhibitors progressed tophase III trials, in part because of the limited efficacy ofthese compounds over placebo and potential adverse-event issues. In our opinion, there is also a perception inthe pharmaceutical industry that rGERD in general, andespecially rGERD symptoms attributable to weakly acidicreflux, is fairly uncommon or difficult to identify, meaningrGERD treatments possibly represent risky investments.

Other reflux inhibitors. Itopride is a benzamide deriv-ative acting both as a dopamine D2 receptor antagonistand as an acetylcholinesterase inhibitor already used forthe treatment of functional dyspepsia106. In healthy sub-

jects, a 50 mg, three times a day dose of itopride reducedthe occurrence of TLESRs and reflux events107. A smalluncontrolled trial in 26 patients with GERD showed that100 mg of itopride three times a day lowered oesopha-geal acid exposure and improved reflux symptoms after1 month of treatment108. Rimonabant, a cannabinoidreceptor 1 antagonist, which alters motility control byacting on endocannabinoid tone in the enteric and/or

central nervous, also reduced the occurrence of TLESRsand reflux events in healthy volunteers109. No stud-ies in rGERD with itopride or with endocannabinoidantagonists have been reported.

Drugs acting on oesophageal sensitivity

Pharmacological agents to treat oesophageal hyper-sensitivity can be targeted at receptors in the oesophagealwall that are involved in symptom generation, or at centralpathways that convey or modulate afferent informationfrom the oesophagus. Oesophageal hypersensitivity isthought to contribute to symptom generation in patientswith symptomatic GERD (especially symptoms relatedto non-acid reflux that persist during PPI therapy), inthose with acid hypersensitivity and in individuals withfunctional heartburn13,39–41.

Drugs targeting acid-sensitive receptors

Inhibitors of acid sensitivity. In the gastrointestinal tract,acid-sensitive receptors have been the target for develop-ment of treatments that decrease reflux sensitivity. The pri-mary candidate receptors for the oesophageal acid-sensingmechanism are transient receptor potential cation channelsubfamily vanilloid member 1 (TRPV1) receptors, whichare activated by acid, capsaicin and heat110. However, twodoses of the TRPV1 antagonist AZD1386 failed to affectoesophageal sensitivity to acid, heat, electrical current

and distention in 22 healthy individuals111. In a controlledcrossover study in 14 patients with rGERD, AZD1386had no analgaesic effect on oesophageal pain elicited byheat, electrical current or oesophageal balloon distention,whereas it increased cutaneous heat tolerance112. Thesedata argue against a major role for TRPV1 in mediatingoesophageal hypersensitivity to a variety of stimuli. Nofurther development of TRPV1 receptor antagonists astreatments for GERD or rGERD has been reported.

Neuromodulators. Psychotropic agents, and especiallyantidepressants, can potentially improve oesophagealhypersensitivity through their effects on pain-processing

pathways in the central nervous system. The evidencethat both tricyclic antidepressants113,114 and selectiveserotonin reuptake inhibitors (SSRIs)115 can decreaseoesophageal sensitivity is mainly based on obser vationsin healthy individuals, although not all studies have foundaltered sensitivity with antidepressants. The efficacy ofthe tricyclic antidepressant nortriptyline (10 mg per dayfor 1 week, followed by 25 mg per day for 2 weeks) wasinvestigated in a placebo-controlled trial by performingan intraoesophageal acid painful infusion test during abrain MRI scan in 20 patients with NERD not takingPPIs. The study results failed to show a difference insymptom improvement between placebo and treatmentarms, although nortriptyline reduced the acid-inducedbrain response in the prefrontal cortex, insula, cingu-late and hippocampus compared with placebo treat-ment116. The results from a controlled trial in patientswith rGERD with no visible oesophageal injury at endo-scopy found no difference in heartburn improvement orheartburn disappearance between patients receiving asingle-dose PPI plus nortriptyline 50 mg, a double PPI

dose or a single PPI dose plus placebo117. In a controlledtrial in 252 patients with acid-hypersensitive oesopha-gus (physiological acid exposure on MII–pH monitoringbut positive SAP), the SSRI citalopram 20 mg once dailywas superior to placebo in improving reflux symptoms(heartburn, regurgitation and chest pain)118. Ostovanehet al.119 randomly assigned 144 patients with rGERD withnegative endoscopy to placebo, fluoxetine or omeprazolefor 6 weeks. Fluoxetine reduced the incidence of heart-burn compared with placebo and omeprazole (medianimprovement in heartburn free days 57.1% with fluox-etine compared with 13.9% with omeprazole, P


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that symptoms are truly typical of GERD) and PPI regi-men compliance, subsequent doubling of PPI dosage inpatients not responding to single-dose PPI and additionof alginates are the recommended initial steps in themanagement of rGERD5,6,8–12,38,121,122 (FIG. 4). In the absenceof access to MII–pH, symptom pattern can be used toguide add-on therapy choices. On the basis of evidencepresented in a meta-analysis of existing trials, baclofencan be considered a potentially useful adjunctive ther-apy for rGERD treatment, although many of these studiesincluded in this analysis evaluated acute administrationand monotherapy, rather than baclofen as an add-ontherapy to PPIs90. For patients with persisting regurgita-tion on adequate PPI dosing, 5–10 mg of baclofen threetimes a day, just before meals, can be considered90 (FIG. 4).Baclofen might also provide therapeutic benefit in thosewith rumination, which might mimic refractory regurgi-tation123. Clinical use of baclofen is often associated withadverse effects (including neurological disturbances andabdominal symptoms), which occur readily in clinicalpractice and can interfere with its use as an adjunctive88,89.

The adverse-effect profile of the drug is more favourablewhen administered at bedtime, and evidence exists thatbaclofen can be recommended as an adjunctive therapyto PPIs in patients with persisting supine or nocturnaltypical reflux symptoms91. Treatment just before bedtimemight improve the occurrence of adverse effects com-pared with daytime use, but nevertheless a daily 5–20 mgevening dose can be considered sufficient for therapeuticbenefit88,89 (FIG. 4).

In patients with persisting heartburn in spite of opti-mized PPI therapy, baclofen is also a potential adjunc-tive therapy, at doses of 5–10 mg three times a day 89,100.Because the prevalence of oesophageal hypersensitivityis probably elevated in this population, add-on treatmentwith SSRIs or tricyclic antidepressants can be consid-ered, especially in patients with rGERD and anxietyand/or depression40,41,120. Although many managementalgorithms propose the addition of a tricyclic anti-depressant in this setting, available evidence shows SSRIsare more efficacious and also have a more favourabletolerance profile113–119. An empirical approach might bethe association of an SSRI (citalopram or fluoxetine) atstandard morning doses with follow-up evaluation ofsymptom improvement after 6 weeks.

MII–pH monitoring can be performed early onin the work-up of patients with rGERD if available(FIGS 1,4). In most instances, this monitoring is done

whilst the patient is on optimized, twice a day PPI acid-suppressive therapy. However, MII–pH monitoring offacid-suppressive therapy should be used to select patientsfor antireflux surgery when symptoms are suspected tobe unrelated to reflux, or when the patient is not capableof using the symptom marker buttons adequately (forexample, due to poor understanding of their meaning).Pathological oesophageal acid exposure is a well-definedselection criterion for GERD surgery, and predicts a morefavourable outcome after Nissen fundoplication50. On theother hand, poor response to PPI therapy is a risk fac-tor for unfavourable clinical outcomes after antirefluxsurgery 50. In our opinion, the ability of an oesophageal

Figure 4 | Current management algorithm for typical rGERD symptoms in the

opinion of the authors, accounting for access to MII-pH monitoring. Endoscopic

treatments have not been added to the algorithm because of inconclusive evidence on

their efficacy in patients with rGERD. *Typical GERD symptoms are heartburn and/or

regurgitation not located in the epigastrium (dyspepsia) or the throat area. ‡Baclofen isstarted at 5 mg three times a day before meals, and increased to 10 mg three times a day

after 1 week. Therapeutic effectiveness can be evaluated after one month. Up-titration

to 20 mg three times a day can be considered in case of good tolerance and partial

efficacy of lower doses. §A neuromodulator can be a tricyclic antidepressant, for

example, nortriptyline 25–50 mg in the evening, or a selective serotonin reuptake

inhibitor, for example, citalopram 20 mg or fluoxetine 20 mg in the morning. ||Baclofen in

the evening is started at 5 mg at bedtime, and can be increased to 10 mg or 20 mg.

Therapeutic effectiveness can be evaluated after one month. ¶pH monitoring on and off

PPI therapy can provide additional evidence before deciding on antireflux surgery.#A properly blinded acid perfusion test can inform the decision of whether to perform

antireflux surgery, yet a positive test should not be considered definitive evidence that

surgery should be undertaken. MII–pH, multichannel intraluminal impedance and pHmonitoring. rGERD, refractory GERD.

Consider otherdiagnosis

Optimizetherapy

Atypical

Typical

Limited

Suboptimal

Poor response toempirical therapy

Good response toempirical therapy

Addbaclofen‡

Add baclofen‡

or neuromodulator§Add baclofenevening dose||

Dominantregurgitation

Dominantheartburn

Nocturnal orbedtime symptoms

Evaluate symptom pattern

EasyAdequate

Access to MII-pHmonitoring

Evaluate PPI regimenand compliance

Evaluate symptoms*

rGERD symptoms

MII-pH monitoringon PPI therapy

NormalAbnormal

Positive fornon-acid reflux

Yes

Functionalheartburn

or dyspepsia

Switch PPIConsider reflux inhibitor

or antireflux surgery

Positive foracid reflux

Negativefor reflux

Surgery considered orsuspected non-GERD?

No

Work-up for surgery

Consider acidperfusion test#

MII-pH monitoringoff PPI therapy¶

MII-pH monitoring

Consider refluxinhibitor or work-upfor antireflux surgery

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acid perfusion test to mimic GERD symptoms can provide additional reassurance when selecting patients withrGERD for antireflux surgery, but the literature provideslittle data on this approach and well-designed studies toconfirm this possibility are lacking124–127. Intensificationof GERD therapies or the use of invasive experimentalapproaches for refractory symptoms should be consid-ered critically, and one should remember that symptomsmight not be driven by GERD. When there is suspi-cion that symptoms are not caused by GERD and thatfunctional heartburn could be a causal factor, MII–pHmonitoring after PPI washout should be considered. Ina study published in 2015, almost one-third of patientswith at least one typical GERD symptom did not have adiagnosis of GERD on the basis of MII–pH monitoring,and the majority of these patients were diagnosed withfunctional heartburn128. Normal oesophageal acid expo-sure in the presence of normal acid secretory capacityprovides the most convincing evidence that GERD isabsent. Assessment of the overall number of reflux eventsand the proportion of symptomatic reflux events during

MII–pH monitoring might indicate oesophageal hyper-sensitivity, which is associated with decreased responseto acid suppressive therapy 29,129. Additional studies areneeded to evaluate whether this approach is clinicallyapplicable in driving treatment towards reflux inhibitors,pain modulators or antireflux surgery (FIG. 4).

Conclusions

Whereas general practitioners mainly manage patientswith GERD who respond well to medical therapy, gastro-enterologists are increasingly challenged by patients withrefractory, typical GERD symptoms. In spite of the high

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prevalence of rGERD, optimal management approachesto this condition have been poorly studied. The uncer-tainty surrounding patient management, combined withthe poor performance of medical approaches beyondacid-suppressive therapies and the view that antirefluxsurgery is less effective in patients with rGERD than inthose with GERD, means that surgical or other invasiveapproaches to treating patients with rGERD should beconsidered carefully. The development of medical thera-pies such as reflux inhibitors and prokinetics deserves to berevisited, preferably with optimized patient selection thatestablishes ongoing (weakly acidic) GERD as the causeof symptoms in those who are studied with these drugclasses. Several aspects of rGERD management should beinvestigated in future studies. In terms of medical thera-pies, the role of newer and stronger acid-suppressivetherapies in rGERD management, the risks and benefitsof empirical use of baclofen as an add-on therapy andthe role of newer prokinetic agents as add-on therapiesshould be assessed. Further important questions include:whether MII–pH monitoring in patients with rGERD on

PPIs can predict the outcome of antireflux surgery; therole of associated psychosocial factors in predicting func-tional heartburn and hypersensitive oesophagus; and thecomparison of outcomes after newer invasive antirefluxtherapies with outcomes after surgery or after conservativemanagement. For the time being, optimal management ofrGERD depends on detailed evaluation of the symptompattern, and judicious use of additional testing (MII–pHmonitoring and possibly oesophageal acid perfusion tests)and add-on therapies on the one hand, and rigorous selec-tion of patients for antireflux surgery and other invasiveprocedures on the other.

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25. Karamanolis, G. et al. Yield of 24-hour esophageal pH

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27. Tutuian, R. et al. Characteristics of symptomatic reflux

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28. Blonski, W., Vela, M. F. & Castell, D. O. Comparisonof reflux frequency during prolonged multichannel

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