Management of Gastroesophageal Reflux Disease that does not Respond Well to Proton Pump Inhibitors

Tiberiu Hershcovici and Ronnie Fass


Curr Opin Gastroenterol. 2010;26(4):367-378. 

In This Article


Evaluation for proper compliance and optimal dosing time should be the first management step in assessing patients with heartburn not responding to PPI therapy.[59] The physician should emphasize the need to take PPIs half an hour before a meal.

Lifestyle Modifications

The benefit of lifestyle modifications in GERD patients who fail PPI treatment has yet to be elucidated. In a recent systematic review of reports on lifestyle modifications for GERD, the authors determined that only weight loss and elevation of head of the bed appear to be effective.[60] There were insufficient data to support any of the other commonly prescribed lifestyle modifications. Nevertheless, in patients with PPI-refractory heartburn, it seems reasonable to recommend avoidance of specific lifestyle activities that appear to trigger GERD symptoms.

Histamine 2 Receptor Antagonists

For GERD patients on PPI twice daily who exhibit NAB, early studies showed that the addition of a histamine 2 receptor antagonist (H2RA) at bedtime significantly reduced the frequency and duration of NAB.[61] Although no studies document any clinical correlation between NAB and nocturnal GERD symptoms, the addition of H2RA at bedtime has become common practice in GERD patients who fail PPI treatment. However, patients rapidly develop tolerance (within 1 week) to the antisecretory effects of H2RAs given at bedtime.[62]

In a study that evaluated 100 patients (58 on twice-daily PPI and 42 on twice-daily PPI + H2RA at bedtime for at least 1 month), the authors demonstrated that the addition of a bedtime H2RA significantly reduced the percentage time with intragastric pH below 4 during upright, recumbent, and the entire monitoring period.[63] Unfortunately, the authors failed to provide any evidence for clinical effects of the bedtime H2RA. Rackoff et al.[64] evaluated 56 GERD patients on PPI twice daily who were receiving H2RA at bedtime for variable durations. The authors found that 72% of patients reported improvement in overall symptoms, 74% in night-time reflux symptoms, and 67% in GERD-associated sleep disturbances.

Proton Pump Inhibitors

Currently, PPIs are the most efficacious treatment for both healing erosive esophagitis and for symptom relief in GERD patients. In those who fail PPI once a day, there are two major potential therapeutic strategies that are utilized in clinical practice – switching to another PPI or doubling the dose of the same PPI. Doubling the PPI dose is by far the most common therapeutic strategy used by practicing physicians, and this strategy is recommended by the 2008 American Gastroenterological Association guidelines for GERD.[65] The Cochrane review suggests that doubling the PPI dose is associated with greater healing of erosive esophagitis, with a number-needed-to-treat (NNT) of 25. However, there is no clear PPI dose–response relationship for heartburn resolution in either erosive esophagitis or NERD.[66]

Switching to another PPI is an attractive therapeutic strategy that could be utilized in the management of patients who failed PPI once daily. In one study, patients who failed lansoprazole 30 mg once daily were randomized to either double-dose lansoprazole or 40 mg once-daily esomeprazole. 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.[67]

Whereas doubling the PPI dose might be considered the standard of care, there is no evidence to support any further escalation of the PPI dose for symptom control or healing of erosive esophagitis. For double-dose therapy, the PPI should be taken before breakfast and before dinner. Support for this regimen comes primarily from studies demonstrating improved control of intragastric pH when one PPI pill is taken before breakfast and dinner rather than taking two pills before breakfast.[68]

A recent study has suggested that a minority of GERD patients may lose PPI efficacy after 2 years of continuous and unmodified treatment with one or two PPIs per day.[69] The sole parameter evaluated in this study was the level of esophageal acid exposure as assessed by pH testing. The authors did not provide any clinical data to correlate with their physiological findings. In another study, the authors demonstrated that infection with Helicobacter pylori in healthy individuals, who are CYP2C19 extensive metabolizers, eliminated the differences in intragastric pH control between standard and double-dose PPI.[70] As with the previous study, the authors did not provide any clinical endpoints to correlate with the pH monitoring data.

The value of utilizing dexlansoprazole MR, an R-enantiomer of lansoprazole that also has dual delayed release (DDR) technology in patients who failed standard-dose PPI, remains to be elucidated.[71,72] Conceivably, the dual release of the drug (separated by 4–5 h), might be helpful in patients who failed PPI once daily.

Transient Lower Esophageal Sphincter Relaxation Reducers

A number of receptors have been shown to be involved in triggering transient lower esophageal sphincter relaxation (TLESR) providing the opportunity to develop novel reflux inhibitors.[73] The most promising of these agents appear to be the gamma-aminobutyric acid B (GABAB) receptor agonists and metabotropic glutamate receptor 5 (mGluR5) antagonists, which can achieve a high level of TLESR inhibition.[73,74]

Baclofen, a GABAB agonist, is a potential add-on treatment for patients who failed PPI therapy.[75,76] The drug reduces the TLESR rate by 40–60%, reduces reflux episodes by 43%, increases lower esophageal sphincter basal pressure, and accelerates gastric emptying.[75–77] Baclofen has been shown to significantly reduce DGER and weakly acidic reflux as well as DGER-related symptoms.[58,78] In patients with persistent heartburn despite PPIs, baclofen doses of up to 20 mg three times daily have been used.[58] Because the drug crosses the blood–brain barrier, a variety of central nervous system (CNS)-related side effects have been reported including somnolence, confusion, dizziness, lightheadedness, drowsiness, weakness, and trembling. The side effects are likely an important limiting factor in the routine usage of baclofen in clinical practice.

Arbaclofen placarbil (also known as XP19986) is a novel, transported pro-drug of the pharmacologically active R-isomer of baclofen. The drug is currently in clinical development for the treatment of refractory GERD. Arbaclofen placarbil was designed to be efficiently absorbed in the gastrointestinal tract and rapidly metabolized to release R-baclofen after absorption. Unlike baclofen, arbaclofen placarbil is well absorbed from the colon, allowing the drug to be delivered in a sustained release formulation that may allow less frequent dosing and thus reduced fluctuations in plasma exposure. This in turn may lead to potentially improved efficacy through a combination of greater duration of action, dosing convenience, and better safety profile compared with baclofen.[79,80]

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 three times daily was well tolerated, and significantly reduced both the percentage of time esophageal pH below 4 and the duration of symptomatic reflux episodes.[81] However, on 14 December 2009 Addex Pharmaceuticals Ltd. ended development of ADX10059 because of a possible link to severe hepatic side effects.

Visceral Pain Modulators

To date, there are no studies that have specifically evaluated visceral pain modulators in refractory GERD patients. However, given the fact that most patients who fail PPI treatment have NERD and most do not have abnormal acid reflux when they are taking PPIs, the use of pain modulators is highly attractive.[39,82] 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 pain.[39,83,84] It is believed that these agents confer their visceral analgesic effect by acting at the CNS and/or peripherally at the sensory afferent level.

For visceral pain syndromes, the pain modulators are used in doses lower than those given for mood alteration. Nevertheless, side effects are common, and may limit the usage of pain modulators 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 who had refractory GERD associated with gastroparesis.[85] There was marked improvement in GERD-related symptoms, which correlated with improvements in gastroparesis-related symptoms and in gastric-emptying as assessed by scintigraphy. The mean duration of response is approximately 5 months.[86]

Antireflux Surgery

A recent surgical study reported that refractory GERD was the most common (88%) indication for antireflux surgery.[87] Interestingly, the most common preoperative symptom reported under failure of medical antireflux treatment was regurgitation (54%). Overall, 82% of 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 patients with refractory GERD who were followed for a period of 12 months, the main preoperative symptoms were regurgitation (93%) and heartburn (60%). At the end of 1 year follow-up after 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 have suggested that a positive symptom index during impedance-pH monitoring in patients with PPI-refractory GERD (on therapy) can predict a favorable response to medical or surgical therapy. The first study by Mainie et al.[88] followed 19 patients who were refractory to double-dose PPI and underwent a successful laparoscopic Nissen fundoplication. Prior to surgery, 18 of the 19 patients were found to have a positive symptom index on MII-pH monitoring (14 with nonacid and 4 with acid reflux). After a mean follow-up of 14 months, 16 of the patients with a positive symptom index were asymptomatic. The second study by Becker et al.[89] assessed 56 patients with persistent symptoms on a single dose of PPI and abnormal MII-pH monitoring. Most of these patients had a positive symptom index, and later demonstrated a significantly higher response rate to doubling the PPI dose compared to patients with normal MII-pH monitoring results. In a third study, a group of Italian investigators prospectively assessed the outcomes of laparoscopic Nissen fundoplication in 62 patients who were PPI-nonresponsive or noncompliant.[90] All surgically treated patients had a positive MII-pH monitoring result. The overall patient satisfaction rate was 98.3%, and no differences were found in clinical outcomes based on 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 symptom index. 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 evaluated in GERD patients who failed PPI once daily. When compared to doubling the PPI dose, adding acupuncture was significantly better in controlling regurgitation as well as daytime and night-time heartburn. This is the first study to suggest that alternative approaches for treating visceral pain may have a role in GERD patients with PPI-refractory heartburn.[91]

Psychological Treatment

Patients with poor correlation of symptoms and acid reflux events display a higher level of anxiety and hysteria than those who have a close correlation between symptoms and acid-reflux.[92] Anxiety and depression have been shown to increase GERD-related symptoms report in population-based studies. Nojkov et al.[93] provided the first evidence that response to PPI treatment may be dependent on the level of psychological distress. Thus, it has been proposed that patients who do not respond to PPIs are more likely to have a psychological comorbidity than those who respond. In those patients, treatment directed toward the underlying psychosocial abnormality might improve the response to PPI therapy.