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INTRODUCTION — Despite treatment with proton pump inhibitors (PPIs), some patients with gastroesophageal reflux disease (GERD) continue to have reflux symptoms or endoscopic evidence of esophagitis. Approximately 10 and 40 percent of patients with GERD fail to respond symptomatically, either partially or completely, to a standard dose PPI [1-4]. Failure of the PPI treatment to resolve GERD-related symptoms has become the most common presentation of GERD among clinical gastroenterologists.
An approach to patients with refractory GERD will be discussed here. A review of the medical management of GERD is presented separately. (See "Medical management of gastroesophageal reflux disease in adults".)
DEFINITIONS — The definition of refractory GERD remains controversial. Because refractory GERD is a patient-driven phenomenon, PPI failure in patients who seek medical attention will exhibit different frequency and/or severity of GERD-related symptoms. As a result, any attempt to narrow the definition of refractory GERD might exclude many true sufferers .
Most investigators believe that only patients with GERD who exhibit partial or lack of response to PPI twice daily (given in a split dose at AM and PM) should be considered as PPI failures . However, we suggest that lack of satisfactory symptomatic response to PPI once a day is sufficient to consider patients as PPI failures.
Most patients with GERD who do not respond to a PPI have either nonerosive reflux (NERD) or functional heartburn. In patients with NERD the pooled symptomatic response rate to PPI once daily at four weeks is 37 percent [7,8]. In contrast, in patients with erosive esophagitis, which accounts for 30 to 40 percent of the GERD population, the pooled symptomatic response rate is 56 percent .
UNDERLYING MECHANISMS OF PPI FAILURE
Timing adherence — PPIs should be taken 30 minutes before a meal to maximize acid inhibition . However, patients commonly take their PPI incorrectly, which may in part be because they have not received adequate instructions . One study found that only 46 percent of patients prescribed a PPI for GERD were taking it properly . Of those not taking it properly, 39 percent took it at bedtime and 4 percent as needed. Although there is no direct evidence that proper dosing can improve symptoms in patients who are not taking a PPI 30 minutes before a meal, there is evidence to show that PPI taken before a meal provides better control of intragastric pH as compared with a PPI taken during or after a meal .
Compliance — Several surveys have demonstrated that poor compliance with PPIs is common in patients with GERD. By the end of one and six months of PPI therapy, only about 55 and 30 percent of the GERD patients, respectively, still consume their PPI once daily as initially instructed . In a large, population-based study, the main factors influencing compliance were the presence or absence of symptoms, the severity of symptoms, and a personal preference about when to take treatment . The results emphasize that GERD is a symptom-driven disease in which patients adhere to treatment instructions as long as they experience symptoms. Other general factors that affect compliance such as knowledge about the treated disorder, desire for personal control, the prescribed drug (taste, consistency, etc), side effects, number of pills per day, concomitant therapies, age, personality, socioeconomic status, and healthcare coverage may also have a role in adherence to treatment instructions .
Compliance should be assessed in all GERD patients who report lack of response to PPI treatment, particularly prior to ordering any evaluative test. Unfortunately, not all patients disclose that they are poorly compliant during their clinic visit. Treating physicians should repeatedly emphasize the need to consume antireflux treatment on a daily basis. It is the role of the treating physician to ensure proper compliance with the prescribed PPI through patient education about the disease and the value of compliance with treatment .
Functional heartburn and reflux hypersensitivity — Studies evaluating patients who did not respond to PPI twice daily demonstrated that up to 58 percent of patients have functional heartburn [16,17]. Thus, functional heartburn is the most common cause for failure of PPI treatment.
According to the Rome IV criteria, a diagnosis of functional heartburn requires all of the following criteria be fulfilled for the last three months with symptom onset at least six months prior to the diagnosis :
●Burning retrosternal discomfort or pain
●Absence of symptom relief despite optimal antisecretory therapy
●Absence of evidence that gastroesophageal reflux (abnormal acid exposure and symptom reflux association) or eosinophilic esophagitis is the cause of symptoms
●Absence of major esophageal motor disorders (achalasia/EGJ outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent peristalsis)
The underlying mechanisms responsible for symptoms in functional heartburn patients remain to be elucidated; most studies used the outdated Rome II criteria to diagnose functional heartburn. Many of these studies demonstrated increased esophageal sensitivity to chemical, mechanical, and electrical stimuli in this patient population [19-22]. However, one report suggested that not all functional heartburn patients (based on Rome II criteria) have increased esophageal sensitivity to intraluminal stimuli (25 percent) , and it is highly likely that functional heartburn represents a heterogeneous group of patients with different physiological mechanisms for their symptoms.
Reflux hypersensitivity is characterized by retrosternal symptoms including heartburn and chest pain with normal acid exposure but a positive symptom association with acid or weakly acid reflux. According to the Rome IV criteria, a diagnosis of reflux hypersensitivity requires all of the following criteria be fulfilled for the last three months with symptom onset at least six months prior to the diagnosis :
●Retrosternal symptoms including heartburn and chest pain.
●Normal endoscopy and absence of evidence that eosinophilic esophagitis is the cause for symptoms
●Absence of major esophageal motor disorders (achalasia/EGJ outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent peristalsis)
●Evidence of triggering of symptoms by reflux events despite normal acid exposure on pH or pH–impedance monitoring (response to antisecretory therapy does not exclude the diagnosis)
Although a subset of patients with esophageal hypersensitivity may respond to acid suppressive therapy, this disorder is analogous to the visceral hyperalgesia described in a variety of other gastrointestinal disorders including noncardiac chest pain, functional dyspepsia, and irritable bowel syndrome. (See "Evaluation of the adult with chest pain of esophageal origin".)
Weakly acidic or alkaline reflux (non-acid reflux) — Studies involving esophageal multichannel intraluminal impedance testing have revealed a potential role of weakly acidic or alkaline reflux in patients with persistent symptoms despite treatment with a PPI. The mechanism by which weakly acidic reflux causes GERD-related symptoms remains poorly understood. Two possible explanations have been proposed: esophageal distension by increased reflux volume and esophageal hypersensitivity to weakly acidic refluxate . (See "Esophageal multichannel intraluminal impedance testing" and "Clinical manifestations, diagnosis, and treatment of non-acid reflux".)
Thus far, there is no evidence that weakly acidic reflux is more commonly associated with increased volume of the refluxate than acidic reflux. Although this association has been proposed, esophageal impedance does not measure the volume of the refluxate and thus cannot define the relationship between the volume and the acidity. Thus, it is impossible to determine individual thresholds for the point at which weakly acidic reflux episodes consistently provoke symptoms. (See "Clinical manifestations, diagnosis, and treatment of non-acid reflux".)
Residual acid reflux — Residual acid reflux has been documented in patients with persistent heartburn despite a PPI once or twice daily [16,17,24-26]. As an example, in one study, 31 and 4 percent of GERD subjects with refractory symptoms who underwent pH testing on PPI once daily or PPI twice daily, respectively, had an abnormal test . On the other hand, several studies demonstrated that reflux characteristics in PPI failure patients are similar to those in PPI success patients . These studies suggest that PPI failure is primarily an esophageal hypersensitivity phenomenon. Furthermore, it appears that proximal immigration of weakly acidic reflux and the presence of gas in the refluxate are pivotal for symptom generation .
Bile acid reflux — Although commonly considered as synonyms, bile reflux and non-acid reflux are different phenomena. Initial studies suggested that bile reflux probably accounts for 10 to 15 percent of non-acid reflux. However, a study using simultaneous Bilitec (a device to measure bile reflux) and impedance monitoring showed no correlation between esophageal bilirubin exposure and non-acid reflux parameters . In other reports, the majority of bile reflux occurred concomitantly with acid reflux events, and thus acid rather than bile appears to be the dominant factor responsible for GERD symptoms [31-33].
On the other hand, experimental data support a role for persistent bile acids in the refluxate as a potential factor involved in refractory heartburn. Although PPI therapy reduces the occurrence of acid as well as bile reflux, complete acid suppression does not guarantee the elimination of bile reflux [34-36]. Perfusion of bile salts with non-acidic pH can still provoke heartburn , and exposure of rabbit esophageal mucosa to weakly acidic solutions containing bile acids (comparable situation to patients on PPI) increased mucosal permeability and induced dilated intercellular spaces, a proposed histopathological mechanism necessary for heartburn generation .
Studies in humans also suggested a possible role for bile reflux in both symptoms and erosive esophagitis in a subset of patients with difficult to manage symptomatic reflux. In a study that included 65 patients with persistent heartburn and regurgitation while on single-dose PPI therapy, a significant number of symptoms occurred in association with bile reflux as measured by Bilitec . Furthermore, in a carefully selected group of patients with symptoms refractory to PPI therapy, baclofen 20 mg three times a day significantly reduced the bile reflux exposure as well as symptoms of heartburn.
These studies suggest a role for measurement of bile reflux in patients with persistent reflux symptoms despite PPI therapy. However, the technique is not commonly available for the practicing physician and is presently limited to less than a handful of centers with interest in gastrointestinal motility. (See "Pathophysiology of reflux esophagitis" and "Clinical manifestations, diagnosis, and treatment of non-acid reflux".)
Nocturnal acid breakthrough — Up to 70 percent of patients takings PPIs twice daily have periods of gastric pH <4 for more than 60 minutes, particularly at night . Nocturnal acid breakthrough (NAB) was initially proposed as a major cause of refractory GERD. In one study, for example, 24-hour pH studies during twice daily proton pump administration were compared in 76 patients with GERD and 31 healthy controls . Abnormal esophageal acid exposure due to nocturnal acid breakthrough was significantly higher in patients with GERD and correlated with the severity of esophagitis (33 percent in patients with GERD and 50 percent in patients with GERD plus Barrett's esophagus versus 8 percent in controls).
However, early reports about NAB did not attempt to demonstrate a correlation between this gastric phenomenon and nighttime GERD symptoms. Subsequent studies have shown that NAB events do not necessarily denote a temporal relationship with reflux-related symptoms . Furthermore, in one report, 71 percent of patients with GERD who did not respond to treatment with PPI twice daily experienced NAB, but only 36 percent had correlation between symptoms and NAB events . In addition, there is no relationship between NAB and nocturnal heartburn . Thus, accumulating data do not support a significant role for NAB in precipitating failure of PPI treatment.
Differences in metabolism — Proton pump inhibitors are metabolized through the hepatic cytochrome system (specifically the CYP2C isoenzyme). As a result, genetically determined variability in the processes underlying drug metabolism may influence their efficacy. Patients with rapid metabolism of PPIs may have a decreased effect on gastric acidity. On the other hand, CYP2C is absent in about 3 percent of Caucasian patients and in substantially higher numbers of Asians (greater than 10 percent), potentially leading to greater suppression of gastric acidity. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders".)
Reduced bioavailability — The bioavailability of the different proton pump inhibitors varies and may be influenced by environmental conditions and manufacturing . However, for most patients, the differences in bioavailability among the proton pump inhibitors are not clinically significant during repeated dose administration since they do not translate into significant differences in the suppression of acid secretion .
As an example, the bioavailability of omeprazole is approximately 30 to 40 percent at doses of 20 to 40 mg. In contrast, the bioavailability of lansoprazole is much higher at approximately 80 percent for doses ranging from 15 to 60 mg. Despite these differences, the two drugs have equivalent efficacy for achieving acid suppression. This was illustrated in a controlled crossover study in which meal-stimulated acid secretion was decreased by 48 and 82 percent with 15 and 30 mg lansoprazole, respectively, and by 39 and 83 percent with 20 and 40 mg of omeprazole, respectively .
The general pharmacokinetic observations may not apply to individuals in whom the bioavailability of these drugs can vary significantly . As a result, some patients may not achieve adequate acid suppression despite standard or relatively high-dose therapy.
Drug resistance — Resistance to proton pump inhibitors is a rare condition that may be caused by mutations in the proton pump gene, a relationship that has only been described in a 1995 abstract [5,47]. It is unlikely that this condition has any significant role in refractory GERD.
Delayed healing — Complete relief of heartburn with proton pump inhibitors occurs at a rate of approximately 11.5 percent per week . Thus, endoscopic healing and symptom relief are achieved within eight weeks in the majority of patients. However, patients with severe esophagitis (eg, Los Angeles C or D esophagitis) may take longer to heal.
Helicobacter pylori status — PPIs produce a modest increase in acid suppression in H. pylori-positive patients than H. pylori-negative patients, potentially leading to higher healing rates in patients with erosive esophagitis [49,50]. The suggested underlying mechanism is migration of H. pylori proximally in the stomach to the corpus or fundus during PPI treatment. These areas of the stomach contain parietal cells, which are responsible for acid production. However, the prevalence of H. pylori infection has been rapidly declining in the United States and other developed countries, resulting in a very low background prevalence that cannot explain the large percentage of PPI failure patients. (See "Helicobacter pylori and gastroesophageal reflux disease".)
Psychological comorbidity — Patients with poor correlation of symptoms with acid reflux events display a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid reflux events . Anxiety and depression increase GERD-related symptoms reported in population-based studies . Thus, it has been proposed that patients who did not respond to PPI therapy are more likely to have psychosocial comorbidity than those who were successfully treated with a PPI .
Acid pocket — The presence of concentrated, highly acidic gastric juice postprandially at the gastroesophageal junction has been termed the "acid pocket." Several authors have suggested that the acid pocket may play an important role in refractory GERD. However, one study demonstrated no difference in the pH or position of the acid pocket between PPI responders and nonresponders .
DIFFERENTIAL DIAGNOSIS — Other diseases that should be considered in patients with refractory GERD are achalasia, esophageal cancer, esophageal stricture, other causes of esophagitis, and gastric stasis:
●Patients with achalasia may develop heartburn as a result of fermentation of retained food in the esophagus. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis".)
●Patients with distal esophageal cancer may continue to have symptoms and have ulceration mimicking peptic esophagitis on endoscopy. (See "Diagnosis and staging of esophageal cancer", section on 'Diagnostic testing'.)
●Patients who have dysphagia associated with reflux may continue to be symptomatic despite adequate acid suppression if they have developed a stricture. Relief usually accompanies adequate dilation.
●Patients who are taking nonsteroidal antiinflammatory drugs (NSAIDs) can experience pyrosis and may be more susceptible to acid-related esophageal disease [55,56]. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)
●Patients with rumination syndrome may be thought to have GERD. However, questioning regarding the symptoms of rumination syndrome should distinguish between the two disorders. (See "Approach to the adult with nausea and vomiting", section on 'Rumination syndrome'.)
●In addition to acid, a variety of caustic and infectious causes are associated with esophagitis. Examples include pill-induced esophagitis, caustic ingestion, Candida, herpes, and radiation. These causes should be excluded. (See appropriate topic reviews.)
●Patients who have impaired gastric emptying are predisposed to reflux. Symptoms may be improved after appropriate treatment. (See "Treatment of gastroparesis".)
●Eosinophilic esophagitis in adults is commonly associated with dysphagia while only about one-third of patients report classic heartburn symptoms [57-62]. Heartburn alone is uncommon. The relationship between eosinophilic esophagitis and reflux is complex and the prevalence of eosinophilic esophagitis in patients with heartburn refractory to PPIs has ranged between 0.9 percent and 8.8 percent. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis".)
●Sensitization to foods appears to be common among patients with refractory GERD. In one study of 65 patients with refractory GERD, sensitization to foods was present in 18 patients (28 percent) based upon the results of skin testing . Eosinophils were found in the esophageal mucosa of patients who were food sensitized more often than in patients who were not (38 versus 7 percent), but only one patient was diagnosed with eosinophilic esophagitis. Fifteen of the food sensitized patients followed a six-week restriction diet, with symptom improvement in 12 patients (80 percent). (See "Clinical manifestations of food allergy: An overview".)
●In one study, patients with GERD who also had irritable bowel syndrome (IBS) perceived their symptoms as more severe and tended not to achieve the same degree of symptom improvement during PPI treatment compared with patients with GERD without IBS .
DIAGNOSTIC EVALUATION — Diagnostic evaluation for refractory GERD should be considered in patients after an evaluation of proper compliance and reinforcement of lifestyle modification (see 'Optimizing therapy' below and 'Lifestyle modifications' below). In patients without alarm symptoms (eg, dysphagia, odynophagia, anorexia, weight loss, or upper GI bleeding), an empiric trial of doubling the dose of a PPI, or switching to a different PPI should be considered prior to initiating diagnostic testing (algorithm 1) (see 'Treatment of residual acid reflux' below).
Upper endoscopy — Patients who fail a PPI once daily and also have alarm symptoms should undergo upper endoscopy. The value of endoscopy in patients with refractory GERD without alarm symptoms is limited; there is no evidence that PPI failure is associated with an increased likelihood of a life-threatening esophageal or gastric lesion. There is some evidence that if endoscopy is performed, biopsies assessing for dilated intercellular spaces might help to separate true refluxers from those who have functional heartburn .
Esophageal pH testing — Patients who fail PPI twice daily should undergo esophageal pH testing. The traditional pH test is abnormal in a third of the patients who failed PPI once daily but in only 7 percent of those who failed PPI twice daily . The pH test can be performed while off treatment in patients without typical GERD symptoms, to determine if reflux is the cause of their symptoms or while on treatment and together with impedance testing in patients with a partial response to PPIs to determine if there is continued pathological acid or non-acid exposure despite a PPI .
A role for wireless pH capsule in patients who failed PPI has been proposed primarily because of the advantage of multiple days recording. The technique may be used over a period of four days (two on and two off treatment) in patients who failed PPI treatment. In addition, the wireless pH capsule can be used off treatment to determine if patients have nonerosive reflux disease or functional heartburn. However, both the wireless pH capsule and traditional pH probe do not measure weakly acidic or alkaline reflux and thus have been replaced by esophageal impedance and pH monitoring . The latter is the currently preferred diagnostic strategy in patients who failed PPI given twice daily. (See "Esophageal multichannel intraluminal impedance testing".)
Esophageal impedance testing — Abnormal esophageal impedance testing combined with pH monitoring while on therapy in patients with a partial response to PPIs can determine if there is continued pathological acid or non-acid exposure despite a PPI . It can also help predict which patients have acid reflux off therapy . (See "Esophageal multichannel intraluminal impedance testing".)
Esophageal manometry — The value of esophageal manometry in refractory GERD is very limited. This is primarily because most of treatment failure patients have NERD or functional heartburn. However, in those with suspected achalasia and in all patients undergoing surgery for GERD, esophageal manometry should be performed . (See "Overview of gastrointestinal motility testing".)
TREATMENT — Management of patients with GERD refractory to proton pump inhibitors should begin with an assessment of compliance and reinforcement of lifestyle modification. In patients who failed PPI once per day, initial options include switching to another PPI or doubling the PPI dose (algorithm 1). Detailed physiologic studies of patients with GERD who failed PPI therapy have suggested that three different types of gastroesophageal reflux are clinically relevant: acidic, weakly acidic/alkaline reflux, and duodenogastroesophageal reflux. Therapeutic options based on the pH of the refluxate are discussed below.
Optimizing therapy — Evaluation of proper compliance and adequate dosing time should be the first management step when assessing patients with heartburn who are not responding to PPI before instituting any other intervention. As noted above, patients should be instructed to take a PPI 30 minutes before a meal.
Lifestyle modifications — The specific value of lifestyle modifications in GERD patients who failed PPI treatment has yet to be elucidated. In patients with persistent heartburn despite PPI treatment, it is reasonable to recommend avoidance of specific lifestyle activities that have been identified by patients or physicians to trigger GERD-related symptoms. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification'.)
Treatment of residual acid reflux — In patients who failed PPI once a day, there are several potential therapeutic strategies aimed at reducing residual acid reflux.
Adjustment of proton pump inhibitor — Switching to another PPI or doubling the PPI dose are options in treating residual acid reflux in patients on once daily PPI.
We usually double the dose for eight weeks before considering an alternative PPI, although either option is effective, as illustrated by the findings of a study of patients who failed lansoprazole 30 mg once daily and were randomly assigned to either double-dose lansoprazole or 40 mg once daily esomeprazole . Single-dose esomeprazole was as effective as double-dose lansoprazole in the percentage of heartburn free days and symptom score for heartburn, acid regurgitation, and epigastric pain. There are no other randomized controlled trials that have compared switching to other PPI brands versus increasing the dose.
Doubling the PPI dose has become a common practice in patients with GERD who failed PPI once daily. In a report of patients with erosive esophagitis, doubling the PPI dose increased the healing rate by 6 percent but had no impact on symptoms . In other reports of patients with symptomatic GERD who failed PPI once a day, doubling the PPI dose increased the rate of overall symptom improvement by 22 to 26 percent .
There is also support for doubling the PPI dose in patients with a reflux hypersensitivity. These patients (normal endoscopy and pH test but positive symptom index) were more likely to respond to PPI twice a day . There is no evidence to support further escalation of the PPI dose in those who failed PPI twice daily.
When doubling the PPI dose, one PPI should be given before breakfast and the other before dinner. The support for splitting the dose originates primarily from physiologic studies demonstrating improved control of intragastric pH when one PPI is given in the A.M. and the other in the P.M. compared with both PPIs being given before breakfast . Another option is to further split the doses and provide double dose PPI four times daily.
Bedtime H2 receptor antagonist — Another strategy that has been suggested is to add a bedtime H2 receptor antagonist (H2RA) only in patients who failed PPI twice daily. The hope is to significantly reduce nocturnal acid breakthrough in patients who failed PPI twice daily . However, the enthusiasm about the value of adding H2RA at bedtime has been subsequently tempered by studies demonstrating rapid development of tolerance to H2RA; in one such report there was no difference in gastric acid suppression between PPI twice daily and PPI twice daily plus H2RA at bedtime after one week of therapy . Similarly, subsequent studies evaluating the efficacy of an H2RA added to a PPI have questioned the benefit of adding a nighttime H2RA [74-77].
On the other hand, observational data and clinical experience have suggested that long-term use of an H2RA at bedtime can be clinically beneficial, at least for some patients . Thus, a nighttime H2RA may be an option in patients who do not respond to PPI twice daily; if clinical tolerance has been encountered, then using the H2RA intermittently or on demand could theoretically be helpful.
Treatments aimed at reducing weakly acidic reflux — A variety of compounds reduce the rate of transient lower esophageal sphincter relaxation (TLESR) and thus the number of reflux events. However, only baclofen, a gamma-aminobutyric acid B receptor agonist, was introduced into the clinical arena as a potential add-on treatment for patients who failed PPI treatment (once or twice daily) [79,80]. The drug reduced TLESR rate by 40 to 60 percent, reduced reflux episodes by 43 percent, increased lower esophageal sphincter basal pressure, and accelerated gastric emptying [79-81]. In other reports, baclofen significantly reduced weakly acidic and bile reflux and gastroesophageal reflux-related symptoms [82-84]. In patients with persistent heartburn despite PPI treatment, doses up to 20 mg three times daily have been used .
Because the drug crosses the blood-brain barrier, a variety of central nervous system (CNS)-related side effects may occur. They primarily include somnolence, confusion, dizziness, lightheadedness, drowsiness, weakness, and trembling. The side effects are an important limiting factor in the routine usage of baclofen in clinical practice. However, several baclofen-like prototypes with better clinical and side-effect profiles are currently in development. In a double-blind, placebo-controlled, randomized phase IIA trial, treatment with lesogaberan, a novel gamma-aminobutyric acid B receptor agonist, resulted in significantly improved heartburn and regurgitation symptoms; however, the proportion of responders was small (16 versus 8 percent). Lesogaberan was well tolerated with adverse events that were comparable to the placebo group (45 versus 37 percent) .
We suggest a trial of baclofen in patients with refractory GERD on PPI twice daily who demonstrate symptoms associated with non-acidic reflux on an esophageal impedance pH study. If access to an esophageal impedance pH study is unavailable, we suggest an empiric trial of baclofen in those whose symptoms are primarily regurgitation. We usually begin by giving 10 mg at bedtime, which can be increased slowly to 20 mg three times daily while carefully monitoring for side effects.
Treatment of esophageal hypersensitivity — There are few studies that have specifically evaluated the value of visceral pain modulators in GERD patients with persistent heartburn despite PPI treatment. However, the use of such agents is potentially attractive since, as noted above, most patients who fail PPI treatment have NERD and more than one-half of these patients do not have pathological reflux on pH testing [15,16,86].
Pain modulators such as tricyclic antidepressants, trazodone, serotonin-norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors have all been shown to improve esophageal pain in patients with functional esophageal disorders [16,87-89]. It is believed that these agents confer their visceral analgesic effect by acting at the central nervous system and/or sensory afferents level. The pain modulators are used in non-mood-altering doses, and they presently provide a therapeutic alternative until more novel and esophageal-specific compounds are available.
In patients with refractory GERD who have an unremarkable esophageal impedance pH study and in patients with non-acid reflux, we suggest a trial of visceral analgesics (pain modulators), such as a tricyclic antidepressant, selective serotonin uptake inhibitor, serotonin-norepinephrine reuptake inhibitors, or trazodone. If access to esophageal impedance pH is not available, and patients primarily report heartburn, we generally begin with a trial of an H2 receptor antagonist (H2RA) at bedtime, suggesting it be used intermittently to avoid tachyphylaxis. In those who do not respond, we then suggest a trial of a tricyclic antidepressant, trazodone, serotonin-norepinephrine reuptake inhibitors, or a selective serotonin reuptake inhibitor.
Treatment of delayed gastric emptying — Few studies have assessed the value of the current therapeutic approach to delayed gastric emptying in patients with GERD who have failed PPI therapy. However, it is likely that these patients will also complain about other dyspeptic symptoms (nausea, abdominal pain, early satiety, and vomiting) related to slow gastric motor activity. As a result, it is conceivable that dietary and medical treatment aimed at improving delayed gastric emptying will improve patients' overall symptoms including those related to GERD. (See "Treatment of gastroparesis".)
Surgical treatments — Antireflux surgery should be considered in patients who require high doses of proton pump inhibitors to control symptoms, particularly in young patients who may require lifelong therapy. Whether surgery is beneficial in patients who have failed PPI therapy remains controversial. Surgery is not recommended in patients who demonstrate a complete lack of response to PPI therapy . (See "Surgical management of gastroesophageal reflux in adults".)
In one study, refractory GERD was the most common (88 percent) indication for antireflux surgery  and a number of surgical studies have suggested that fundoplication may be of benefit in patients with refractory GERD [16,90]. However, many of these reports had important methodologic limitations such as variable definitions of "refractory" GERD, different clinical end points, and accounting for dropouts. Furthermore, patients who have undergone fundoplication may continue to use antisecretory medications (ranging from 10 percent to almost two-thirds of patients in a systematic review) . The predictors of successful outcomes following fundoplication also remain poorly defined .
Another surgical approach is laparoscopic sphincter augmentation using a device comprised of a string of magnetized beads [93-96]. The device is implanted at the lower esophageal sphincter to maintain closure of a weak lower esophageal sphincter, preventing reflux. The beads then separate when the patient swallows to allow passage of a food or liquid bolus. In one prospective study, 100 patients with GERD that was partially responsive to PPIs underwent implantation of a magnetic esophageal sphincter device . At three-year follow-up, a 50 percent or greater reduction in esophageal acid exposure was achieved in 64 percent of patients and 87 percent of patients reported complete cessation of PPI use. The most frequent adverse event was dysphagia, which occurred in 68 percent of patients. Serious side effects occurred in six percent of individuals. However, randomized controlled trials are needed to confirm these results and to assess the long-term safety of magnetic devices to treat refractory GERD.
Other therapeutic approaches
●The role of bile acid binders such as cholestyramine or sucralfate in patients with GERD who failed PPI treatment remains unclear. Reducing bile reflux in this patient population is desirable, but it is unclear if any of the currently available bile acid binders are sufficiently effective to improve symptoms .
●Acupuncture has been evaluated in patients with GERD who failed PPI once daily . When compared to doubling the PPI dose (standard of care), adding acupuncture was significantly better in controlling regurgitation, daytime and nighttime heartburn. The potential benefit may be related to treatment of visceral pain but more data are needed.
●There are no rigorous studies that have evaluated the value of screening for psychological comorbidity in patients who failed PPI treatment. However, one study demonstrated that response to PPI treatment may depend upon the level of psychological distress . Similarly, a systematic review found that psychological comorbidities were associated with worse outcomes after fundoplication . More data are needed to determine what role, if any, treatment of psychological disturbances has in the management of patients with refractory GERD.
●Two endoscopic approaches for treating GERD include application of controlled radiofrequency (RF) energy to the lower esophageal sphincter region (Stretta procedure) and transoral incisionless fundoplication . Both techniques have demonstrated a significant decrease in PPI dose. However, the role of both techniques in patients with non-acid reflux remains to be elucidated. (See "Radiofrequency treatment for gastroesophageal reflux disease".)
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●Beyond the Basics topics (See "Patient education: Acid reflux (gastroesophageal reflux disease) in adults (Beyond the Basics)".)
SUMMARY AND RECOMMENDATIONS
●The definition of "refractory" GERD is unsettled. Some authorities suggest that it represents patients who have a lack of a clinical response to a PPI given twice daily. We consider that lack of satisfactory symptomatic response to PPI once a day is sufficient to consider patients as PPI failures. (See 'Definitions' above.)
●Most patients with GERD who do not respond to a PPI have nonerosive reflux disease (NERD) or functional heartburn. (See 'Definitions' above.)
•Ensure proper dosing of a PPI. In particular, patients should be asked if they are taking a PPI 30 minutes before a meal and if they are taking it regularly.
•Suggest lifestyle modifications, particularly if patients note an association with symptoms. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification'.)
•Consider alternative diagnoses including an esophageal motility disorder, use of drugs (such as NSAIDs) that can lead to pyrosis, Candida esophagitis in patients with risk factors, gastroparesis, and eosinophilic esophagitis in patients who have dysphagia.
●In patients with refractory GERD who have not already undergone upper endoscopy and who have alarm symptoms such as dysphagia, odynophagia, anorexia, weight loss, or upper GI bleed, we suggest performing an upper endoscopy. (See 'Upper endoscopy' above.)
●In patients with persistent symptoms despite the above, we suggest giving a PPI twice daily (30 minutes before breakfast and 30 minutes before dinner) (Grade 2B). Switching to a different PPI may be an equally effective alternative. (See 'Treatment of residual acid reflux' above.)
●If symptoms continue despite the above (twice daily PPI), we suggest performing esophageal impedance and pH testing on PPI treatment where available. (See "Esophageal multichannel intraluminal impedance testing".)
●In patients with persistent acid reflux on esophageal impedance and pH testing or when testing is unavailable and patients primarily report heartburn, we suggest adding a bedtime H2RA (Grade 2C). If clinical tolerance develops, H2RA can be used intermittently or on demand. (See 'Bedtime H2 receptor antagonist' above.)
●In patients with refractory GERD on PPI twice daily who demonstrate symptoms associated with non-acidic reflux on an esophageal impedance pH study, we suggest a trial of baclofen (Grade 2C). If access to an esophageal impedance pH study is unavailable, we suggest an empiric trial of baclofen in those whose symptoms are primarily regurgitation (Grade 2C). We usually begin by giving 10 mg once daily, which can be increased slowly to 20 mg three times daily. Patients should be monitored for side effects such as somnolence, confusion, dizziness, lightheadedness, drowsiness, weakness, and trembling.
We have observed that this subset of patients (ie, symptoms primarily related to regurgitation despite treatment with a PPI twice daily) may benefit from a Nissen fundoplication. However, only patients who underwent esophageal impedance and pH study should be considered for antireflux surgery. Such patients should also be advised that there are limited data that have established the efficacy of fundoplication in this setting. They should also be advised of the potential morbidity after fundoplication. (See "Clinical manifestations, diagnosis, and treatment of non-acid reflux" and "Surgical management of gastroesophageal reflux in adults".)
●In patients with refractory GERD who have a normal esophageal impedance and pH study or even those with non-acid reflux, we suggest a trial of visceral analgesics (pain modulators), such as a tricyclic antidepressant, serotonin-norepinephrine reuptake inhibitor, selective serotonin uptake inhibitor, or trazodone (Grade 2C). If access to esophageal impedance pH is not available, patients primarily report heartburn and have failed the addition of an H2RA, we suggest a trial of a tricyclic antidepressant, trazodone, serotonin-norepinephrine reuptake inhibitor, or a selective serotonin reuptake inhibitor.
●In patients with persistent symptoms despite the above and who have symptoms suggestive of delayed gastric emptying (nausea, abdominal pain, early satiety, and vomiting), we suggest treatment aimed at improving gastric emptying (Grade 2C). (See "Treatment of gastroparesis".)
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