1. Refractory GERD Aaron Sinclair, MD
University of Kansas School of Medicine – Wichita
Wesley Family Medicine Residency
Assistant Clinical Professor
Department of Family and Community Medicine

2. Learning Objectives
Differentiate the potential causes of refractory GERD.
Discuss the diagnostic options for refractory GERD.
Review different treatment options for refractory GERD.
 Differentiate the potential causes of refractory GERD.
 Discuss the diagnostic options for refractory GERD.
 Review different treatment options for refractory GERD.

3. Definition of Refractory GERD
Refractory reflux symptoms:
<50% improvement in the chief complaint after at least 12 weeks of PPI therapy OR at least 3 times a week for the last 3 months.
The symptom burden must be to a degree that impairs quality of life, and symptoms must be ‘reflux-related’
Estimated that between 10% and 40% of the patients with GERD fail to respond symptomatically, either partially or completely, to a standard dose PPI.
Because over 20% of the population in the United States at some time has reflux related symptoms, it would be difficult to do a work-up on every single patient. However, when s/s do not resolve with standard care, then an evaluation should be considered when it affects their ADL’s.
Refractory reflux symptoms:
<50% improvement in the chief complaint after at least 12 weeks of PPI therapy.
This distinction in clinical practice can be difficult because of our imperfect tools for establishing whether or not symptoms are attributable to reflux, be it acid reflux, non-acid reflux or gas reflux.
Estimated that between 10% and 40% of the patients with GERD fail to respond symptomatically, either partially or completely, to a standard dose PPI.

4. The purpose of this diagram is to stress the importance of the multifactorial components that exist with PPI failure/refractory GERD.

5. Outline Medication Failures Diagnostic Tools Diagnosis and Treatments
Treatment Options
Really going to try and breakdown refractory GERD to 5 different components:
Medication Failures
Diagnostic Tools
Anatomical Failures
Diagnosis and Treatments
Treatment Options

6. Outline Medication Failures Diagnostic Tools Diagnosis and Treatments
Initial Treatment Steps
Mechanisms of PPI Failure
Compliance with PPI
Timing Adherence with PPI
PPI Metabolism
Incomplete Healing
Diagnostic Tools
Diagnosis and Treatments
We are going to get started with medication failures largely because it is the easiest and cheapest to treat.

7. Initial Treatment Steps – Doubling the PPI
Common to double the PPI dose
A study of 196 patients with severe peptic esophagitis
Increased healing rate by 6%
No change in symptom control
Another study of 96 patients with GERD, PPI doubled
No statistically significant findings but there were consistent trends toward better symptom control
In what gets me in trouble with chocolate chip cookies, the old adage of “If one is good, then two must be better!”
Common to double the PPI dose
A study of 196 patients with severe peptic esophagitis
Increased healing rate by 6%
No change in symptom control
Another study of 96 patients with GERD, PPI doubled
No statistically significant findings but there were consistent trends toward better symptom control
However for every study it seemed that suggested a benefit, I saw many that showed no benefit. I did not see that showed a negative effect for increasing to twice a day.

8. Initial Treatment Steps – Switching PPI’s
Switching to another PPI
No strong scientific data (neither pharmacological, nor clinical)
Shown to be cost – effective and some symptom relief.
Finally, comparison of Switching to Another PPI or Doubling the Dose
Study of 144 patients with refractory GERD
Number of heartburn-free days during the study period (54.4% and 57.5%, respectively).
Heartburn improved from baseline (83.3% of patients in each group)
Acid regurgitation (76.8% vs 72.9%, P = .58)
Epigastric pain (67.4% vs 61.1%, P = .32)
Rescue antacid use was also similar (0.4 tablets/day vs 0.5 tablets/day, P = .50)
In several studies that has driven all of us crazy from a prior authorization standpoint with insurance companies:
Switching to another PPI has not shown any strong scientific data (neither pharmacological, nor clinical)
Essentially, all brands and doses seem to be the same with similar symptom relief. Yet some patients will note some improvement in s/s with a switch.
So is there any difference in Switching to Another PPI or Doubling the Dose
Study of 144 patients with refractory GERD showed that Switching patients with persistent heartburn on a standard-dose proton pump inhibitor to a different proton pump inhibitor was as effective as increasing the proton pump inhibitor dosage to twice daily for controlling heartburn symptoms.

9. Initial Treatment Steps – Bedtime H2 Receptor Antagonist
Considered for patients that have failed PPI twice daily.
Proposed pathophysiology is to suppress nocturnal acid breakthrough
Some patients can demonstrate rapid tolerance of H2RA in as soon as one week.
Clinical Practice:
Mixed results – for every study that seems to show an improvement there is another that questions it’s efficacy.
Adding a bedtime H2RA, has something I have done in patients that have failed PPI twice daily.
Proposed pathophysiology is to suppress nocturnal acid breakthrough
Something to consider is that some patients can demonstrate rapid tolerance of H2RA in as soon as one week.
In a study of 22 patients with refractory GERD were monitored with serial combined esophageal and gastric 24-h pH monitoring, combination of H2RA and PPI therapy reduced NAB only with the introduction of therapy. Because of H2RA tolerance, there is no difference in acid suppression between PPI twice daily and PPI twice daily + H2RA after 1 week of combination therapy.
In practice, I tell patients to use the H2RA at night as needed and not scheduled.

10. Initial Treatment Steps – Lifestyle Changes
Beneficial
Carbonated beverages
Weight Loss – if overweight
Peppermint
No consistent data
Elevation of the head of the bed
Tight fitting clothes
Potentially beneficial
Alcohol
Smoking
Food Elimination if correlation noted
Oral lozenges
Fatty foods
Abdominal breathing exercises
Caffeine
Chocolate
Spicy foods
Although several lifestyle and dietary modifications have been used in clinical practice, a systematic review of 16 randomized trials that evaluated the impact of these measures on GERD concluded that only weight loss and elevation of the head end of the bed improved esophageal pH-metry and/or GERD symptoms
Elevation of the head of the bed in individuals with nocturnal or laryngeal symptoms (eg, cough, hoarseness, throat clearing). This can be achieved either by putting six- to eight-inch blocks under the legs at the head of the bed or a Styrofoam wedge under the mattress. We also suggest a corollary to this recommendation: refraining from assuming a supine position after meals and avoidance of meals two to three hours before bedtime.
Selective elimination of dietary triggers in patients who note correlation with GERD symptoms and an improvement in symptoms with elimination.
Other measures that have a physiologic basis but have not consistently been demonstrated to improve reflux symptoms include are listed.

11. Compliance with Proton Pump Inhibitors
Compliance at one month – 55%
Compliance at six months – 30%
Factors:
Number of pills
Side Effects
Symptom Driven Disease
Socioeconomic variables
Healthcare coverage
Desire for personal control
Another study looked at compliance to once daily PPI in GERD patients.
Refractory symptom patient compliance (46%–55%)
Patients with adequate relief compliance (84%)
In a study of over 200 patients,
Compliance at one month – 55%
Compliance at six months – 30%
Numerous Factors were identified.
Another study looked at compliance to once daily PPI in GERD patients.
Refractory symptom patient compliance (46%–55%) was much less than patients with adequate relief compliance (

12. Timing Adherence with Proton Pump Inhibitors
PPIs should be taken 30 minutes before a meal to maximize acid inhibition.
Study of 100 people with refractory GERD
54% of patients dosed proton pump inhibitors sub-optimally
12% dosed in a manner that maximized acid suppression
6% as needed

13. Timing Adherence with Proton Pump Inhibitors
Some argue that there is no direct evidence that proper dosing can improve symptoms in patients who are not taking a PPI 30 minutes before a meal.
Seven way crossover study of 42 patients evaluating multiple different medication timing regimens showed minimal differences on symptom profiles and pH esophageal probe.
However, there is a lot of variability in studies. Seven way crossover study of 42 patients evaluating multiple different medication regimens showed minimal differences in symptoms associated with GERD.

14. Proton Pump Inhibitor Metabolism
Proton pump inhibitors are metabolized through the hepatic cytochrome system (CYP2C isoenzyme)
Rapid metabolizers may have a decreased effect on gastric pH.
These polymorphisms have been studied widely in different populations with reported frequencies ranging from 6 to 39%.
Another study of 460 people who did not respond to standard PPI dosing showed:
16.5% (76/460) of the urban subjects are rapid metabolizers
3.2% (15/460) are ultra-rapid metabolizers, who did not respond to standard dose of PPIs
Over recent years, the hepatic cytochrome system has been increasingly studied with a huge impact on pharmaceutical treatment decisions.
Proton pump inhibitors are metabolized through the hepatic cytochrome system (CYP2C isoenzyme)
Rapid metabolizers may have a decreased effect on gastric pH.
These polymorphisms have been studied widely in different populations with reported frequencies ranging from 6 to 39%.
Another study of 460 people who did not respond to standard PPI dosing showed:
16.5% (76/460) of the urban subjects are rapid metabolizers
3.2% (15/460) are ultra-rapid metabolizers, who did not respond to standard dose of PPIs

15. Proton Pump Inhibitor Metabolism
CYP2C Isoenzyme Inducers with unknown/unspecified potency
Rifampicin
Artemisinin
Carbamazepine
Norethisterone
Prednisone
Aspirin

16. Incomplete Healing with PPI Treatment
Endoscopic healing and symptom relief are achieved within eight weeks in the majority of patients.
Severe esophagitis may require more time.
Healing rate:
PPIs: 11.7% per week
H2RAs: 5.9% per week
Sometimes, when treating GERD, we have to just give it more time to completely heal. So in 8 weeks, roughly 10% of patients with severe esophagitis may not be completely healed. This may be the cause of the refractory gerd.

17. Outline Medication Failures Diagnostic Tools Diagnosis and Treatment
Endoscopy
Esophageal pH Testing
Esophageal Impedance Testing
Esophageal Manometry
Diagnosis and Treatment
So when the easy, non-invasive things do not seem to work in fixing the GERD. Further work-up may be necessary.
Endoscopy
Esophageal pH Testing
Esophageal Impedance Testing
Esophageal Manometry

18. Diagnostic Tools – Endoscopy
If endoscopy has not been done, it should
Low diagnostic yield
If normal esophagus
 NERD (Non-Erosive Reflux Disease)
PPI healed the mucosal breaks
If endoscopy has not been done, then there is an indication now and it should be performed. Overall endoscopy has a low diagnostic yield. If normal esophagus, then the working diagnosis is NERD or interval healing of erosive esophagitis has occurred.

19. Diagnostic Tools – Endoscopy
Esophageal biopsies samples should be obtained regardless of the gross appearance of the esophageal mucosa to rule out Eosinophilic Esophagitis.
Upper endoscopy with biopsies has been demonstrated to be a cost-effective approach when the prevalence of eosinophilic esophagitis is 8% or greater.
Other studies suggest that this prevalence would not exceed 0.9%–4% of patients in this clinical situation.
It is strongly encouraged that esophageal biopsies should be obtained as 1-8% of these patients will have eosinophilic esophagitis.
Most recommend to rule out Eosinophilic Esophagitis (<4%) at least five biopsy samples.

20. Diagnostic Tools – Endoscopy
The rare considerations:
Zollinger-Ellison Syndrome – presence of mucosal breaks despite PPI therapy
Pill-induced esophagitis and skin diseases with esophageal involvement
Lesions located at the lower third of the esophagus.
Rare conditions such as Zollinger – Ellison Syndrome or pill induced esophagitis may be identified.

21. Diagnostic Tools – Endoscopy - Summary Slide
Diagnosis of Erosive Esophagitis or Barrett's Esophagus (<10%).
Rule out Eosinophilic Esophagitis (<4%) with at least five biopsy samples.
Keep severe esophageal motility disorders (stasis, spasms) in the differential diagnosis if no abnormalities are seen on endoscopy.
Suspect pill-induced Esophagitis or Esophageal lesions associated with skin diseases.

22. Diagnostic Tools – Esophageal pH Testing
The goal of Esophageal pH testing is to detect residual acid reflux.
This has been documented in patients with persistent heartburn despite PPIs once or twice daily.
Refractory GERD patients – Esophageal pH Testing
% of patients on PPIs once a day had an abnormal test
4-16% of patients on PPIs twice a day had an abnormal test twice daily, respectively.
The role of residual acid reflux in the pathogenesis of PPI failure remains controversial as studies show that the amount of residual acid reflux was not different in responders and non-responders to PPI’s.
The goal of Esophageal pH testing is to detect residual acid reflux.
This has been documented in patients with persistent heartburn despite PPIs once or twice daily.
Refractory GERD patients – Esophageal pH Testing
% of patients on PPIs once a day had an abnormal test
4-16% of patients on PPIs twice a day had an abnormal test twice daily, respectively.
The role of residual acid reflux in the pathogenesis of PPI failure remains controversial as studies show that the amount of residual acid reflux was not different in responders and non-responders to PPI’s.

23. Diagnostic Tools – Esophageal pH Testing
Disadvantage:
Test abnormal in small portion of patients
Does not measure weakly acidic or alkaline reflux
Advantages:
May be combined with Esophageal Impedance Testing
May be combined with Esophageal Mannometry
Wireless pH capsule
Advantages: Multiple days – sometimes two off PPI and two on PPI
Disadvantage: Does not measure weakly acidic or alkaline reflux

24. Esophageal pH monitoring is usually an ambulatory procedure, and patients are asked to fast for at least 4 hours prior to placing the pH probe. The catheter is typically inserted transnasally, and the pH sensor is placed in the distal esophagus. In the adult population the distal esophageal pH sensor is positioned 5 cm above the manometrically located proximal border of the lower esophageal sphincter
In other circumstances (e.g., on acid suppressive therapy) a second pH sensor is placed in the stomach, 10 cm below the LES in order to monitor intragastric acidity. Once the catheter is positioned and taped to the nose to limit its movement, the recording of pH data is initiated. Most commercially available systems sample data points every 4 to 5 seconds.
Patients are provided with diaries and asked to record the timing and content of ingested meals, periods of upright and recumbent position, and the time of symptoms. Typically ambulatory pH data are recorded over 24 hours
a: Dual-channel proximal and distal esophageal pH monitoring is used to monitor patients with reflux symptoms off therapy. b: Dual channel distal esophageal and gastric pH monitoring is used to monitor patients with reflux symptoms on acid suppressive therapy.

25. Negative pH probe with no readings consistently below pH of 4.

26. GI Motility online (May 2006) | doi:10.1038/gimo31
Figure 3 Reflux episode identified by pH monitoring as a rapid drop in pH from above to below 4.0 distally longer than proximal.
GI Motility online (May 2006) | doi: /gimo31

27. Diagnostic Tools – Esophageal Multichannel Impedance Testing
Multichannel intraluminal impedance (MII) is a catheter-based method to detect intraluminal bolus movement within the esophagus.
MII is performed in combination with manometry or pH testing.
When combined with manometry, it provides information on the functional (ie, bolus transit) component of manometrically detected contractions. (MII-EM)
When combined with pH testing, it allows for the detection of gastroesophageal reflux independent of pH (ie, both acid and non-acid reflux). (MII-pH)

28. Diagnostic Tools – Esophageal Multichannel Impedance Testing
Combined Multichannel Intraluminal Impedance and pH (MII-pH) Monitoring
Mounting a series of impedance-measuring segments on a catheter (i.e., multichannel impedance) allows not only detecting the bolus presence at various levels but also determining the direction of bolus movement. Swallows are detected as impedance changes, progressing proximally to distally indicating an aboral bolus movement. These changes in impedance are very sensitive and detect swallows as small as 1 mL. This high sensitivity has drawbacks because impedance changes do not accurately determine the volume of swallows or refluxate.

29. GI Motility online (May 2006) | doi:10.1038/gimo31
Figure 9 Gastroesophageal reflux detected by combined multichannel intraluminal impedance and pH (MII-pH) monitoring.
GI Motility online (May 2006) | doi: /gimo31

30. Diagnostic Tools – Esophageal Manometry
Most important role of esophageal manometry in patients with gastroesophageal reflux disease (GERD) is prior to antireflux surgery.
Serves to exclude
Scleroderma
Achalasia
Not diagnostic for GERD
Not able to predict disease severity
Non-specific GERD manometric findings
Impaired peristalsis
Decreased peristaltic amplitude
Hypotensive lower esophageal sphincter
Excessive transient relaxations.
Gastroesophageal reflux disease management — The most important role of esophageal manometry in patients with gastroesophageal reflux disease (GERD) is prior to antireflux surgery. Manometry serves to exclude an alternative diagnoses, such as scleroderma or achalasia, for which antireflux surgery may be contraindicated. In addition, manometry may lead to a modification of the surgical approach or a change in management. Esophageal manometry is not diagnostic for GERD and manometry cannot predict disease severity. Non-specific manometric findings that may be seen in patients with GERD include impaired peristalsis, decreased peristaltic amplitude, hypotensive lower esophageal sphincter, and excessive transient relaxations.

31. GI Motility online (May 2006) | doi:10.1038/gimo42
Endoscopy
GI Motility online (May 2006) | doi: /gimo42

32. Make an Accurate Diagnosis
Erosive esophagitis is confirmed when symptoms and biopsy or visually proven erosion of the esophagus is present (abnormal endoscopy).
NERD is diagnosed when pathologic esophageal acid exposure (abnormal pH testing) is present without evidence of erosion (normal endoscopy).
Reflux hypersensitivity is diagnosed when no esophageal erosion is present (normal endoscopy) and the patient has symptom-reflux association; however, only physiologic acid exposure is confirmed (normal pH testing).
Functional heartburn is generally a diagnosis of exclusion when patients have no symptom-reflux association, normal visual or biopsy-proven esophagus (normal endoscopy), and physiologic acid exposure (normal pH testing).

33. Outline Medication Failures Diagnostic Tools Diagnosis and Treatment
Non-Reflux Related
Helicobacter Pylori Infection
Psychiatric Disorders
Nocturnal Acid Breakthrough
Visceral Hypersensitivity
Weakly Acidic Reflux
Duodenogastroesophageal (Bile) Reflux

34. Diagnosis and Treatments
Weakly Acidic Reflux
Nocturnal Acid Breakthrough
Duodenogastroesophageal (Bile) Reflux
Psychiatric Disorders
Visceral Hypersensitivity
Helicobacter Pylori Infection

35. Diagnosis - Weakly Acidic Reflux
True pathophysiology is unclear
Reflux symptom with esophageal pH between measured on MII-pH
Two proposed explanations
Esophageal distension by increased reflux volume
Esophageal hypersensitivity to weakly acidic refluxate
However, NO evidence that weakly acidic reflux is more commonly associated with increased volume of the refluxate than acidic reflux.
AND there is no current testing available to 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. 
No definitive treatment – treat like NERD
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. 

36. Diagnosis - Nocturnal Acid Breakthrough
Nocturnal acid breakthrough (NAB) has been defined as the presence of gastric pH below 4 for at least 1 h during the night.
Diagnosis on MII or MII-pH
No temporal relationship occurs with reflux-related symptoms.
So unlikely that NAB causes a significant role, may be a multifactorial contributor.
Treatment consideration: H2RA at night intermittently
Nocturnal acid breakthrough (NAB) has been defined as the presence of gastric pH below 4 for at least 1 h during the night. It has been suggested that this gastric physiological phenomenon causes failure of PPI treatment by promoting gastro-oesophageal reflux (GOR) during sleep but several studies have shown that NAB events do not necessarily denote a temporal relationship with reflux-related symptoms; Thus far, accumulating data do not support a significant role for NAB in precipitating the failure of PPI treatment.

37. Diagnosis - Duodenogastroesophageal (Bile) Reflux
Once thought that Bile Reflux and Non-Acid Reflux were synonymous
Actually they are both really different phenomena
Study using Bilitec (detects bile in the reflux) and MII showed no correlation between bilirubin and non-acid reflux parameters
In fact most Bile Reflux correlated with concomitant acid reflux events (likely the dominant factor)
PPI’s reduces the occurrence of both in treatment
Bile Reflux has been linked to dilated intracellular spaces (DIS) of the lower esophagus and potentially a cause of heartburn
However, a study of 24 patients (12 PPI responders and 12 PPI non-responders) only 9% of symptoms were correlated to Bile Reflux suggesting that bile reflux plays a limited role in symptom elicitation in refractory GORD patients.
Once thought that Bile Reflux and Non-Acid Reflux were synonymous
Actually they are both really different phenomena
Study using Bilitec (detects bile in the reflux) and MII showed no correlation between bilirubin and non-acid reflux parameters
In fact most Bile Reflux correlated with concomitant acid reflux events (likely the dominant factor)
PPI’s reduces the occurrence of both in treatment
Bile Reflux has been linked to dilated intracellular spaces (DIS) of the lower esophagus and potentially a cause of heartburn
However, a study of 24 patients (12 PPI responders and 12 PPI non-responders) only 9% of symptoms were correlated to Bile Reflux suggesting that bile reflux plays a limited role in symptom elicitation in refractory GORD patients.

38. Treatment Options – Unclear Benefits
Bile acid binders (cholestyramine) - No studies showing clear benefit, even in Bile Reflux
Sucralfate – no clear benefit in refractory GERD
Accupuncture – more efficacious than doubling the PPI dose in GERD patients, not really tested in refractory GERD patients

39. Treatment Options – Clamp the LES
Transient lower esophageal sphincter relaxations (TSLER) account for considerable number of reflux events
Drugs studied with evidence
Baclofen (5 to 20 mg three times daily at meals)
Limited efficacy largely because of poor tolerability
Reduced TLESR rate by 40 to 60 percent
Reduced reflux episodes by 43 percent
Increased lower esophageal sphincter basal pressure
Accelerated gastric emptying
Other GABA Agonist – abandoned due to poor clinical efficacy
? lesogaberan, a novel gamma-aminobutyric acid B receptor agonist
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.

40. Treatment Options - Endoscopy
Endoscopic procedures
Stretta Procedure – radiofrequency energy to the LES
Transoral incisionless fundoplication
Advantages
Both show decrease in PPI use
Unclear with benefit in non-acid reflux

42. Surgical Treatments – Antireflux Surgery
Only considered if requiring high doses of PPI’s
Fundoplication
Controversial about whether beneficial long term
Up to 2/3 of patients will continue to use medication
Laparoscopic sphincter augmentation
String of magnetized beads implanted at the LES
Three year follow-up
>50% reduction in esophageal acid exposure in 64% of pts
87% of pts reported no PPI use
68% of patients reported dysphagia
6% serious side occurred
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

44. Diagnosis - Visceral Hypersensitivity
Patients with persistent symptoms of reflux
Normal upper endoscopy
Normal esophageal acid exposures (pH probe)
Strong correlation between physiological acid reflux events and symptom (MII-pH)
Experimental data indicate that patients with NERD and functional heartburn are more sensitive to intraesophageal acid challenge, balloon distension or electrical stimulation than patients with erosive disease or controls.
The mechanism of oesophageal hypersensitivity is unclear but involves (among other potential mechanisms) DIS and exposure of subepithelial nerves to acid. This leads to sensitisation of peripheral afferent nerves (peripheral sensitisation) and also sensitisation of spinal dorsal horn neurons (central sensitisation). Once central sensitisation is established, it can continue to potentiate pain after the initiating peripheral stimulus is discontinued.

45. Diagnosis - Psychiatric Disorders
Psychiatric Disorders have been linked to increased patient symptom scores, physician visits, medication usage.
Anxiety
Somatization
Irritable Bowel Syndrome

46. Treatment Options – Pain Modulators
Pain modulators that have shown improvement in pain
Tricyclic antidepressants
Trazodone
SSRI’s
SNRI’s
Proposed mechanism of action is a visceral analgesic effect at the CNS and/or sensory afferents level
Doses should be kept low, not at the levels to treat mood
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.
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.

47. Diagnosis and Treatments - Helicobacter Pylori Infection
Consider testing
Unlikely a major contributor based on prevalence rates and the number of refractory GERD cases.

48. References
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49. References
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