Efficacy and Safety of Fixed Dose Combination of Pantoprazole and Low Dose Amitriptyline in Indian Population Suffering From GERD with Co-Existing Anxiety

Presently, up to 70% of the patients with complaints of reflux symptoms have been noted to have NERD [2]. Despite the potency of proton pump inhibitors (PPIs) on gastric acid secretion, it is now evident that they do not suppress symptoms in patients with GERD as completely as was once supposed. Indeed, with the advent of more thorough symptom evaluation, it is now well recognized that both in the clinical study setting and in ordinary clinical practice, many GERD patients experience persistence of troublesome reflux symptoms while taking PPI therapy [3].


Introduction
Gastroesophageal reflux disease (GERD) is a condition characterized by the reflux of stomach contents into the esophagus, which causes several symptoms, such as heartburn and regurgitation.It is typically divided into three subtypes: reflux esophagitis (RE), nonerosive reflux disease (NERD) and Barrett's esophagus [1].
Presently, up to 70% of the patients with complaints of reflux symptoms have been noted to have NERD [2].Despite the potency of proton pump inhibitors (PPIs) on gastric acid secretion, it is now evident that they do not suppress symptoms in patients with GERD as completely as was once supposed.Indeed, with the advent of more thorough symptom evaluation, it is now well recognized that both in the clinical study setting and in ordinary clinical practice, many GERD patients experience persistence of troublesome reflux symptoms while taking PPI therapy [3].Some 40-50% of patients with NERD, and 6-15% of those with erosive esophagitis (EE), has been reported as refractory to PPI therapy [4].
According to the literature psychological factors, including anxiety and depression, play an essential role in the development of GERD and especially that of NERD [1].
One population based study showed that there is increase in GERD related symptoms due to presence of anxiety and depression [5].
In a recent study by Yang XY et al it was demonstrated that the presence of anxiety in NERD & RE was 49.66% & 44.03% respectively [1].
Predictions by many physicians and previous studies have established that patients with concurrent anxiety or depression would respond poorly to GERD treatment [6].
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 [7].
Consequently, anti-anxiety medications may be alternative therapies for patients with NERD and RE if antacids cannot produce a satisfactory effect [1].

Design and Participants
This was a non-randomized, non-comparative, observational, multi-centric study to determine the effectiveness and safety of the fixed dose combination of Amitriptyline 10mg and Pantoprazole 40mg once daily for 4 weeks.
During the trial duration, patients were allowed to take additional medications like Levosulpiride, Domperidone, Antacids etc. for symptomatic relief.

Inclusion and Exclusion Criteria
GERD patients experiencing partial relief with PPI twice daily were included in the study.Total 211 patients with GERD & anxiety symptoms who gave their informed consent in the vernacular language were included in the study.Eligible patients were in the age range of 20-84 years and were diagnosed to have GERD with co-existing anxiety by utilizing GERD and HADS questionnaire at the baseline.

The exclusion criteria included patients with any of the several conditions listed as follows:
Use of prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin; a history of upper gastrointestinal surgery; comorbidities, such as scleroderma, diabetes mellitus, autonomic or peripheral neuropathy, myopathy, functional bowel disorder or any underlying disease (or medication) that might affect the lower esophageal sphincter pressure or increase the acid clearance time and inability or unwillingness to provide informed consent.Females who were pregnant or planning to conceive and lactating mothers were also excluded from the study.

Results
From total 211 patients included in the study, 23 were dropped out because they did not turn up to follow up at week 4, hence the data was extractable in total 188 patients.In this observational study we observed higher prevalence of GERD with co-existing anxiety in males compared to females (Figure 1).

Evaluation of GERD symptoms using GERD questionnaire
The mean reduction in overall GERD symptoms was found to be clinically significant (p Value <0.0001) at week 4 compared to baseline (Figure 2).The mean change of individual symptom score using unpaired t-test is shown in Table 1.

Anxiety Score
The change in anxiety score was statistically significant (p Value <0.0001) at week 4 compared to baseline (Figure 3).The mean change in anxiety score was performed using unpaired t-test and is described in Table 2.

Evaluation of physical and mental health using SF-8 Questionnaire
All parameters were found to be significantly (p Value < 0.0001) improved at week 4 when compared with baseline (Figure 4).Improvements in mean change of SF-8 questionnaire parameters at week 4 using unpaired t-test are presented in the Table 3.

Efficacy and Safety of Fixed Dose Combination of Pantoprazole and Low Dose Amitriptyline in Indian Population Suffering From GERD with Co-Existing Anxiety
Copyright: © 2018 Arif AF.

Efficacy and Safety of Fixed Dose Combination of Pantoprazole and Low Dose Amitriptyline in Indian Population Suffering From GERD with Co-Existing Anxiety
Copyright: © 2018 Arif AF. be good, only 59 out of 188 (31.38%) patients reported to have adverse events (Table 4) of mild intensity which were self limiting and hence resolved on its own.None of the patients discontinued the treatment.

Discussion
In our study we observed positive association between anxiety and GERD patients.Both GERD and anxiety were found to be significantly improved at week 4 in patients who were getting partial or no relief from PPI twice daily.Typical GERD symptoms such as heartburn and regurgitation were significantly (p < 0.0001) reduced by 72.37% & 91.79% respectively along with improvement in anxiety score by 70.27%.In addition to symptomatic improvement, in this study we found that there was significant improvement in QoL of patients assessed by SF-8 questionnaire.There was significant (p < 0.0001) improvement in general health, physical functioning, role physical, bodily pain, vitality, social functioning, role emotional and general health from baseline to week 4.The tolerability of this fixed dose combination was also found to be good as only 34.57% of patients observed to have mild intensity adverse events & there were no serious adverse events reported throughout the study duration.Reduction in intake of additional medication (Domperidone, Levosulpiride & Antacids) by 87.50% shows that the reported adverse events were self limited thus establishing an excellent tolerability and enhanced patient adherence for this combination.
Various studies evaluated the effect of stress on the gastrointestinal tract.More recent studies have focused on the relationship between stress and reported symptoms of GERD.Bradley et al. evaluated the relationship among stress, psychological traits associated with chronic anxiety, acid reflux parameters and perceptions of reflux symptoms [8].Jansson et al reported that patients with anxiety but no depression had a 3.2-fold (95%CI: 2.7-3.8)increased risk of reflux symptoms [9].Another significant finding was that reflux patients who were chronically anxious and exposed to prolonged stressful stimuli may be more likely to perceive low-intensity esophageal stimuli as painful reflux symptoms.Therefore, even normal esophageal acid exposure could trigger complaints of GERD symptoms.Also, it is not a specific psychiatric disorder that may be responsible for gastrointestinal distress but the presence of psychological distress predisposes the fact to have clinical manifestations of GERD [10].
Based on result of our study and the literature it can be postulated that anxiety plays a crucial role in precipitation & increase in GERD symptoms and subsequent reduction in quality of life of the patients.Hence consideration can be given to a low dose Amitriptyline in combination with Pantoprazole for the management of GERD with co-existing anxiety.Nonetheless this combination also has potential to reduce the PPI failure rate in patients with PPI refractory GERD which is particularly very common.Small duration and open label nature of the study were the only limitations, further long duration and double blind studies are warranted.

Conclusion
The fixed dose combination of Amitriptyline and Pantoprazole caused significant reduction in GERD symptoms along with improvement in anxiety & quality of life of the patients with good safety profile.This result justifies the presence of anxiety in patients suffering from GERD and it may have potential to reduce PPI failure rate in patients with PPI refractory GERD.

Figure 1 :
Figure 1: Prevalence of GERD with Co-existing anxiety

Figure 2 :
Figure 2: Improvement in GERD symptoms at Week 4

Figure 3 :Figure 4 :
Figure 3: Improvement in anxiety score at Week 4

Table 1 :
Evaluation of GERD Using GERD Questionnaire

Table 2 :
Evaluation of Anxiety Using HADS Questionnaire

Table 3 :
Evaluation of Physical and Mental Health using SF-8 Questionnaire

Table 4 :
Total No. of Adverse Events in 59 Patients