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A preliminary report on the use of Midodrine in treating refractory gastroesophageal disease: Randomized Double-Blind Controlled Trial

Background: Gastroesophageal reflux disease (GERD) is a common disease with various clinical presentations. Acid suppression with proton pump inhibitors and lifestyle modification may not lead to satisfactory response in a substantial portion of patients. We investigated the possible effect of midodrine in patients with refractory GERD. Methods: Patients suffering from GERD and were refractory to one-month course of pantoprazole 40mg twice daily entered the study. This was a pilot, randomized, double-blind, and placebo-controlled study. After randomization, one group received Midodrine 5mg before meals for one month, and the other group received placebo for the same period. Meanwhile, pantoprazole was continued 40mg twice daily in both arms. The severity of symptoms was evaluated by the visual scoring system. Quality of life (QoL) in both groups was measured using a standardized version of Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD). Results: A total of twenty patients were enrolled in this study. There was a significant interaction between the groups and time on all measured scores based on QOLRAD questionnaire. All the markers in the Midodrine group had significant improvement over time, but the placebo group did not show any significant improvement. Both visual severity score and total QoL score in Midodrine arm showed a U shape change during 6 weeks. Conclusions: Midodrine before a meal could be useful in alleviating symptoms and improving QoL in the patients with refractory gastroesophageal disease. (www.actabiomedica.it)


Introduction
Gastroesophageal reflux disease (GERD) is common with a variety of clinical presentations, imposing a considerable economic burden on patients and healthcare systems. Pathologic GERD occurs when reflux of stomach contents leads to heartburn, regurgitation, and/or complications due to chronic mucosal injury (1). Quality of life (QoL) of 40% of the population may be affected by this condition (2)(3)(4)(5).
Despite good response to lifestyle modification and acid suppression with proton pump inhibitors (PPIs) in the majority of patients, there are still group of patients who are refractory to these measures. It is estimated that about 10-40% of patients do not show a satisfactory response to PPI. In addition to inad-equate dosing or improper timing of PPIs, there are other causes of refractory GERD including non-acid reflux, hypersensitivity, and eosinophilic esophagitis. The clinical definition of refractory GERD is controversial in the literature. Most experts consider refractory GERD in those who fail to show improvement in their symptoms, either partially or entirely, with PPIs twice daily (6)(7)(8)(9)(10)(11)(12)(13).
The main pathogenesis of classical GERD, as well as refractory cases, are considered to be increased transient lower esophageal relaxations. A variety of medications might reduce this event including baclofen, lesogaberan, or acotiamide through various mechanisms (14)(15)(16)(17).
These drugs have either significant side effects or in many cases, are not affordable. Midodrine is an alpha-1 adrenergic agonist with an excellent safety profile. Since alpha-adrenergic receptor stimulation causes lower esophageal sphincter contraction in physiologic studies, midodrine could theoretically reduce reflux episodes. For the first time, in this study, we investigated the possible effect of midodrine in managing patients with refractory GERD.

Patients
Patients who presumed to have refractory GERD referred to a special clinic affiliated to Shiraz University of Medical Sciences in 2015-2017. Before entering the study, all cases were given one-month course of pantoprazole 40 mg (ACTOVERCO Pharmaceutical Factory, Karaj-Iran under license of KRKA Company, Slovenia) twice daily. Those who completed this course of medication and their symptom failed to improve were considered for this study. Patients with the following criteria were deemed to be eligible: age 18-65 years, having had at least one symptom consistent with GERD (such as retrosternal burn or regurgitation), and lack of response to pantoprazole 40 mg twice daily for one-month. Exclusion criteria included prior abdominal surgery, dysphagia, significant comorbid illnesses that could interfere with the study or compromise patients' safety such as malignancy, peptic ulcer disease, hypertension(HTN), urinary retention, heart disease, vascular insufficiency, renal failure, pheochromocytoma, severe respiratory disorders, cirrhosis, hypersensitivity to midodrine, use of other medications affecting LES pressure or relaxation (including beta-blockers, steroids, theophylline, inhalers, antihistamines), any mental or psychiatric illness, pregnancy or breastfeeding in women, and consuming alcohol. Twenty patients were included in this study based on the inclusion criteria. All the patients signed a written informed consent before entering the study.
The histologic diagnosis of GERD is based on papers written in the early days of endoscopic biopsies, and the criteria described are still in use today. The typical features of GERD are increased thickness of the basal cell layer (thickness of the basal layer exceeds 15%); increased length of the papillae with suprapapillary thinning (extension above the midportion of the squamous mucosa); intraepithelial inflammation, including eosinophils, neutrophils and lymphocytes; and intercellular edema (spongiosis) (18,19). The endoscopic diagnosis of GERD is based on erosive picture and experts seen erosion for all cases and just the patients with typical symptoms alone were included.

Study design
This was a pilot, randomized, double-blind, and placebo-controlled study (20,21). The study was approved by the local Ethics Committee of Shiraz University of Medical Sciences, code number CT-P-92-6683. The study design and protocol was approved by the Iranian Clinical Trial Registry (IRCT) with identification # IRCT201402274226N2.
All twenty qualified patients underwent upper endoscopy at the beginning and biopsy was taken from the distal and mid part of esophagus following standard protocols. The participants were randomized using a computer-generated scheme into two groups with 10 cases each. All cases completed the study period. Both arms of the study were given pantoprazole 40mg twice daily. One group received 5mg midodrine tablets (Takeda pharmaceutical company, Linz-Austria, purchased from local market) three times per day before meals, and the other group was given a placebo with similar shape, packaging, and instruction for consumption for four weeks. After completing the treatment course, all cases were followed for another two weeks while continuing to consume pantoprazole 40mg twice per day. All the participants were asked to complete a visual score of their symptoms severity from 1 to 10 (with higher scores indicating higher severity) at the onset of study (before drugs consumption), and at weeks 2, 4, and 6 (two weeks after drug cessation), successively.
Furthermore, all the patient filled out the verified and standardized Persian version of QoL in Reflux and Dyspepsia (QOLRAD) questionnaire at the beginning of the study (22), visits on weeks 2, 4, and 6, successively. This questionnaire assesses five different dimensions in GERD including emotional distress, sleep disturbance, food problems, physical/social functioning, and vitality. Each question scores from 1 to 7. score one shows low QoL, and a higher score indicates a better QoL. During all visits, blood pressure was measured. All women in childbearing age had a serum HCG test before being enrolled into the study and were asked to practice some forms of contraception during their participation.

Statistical analysis
All statistical analyses were done using statistical package for social sciences (SPSS) version 25. The repeated measure analysis of variance (RM-ANOVA) was employed to compare the changes during time between the groups. Within and between groups comparisons were done through the paired t-test and independent t-test. Chi-square test and Fisher exact test were used to compare qualitative variables between the groups. Qualitative and quantitative variables were described using frequency (percent) and mean ± standard deviation (SD). P-value less than 0.05 was considered to be statistically significant. Overall observed power (partial eta-squared as effect size), through a multivariate test, was 99% (0.33) for time, 68% (0.64) for group, and 98% (0.25) for time*group (supplement 1).

Results
Figure1 shows the trial profile and patient flowchart, based on the CONSORT-statement (http:// www.consort-statement.org) guideline. A total of 20 patients were screened and divided into two groups of patients with refractory GERD. The mean age in the midodrine group (36.30 ± 11.44) and placebo group (37.50 ± 10.30) were not significantly different (P = 0.808). The mean duration of GERD symptoms was not significantly different between the groups (midodrine: 49.10 ± 46.90, Placebo: 50.80 ± 74.27 months; P = 0.952). Also, BMI, gender, ethnicity, smoking status, sign and symptom, endoscopic and pathologic findings were the same in either arm of the study. The demographic and clinical information of both groups are shown in Table 1. Table 2 shows the detailed comparison of the measured scores between the groups over the time. Repeated measure ANOVA showed that there was a significant interaction effect between the group and time on all of the measured scores (Table 2). Although all the markers in the midodrine group had significant changes over the time, the placebo group did not show any significant changes. These changes with related confidence interval in each time point are shown in Figure 2. Visual severity score in midodrine shows a U shape change during the time. It had a significant decrease in week 2 (P = 0.001) and week 4 (P = 0.001) compared with the baseline and a significant increase in week 6 (P = 0.05). Emotional score, sleep score, food score, physical score, vitality score, and total QoL in Midodrine group showed an inverse U shape changes during the time. All of them had a significant increase in week 2 and week 4 compared with the baseline and a significant decrease in week 6.
In week 2, visual severity score in midodrine group had higher mean than placebo group (P = 0.004); and emotional score (P = 0.020), food score (P = 0.045), vitality score (P = 0.010), and total QoL (P = 0.040) in midodrine group had significantly higher mean than placebo group. In week 4, the same pattern in differences between the groups remained statistically significant only for visual severity score (P = 0.002), Emotional score (P = 0.049), and Vitality score (P = 0.028). There were not any significant differences between the groups in week 6. No significant adverse effect/change in blood pressure was observed in either case or control groups.

Discussion
Gastroesophageal reflux disease (GERD) is a prevalent disease, which can adversely affect several aspects of patients' lives including their productivity at work (23).
Although proton pump inhibitors (PPIs) are the mainstay in GERD medical management, around one third of these patients do not respond to PPIs once daily. Significant proportion of these patients show improvement in their symptoms after increasing the standard dose of PPIs twice (BID) daily. As a result, the use of PPIs in BID dosages is a common practice and standard of care in GERD patients who stay refractory to PPIs once daily. In this investigation, we studied this group of patients with refractory GERD who remained symptomatic despite being treated with PPI BID (8,(24)(25)(26)(27)(28).
Although gastric acid is the principal noxious agent in GERD, increased episodes of transient lower esophageal relaxations (TLESRs) has been considered as one of the major pathogenetic factors in GERD. TLESR occurs as a physiologic response to gastric distension through vagal stimulation in healthy individuals. Increased episodes of TLESRs accounts for 65% of reflux episodes. Based on these findings TLESR has been considered as an attractive target for treating GERD. Gamma-aminobutyric acid (GABA) receptor type B agonist such as baclofen and lesogaberan have been shown to reduce TLESRs and decrease acid reflux episodes and increase LES pressure in several clinical trials. These drugs have major side effects including somnolence, fatigue, and dizziness, which some patients cannot tolerate (14,15,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Acotiamide has been recently introduced as an option for treating refractory GERD, which reduces TLESRs and enhances Within rows, the same lower letter indicates the significant difference between two time periods 1 QOLRAD: Quality of Life in Reflux and Dyspepsia questionnaire esophageal motility. However, its efficacy in improving symptom of refractory GERD remains to be elusive (16). Midodrine, an alpha-1 adrenergic agonist, in clinical practice is mainly used to treat orthostatic hypotension and hepatorenal syndrome. It is metabolized to its active metabolite, desglymidodrine, with peak blood levels reaching within 30-60 minutes after oral intake. The drug has good oral bioavailability and safe side effect profile (41,42). In this double-blind, randomized controlled study on patients with refractory GERD midodrine 5mg 30 minutes before meal significantly improved symptom severity based on visual scorings. The beneficial effect increased during treatment for four weeks, but was aborted two weeks after discontin-uation of treatment. Through QOLGAD, the standardized and validated questionnaire for measuring the QoL in patients suffering from GERD, we were able to show a significant improvement in both overall QoL score and all other aspects after midodrine usage. As with severity score, changes in QOLGAD parameters had a time pattern. The scores improved in the second and fourth week while being on midodrine and then decreased to baseline two weeks after discontinuation of midodrine. No adverse event was reported. For the first time in this study, we showed that midodrine could be useful in managing refractory GERD. Maybe, some patients suffering from functional heartburn rather than acid-based reflux. But at this Figure 2. Comparison of the measured scores according to Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD) questionnaire between the groups over the study time group, midodrine had efficacy and in this group, they also benefit from taking medication. Finally, Even in this group using midodrine is better in compare to use Common treatment such as anti-depressant.
This study used rigorous inclusion criteria to avoid the effect of confounders. Since this is a pilot study, it has several limitations. Small sample size (supplement 1) and lack of pH-metric and impedance results are amongst the major weaknesses of our study. However, this is the first study on the effect of midodrine in refractory GERD patients and in future studies these limitations should be acknowledged.
In conclusion, midodrine before a meal could be effective in alleviating symptoms and improving QoL in patients with refractory GERD. We recommend larger trials with adequate sample size; in addition to pH-metric and impedance to unravel the probable midodrine mechanism of action.

Key Points
• A proportion of patients with gastroesophageal disease are refractory to potent anti-acid agents including proton pump inhibitors. This study evaluated the role of midodrine in the management of refractory patients. • Use of midodrine lead to significant improvement in both severity of symptoms and quality of life of refractory reflux patients. • Midodrine could be an upcoming safe medication in the management of reflux disease in refractory patient.