1. BackgroundIneffective esophageal motility disorder is the most common esophageal motility disorder and is associated with low to moderate amplitude contractions (less than 30 mm Hg) in the distal esophagus in conventional manometric studies. It is characterized by a distal contractile integral (DCI) of less than 450 mm Hg/s/cm in high-resolution magnetometry in more than 50% of swallowing test cases, which can be defined as either failed (less than 100 mm Hg/s/cm) or weak swallows (100–450) according to the Chicago classification IV [1,2].This disorder is mainly seen along with symptoms such as dysphagia or heartburn and is associated with diseases such as gastroesophageal reflux disease (GERD). IEM has been reported to be the primary motility disorder, in 50% of patients with GERD [3]. Other diseases contribute to this disorder, like diabetic neuropathy, amyloidosis, ethanol consumption, chronic calcium-induced neuropathy, adenocarcinoma, eosinophilic esophagitis, chronic cough, and rheumatic diseases [4,5]. Based on the results obtained for esophageal impedance, ineffective esophageal motility can result in the ineffective transfer of food through the esophagus [6,7]. This disorder occurs in 20–30% of individuals who undergo manometric evaluations [8,9].

Esophageal motor peristalsis is controlled by the inhibitory and excitatory neuronal activity of the CNS, vagal dorsal motor, and intramuscular interstitial cells of Cajal (ICC), which are pacemakers of esophageal cells. Numerous sensory and motor neuron receptors modulate vagal activity. IEM is thought to be associated with an abnormal vagal tone derived from abnormal sensory and/or motor vagal pathways from the stomach via the solitary nucleus to the esophagus.

Buspirone is an anxiolytic drug, a relative agonist of 5-HT1A (hydroxytryptamine) receptors and an antagonist of dopamine D2 receptors, and evidence of a weak agonist effect on 5-HT2 receptors. In the intestinal nervous system, activation of 5-HT1A receptors can release acetylcholine from nerve endings and stimulate esophageal motor function via muscarinic receptors on smooth muscle cells [10]. Buspirone has been shown to increase the esophageal peristaltic amplitude in healthy individuals.There is still no effective drug for the treatment of ineffective esophageal motility disorders. One of the therapies introduced to improve patients with this disorder is buspiron [11,12]. However, despite some preliminary studies, there is no consensus on the efficacy of this drug, and its efficacy in Iranian patients has not yet been studied. Considering the prevalence of this disorder among patients with GERD and dysphagia, this study aimed to determine the effect of buspirone on concomitant GERD and ineffective esophageal motility. 3. ResultsThirty-one patients were enrolled. One patient did not complete the study due to the COVID pandemic. Of the remaining 30 participants, 15 patients received pantoprazole and 15 patients received pantoprazole plus Buspirone (63.3% of patients were female and the mean age was 45.33 ± 11.15 (Table 1).The results of the Mann–Whitney U test showed that all of the manometric, MAYO scores (13.33 ± 5.16 in the Pantoprazole group and 11.00 ± 6.72 in Pantoprazole + Buspirone group before treatment, p = 0.29 vs. 8.80 ± 4.72 in the Pantoprazole group and 8.40 ± 6.13 in Pantoprazole + Buspirone group after treatment, p = 0.84), and swallowing disorder questionnaire variables were no different across the two groups of patients (1.93 ± 0.88 in the Pantoprazole group and 1.46 ± 0.99 in Pantoprazole + Buspirone group before treatment, p = 0.18 vs. 1.13 ± 0.83 in the Pantoprazole group and 0.88 ± 0.73 in Pantoprazole + Buspirone group after treatment, p = 0.21) (Table 2).The results of the Wilcoxon test showed that the Swallowing Disorder Questionnaire, MAYO score, DCI, and resting LES pressure significantly changed after treatment (Table 3) (Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5). The MAYO score and Swallowing Disorder Questionnaire significantly decreased after treatment in both groups of patients. The difference (md) of the MAYO score in the Pantoprazole group was +4.533 (p = 0.009) and 2.600 in the Pantoprazole + Buspirone group (p = 0.015). The Swallowing Disorder Questionnaire md was also 0.800 in the Pantoprazole group (p = 0.028) and 0.733 in the Pantoprazole + Buspirone group (p = 0.005) (Figure 3, Figure 4, Figure 5, Figure 6 and Figure 7).

Resting LES pressure (md = −5.6 pantoprazole group, p = 0.017, and −3.066 in Pantoprazole + Buspirone group, p = 0.014) and DCI (md = −269.933 pantoprazole group, p = 0.007, and −181.333 in Pantoprazole + Buspirone group, p = 0.023) experienced a significant increase after treatment in both groups. Meanwhile, integrated relaxation pressure increased across both groups, but it was not statistically significant (md = −1.162 pantoprazole group, p = 0.196, and −0.390 in the Pantoprazole+ Buspirone group, p = 0.706).

An ANCOVA was performed to examine the mean differences in post-intervention manometric variables (Resting LES, DCI, IRP) among the two groups after adjusting for the baseline. The results indicated that the post-intervention values of manometric variables did significantly differ between the two groups after controlling for the baseline values of the variables.

4. DiscussionAccording to the Chicago Classification for primary esophageal motility disorders, ineffective esophageal motility disorder is the most common disorder that is found on manometry in patients who are referred for evaluation of dysphagia [15]. This disorder leads to a significant number of referrals to gastroenterologists. It has been shown that some disorders are related to this disorder, such as amyloidosis, diabetes, and eosinophilic esophagitis, but the most common disorder attributed to this disorder is GERD.The balance between neurotransmitters, including acetylcholine, VIP, and nitric oxide, is crucial in the pathophysiology of esophageal motility. Activation of 5HT1A leads to an increase in acetylcholine, which is a positive mediator for smooth muscle activation in the esophagus. Theoretically, buspirone, which is a partial agonist for 5-HT (hydroxy-tryptamine) 1A receptors, and has a weak agonistic effect on 5-HT2 receptors, could be effective in the treatment of IEM [16,17].

In the present study, we investigated the therapeutic effects of two drug regimens (pantoprazole monotherapy and pantoprazole plus buspirone) on patients’ symptom scores and manometric findings of IEM in patients with GERD disease. The results of our study showed that pharmacologic treatment with PPI improves the clinical condition and quality of life of patients. The therapeutic intervention caused a statistically significant improvement in manometric and clinical parameters. The Mayo score, and swallowing score decreased, and the resting pressure of LES and DCI increased after the treatment, which all were statistically significant.

Although the parameters studied in this study responded to treatment, the combination with buspirone did not make a significant difference. In fact, the addition of buspirone to the treatment regimen does not seem to have a significant effect on either clinical or manometric variables. To our knowledge, at least five different research centers have studied the effects of buspirone on IEM. In two studies, 20 mg of buspirone was administered to healthy adults, and esophageal motility was measured by conventional manometry within 60 min of administration in a blind, placebo-controlled trial. The results showed that the mean amplitude and duration of contraction in the distal esophagus increased in both studies after a single dose of buspirone [8,18]. This was against our findings. This study was conducted by Di Estefano et al. His study revealed that buspirone overcame the placebo in increasing LES tone and distal esophagus smooth muscle amplitude. The difference in the results of this study and ours could be due to differences in the study population. In addition, they have reached these results only after the administration of a single dose of buspirone and not continuous use [18]. Karamanolis et al. investigated buspirone in two different studies, including patients suffering from scleroderma and dysphagia. In the first study, buspirone was compared with domperidone and showed a beneficial effect in the manometric criteria conducted 30 min after ingestion. The second study examined the effect of buspirone on a four-week trial, and the only manometric value that showed a significant change was LES pressure [19,20]. Aggarwal et al. also examined buspirone against a placebo in the United States. As buspirone and the placebo both had a 30% increase in manometric variables, they did not consider buspirone superior to the placebo [21]. Nitin Aggarwal et al. conducted a cross-over study in 10 patients with functional dysphagia and IEM with six weeks of buspirone and a placebo. Similar to our study, they showed no improvement in a patient’s symptom score and manometric findings after four weeks of use of this drug [21].Studies by Wang et al. [22], and Shetler et al. [23] showed that IEM is accompanied by the severity of GERD disease, and interestingly, our study showed that treatment with PPI improves patient distal contractile integral, which could be an indicator of esophageal motility improvement.A recent study by Taghavi et al. [24] examined the effectiveness of buspirone in patients with functional dyspepsia. The first group received buspirone 5 mg three times daily for the first month and 10 mg three times daily for the second month. During the course of treatment, patients were advised to report any adverse reactions. This study shows that there was no significant difference between the two groups of buspirone and placebo in terms of quality of life (p = 58.0), anxiety and depression (p = 36.0), and severity and frequency of functional dyspepsia symptoms (p = 0.22) before and after the intervention. They suggested that further studies are needed to introduce effective treatments based on the pathophysiology of functional dyspepsia. However, some previous studies have suggested that buspirone may improve the therapeutic response.

Recent limited data has shown the role of acetylcholine and 5HT1A on esophageal smooth muscle and a single use of 10 mg buspirone was effective in increasing LES pressure and DCI, but the main effect of this drug was seen in single and short-term use of this drug. Our study showed that using 10 mg buspirone for four weeks was not superior to using PPI for improving symptoms and manometric findings. Interestingly, PPIs themselves could increase DCI and LES resting pressure, which indicates that the most important treatment in patients with GERD and ineffective esophageal motility could be an early and effective dose of PPIs. However, it should be noted that the sample size of this study is small and this result cannot be considered definitive, and to confirm or reject these findings, large clinical trials with a larger sample size are needed. In addition, the proper dose of buspirone for inducing acetylcholine release, increasing DCI, and augmenting smooth muscle strength thereafter has not been determined yet. We could not use more doses of this drug due to its severe sedative effect. Other detailed studies with different doses of buspirone will overcome this limitation.

Limitations: During the COVID-19 pandemic, fewer patients sought medical care for non-emergent problems such as dysphagia or heartburn, leading to a smaller sample size in the study than predicted. This study was also conducted in a single center; multicenter studies could be considered for future studies. Finally, we did not have any placebos in this study.