Effects of antacid treatment on abnormal sensation in the throat
The 4-week P-CAB treatment significantly improved the FSSG acid reflux subscale scores (Fig. 2a), GETS-J pain/swelling subscale scores (Fig. 1a) and somatic distress due to the disease (Fig. 1a). The improvement ratio of somatic distress showed significant correlation with that of the pain/swelling subscale (Fig. 3). These results suggest that P-CAB treatment may decrease acid secretion leading to a decrease in the FSSG acid reflux score and the GETS-J pain/swelling score. Pain/swelling in the throat may be a characteristic symptom and one of the factors that cause somatic distress in patients with AST. The HADS anxiety subscale scores also decreased after antacid treatment (Fig. 2a). Given that P-CAB itself does not have any psychoactive effects, the decrease in anxiety may have resulted from alleviation of somatic distress.
There were 14 responders and 17 non-responders, indicating that the overall effective rate of the P-CAB treatment on AST was 45.1%. Pantoprazole (40 mg), one of the PPIs, for four weeks showed an effective rate of 35.7%  and 53.7%  when the same threshold to determine the responders (> 50% reduction in symptom scores) was used. Our results of P-CAB (45.1%) were comparable with these studies. As also reported previously, the effective rate of long-term PPI treatment for patients with globus sensation is approximately 44% . One may argue that antacid treatment for 4 weeks is too short a duration. However, the overall effective rate of the 4 weeks P-CAB treatment in this study was comparable with that of long-term PPI treatment, perhaps because P-CABs are more potent acid suppressing agents than PPIs . It is expected that the effective rate may be improved if only patients with reflux disease are selected based on MII results .
Responders vs. non-responders to antacid treatment
Because the P-CAB treatment was not always effective, with an effective rate of approximately 45%, discrimination of the responders from non-responders before treatment is an important issue in terms of cost effectiveness. The GETS-J pain/swelling, globus, and somatic distress subscale scores were significantly higher in the responders than in the non-responders before treatment (Fig. 4a), suggesting that these three scales may be potential prognostic predictors of P-CAB effectiveness. ROC curves for each subscale were plotted on the same graph to compare the predictive capabilities. Among these three subscales, the AUC for pain/swelling and globus was approximately 0.8, whereas that for somatic distress was approximately 0.7 (Fig. 5a). Given that the globus subscale score did not decrease after treatment (Fig. 1a) and that the improvement ratio of pain/swelling showed significant correlation with that of somatic distress (Fig. 3), it is suggested that the pain/swelling subscale rather than the globus subscale may be more suitable as a prognostic predictor. When the cut-off point of 11 (full score 21) was adopted, the sensitivity and specificity to predict more than 50% decrease in pain/swelling symptoms (responders) with P-CAB treatment were 62.5 and 80%, respectively.
In contrast to the current results, it was reported that in patients with globus sensation and GERD, the FSSG acid reflux score before PPI treatment was higher in responders than in non-responders and that non-responders had ineffective esophageal motility on high-resolution manometry . This discrepancy in the results may be due to differences in patient background (AST vs. globus sensation with GERD) and the medication used (P-CAB vs. PPIs).
Effects of SNRI treatment on abnormal sensation in the throat
AST and globus sensation may be multifactorial conditions that include structural, functional, and psychological disorders [3,4,5,6,7,8,9,10,11,12]. Indeed, it was reported that psychosocial stress induced constriction of the esophageal wall  and that depression had significant effects on prognosis of GERD . In the present study, SNRI treatment for 4 weeks significantly improved the HADS anxiety subscale (Fig. 2b) and somatic distress due to the disease (Fig. 1b). On the contrary, SNRI treatment had no effect on the other GETS-J symptom subscales (Fig. 1b). SNRI treatment differed from antacid treatment in that it did not show direct effects on throat symptoms; however, it decreased patients’ somatic distress perhaps by reducing anxiety.
Responders vs. non-responders to SNRI treatment
There were 10 responders and 11 non-responders, indicating that the overall effective rate of SNRI on AST was 48%. The GETS-J globus subscale was significantly lower in the responders than in the non-responders before SNRI treatment (Fig. 4b), suggesting that the globus subscale may be a potential prognostic predictor of SNRI effectiveness. The ROC curve for the globus subscale has an AUC of 0.741 (Fig. 5b) showing moderate accuracy. When the cut-off point of 6.5 (full score 21) was adopted, the sensitivity and specificity to predict responders to SNRI treatment were 70% and 73%, respectively. SNRI affected the somatic distress in mild cases.
Selection of antacid agents or SNRIs in treating AST
Laryngopharyngeal reflux may be one of the major causes of globus sensation and AST. Therefore, antacid agents are often used for these conditions. In treating suspect laryngopharyngeal reflux disease (LPRD), up-front, pH-impedance, and manometry testing are superior to empiric PPI trials in terms of minimizing cost, although the latter are still common . Although ideal, it would be unrealistic to perform pH-impedance and manometry testing for all AST patients. Alternatively, based on the present results, we suggest that the GETS-J pain/swelling subscale can predict responders to antacid treatment among patients with AST. A score of 11 showed high specificity (80%) in predicting the response to treatment, whereas the sensitivity was relatively low (62.5%). Therefore, if a patient with AST has a score lower than 11 on the pain/swelling subscale, P-CAB treatment is not recommended.
Although SNRI treatment did not show direct effects on throat symptoms, it was beneficial in relieving patients’ somatic distress perhaps through decrease in anxiety. However, its effects on somatic distress were limited to patients with mild globus sensation: score of 6.5 had sensitivity (70%) and specificity (73%) to predict responders. Therefore, SNRI treatment may be recommended for AST patients with milder throat symptoms with globus sensation subscale scores of 6.5 or less. Nonetheless, we cannot exclude the possibility that these effects on somatic distress might be non-specific ones, since there was no correlation between the improvement ratios of somatic distress and HADS anxiety subscale.