Menthol is a major component of peppermint oil which has numerous effects on gastrointestinal physiology relevant to clinical management.¹ The mechanisms of peppermint oil appear to involve smooth muscle relaxation via enteric nervous system or calcium channel blockade, visceral sensitivity modulation via transient receptor potential melastatin 8 (TRPM8), and other anti-inflammatory effects.^2-5 Previous studies in healthy adults have demonstrated that peppermint oil decreases the pressure of lower esophageal sphincter (LES) by which may predispose to increase the risk of acid reflux.⁶ The other study did not observe the effects on the pressure of LES, but did reveal improve esophageal manometric findings by reducing esophageal spasms.⁷ The discrepancy in the effects of peppermint oil on esophageal motility may be possible due to the difference in the methodology or dosage of peppermint used.

A recent work in healthy adults has applied high-resolution manometry (HRM) to determine whether menthol infusion could affect the esophageal peristalsis in healthy adults.⁸ They found that menthol infusion reduced basal pressure of upper esophageal sphincter (UES) and secondary peristaltic frequency as induced by rapid air distension.⁸ It appears that activation of TRPM8 receptors will reduce secondary peristaltic frequency with limited influence on esophageal motility. Ineffective esophageal motility (IEM) is a common motility diagnosis based on HRM,⁹ but it is unknown whether menthol may also influence esophageal peristalsis in patients with IEM. This study aims to investigate the effects of menthol on esophageal peristaltic physiology in patients with IEM by using HRM. Specifically, we hypothesized that acute esophageal menthol infusion would influence primary and secondary peristalsis in patients with IEM.

Subjects

This study was a cross-sectional prospective study enrolling 20 eligible patients (9 females, mean age 36.1 years, range 21-60 years), all of whom had untaken HRM, which showed IEM based on previous criteria⁹ before this study. Patients were excluded if they had previous history of esophageal and/or gastroduodenal surgery, esophageal strictures, chronic use of medications that would influence esophageal motility, and recent use of menthol. Study protocol was approved by the Research Ethics Committee of Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (IRB109-011-A), and all patients gave written informed consent form before participating in this study.

High-resolution Manometry

HRM was performed in all patients using a 22-sensor catheter including 1 air injection port in the mid-esophagus (MMS, Enschede, The Netherlands) after a 6-hour fast. On the day of the study, all patients received transnasal passage of the HRM assembly which was passed and positioned to record the data from hypopharynx to the stomach with at least 3 sensors positioned in the stomach. The differentiation between primary and secondary peristalsis was performed by the most proximal sensor to detect individual swallowing attempt.

Study Protocol

All patients had HRM evaluations in the supine position. Pre-treatment with either 160-mL of 3 mM menthol¹⁰ or 0.9% saline infused into the mid-esophagus at a rate of 8 mL/min was performed. All patients had ten 5-mL liquid swallows of normal saline. Secondary peristalsis was evaluated by rapid 20-mL air injection into mid-esophagus. A dry swallow was allowed after each air injection in order to prevent any swallow event within next esophageal stimulation for generating secondary peristalsis.

Analysis of High-resolution Manometry Data

HRM data were analyzed using comprehensive software (MMS). The measurement of HRM metrics was using Chicago classification version 4.0.⁹ Esophageal peristalsis was considered normal if the typical peristaltic topography was shown on HRM. The measurement of the frequency (%) for primary and secondary peristalsis was calculated as the number of successful responses divided by total primary or secondary peristalsis. Peristaltic metrics included distal contractile integral (DCI) representing contractile vigor of esophageal peristalsis, 4-second integrated relaxation pressure (IRP-4s; mmHg), distal latency (DL; second), and LES resting pressures. The esophagogastric junction contractile integral (EGJ-CI) was also measured.¹¹ Analysis of multiple rapid swallows (MRS) included completeness of esophageal body inhibition and LES relaxation, whereas DCI after MRS was measured immediately after the last MRS.¹²

Statistical Methods

All HRM data were compared between menthol and the placebo. Continued variables were reported as mean ± standard error of the mean, while categorical variables were reported using frequency or proportion. Continued variables were compared using pair t test, while categorical data were analyzed using chi-square analysis and Fisher’s exact tests. Evaluation of data normality was performed using D’Agostino’s K-squared test. Statistical differences were considered significance at P < 0.05.

Sample Size Calculation

Our previous study has demonstrated that menthol significantly reduced the frequency of secondary peristalsis and UES pressure as compared with the placebo;⁸ therefore, the sample size was determined to be not less than 18 cases that allowed to reach a statistical power of 80% and α of 0.05 that could achieve statistically significant difference.

Primary Peristalsis Between Menthol and the Placebo

Table 1 shows the results of primary peristalsis between the administration of menthol and the placebo patients with IEM. Menthol infusion did not change DCI (P = 0.471), or DL (P = 0.583) as compared with the placebo (Table 1). There was no difference in the frequency of primary peristalsis between menthol infusion and the placebo (P = 0.251) (Table 1). No difference was found for total break length between menthol infusion and the placebo (P = 0.852). Menthol infusion had no effects on basal LES pressure (P = 0.321), EGJ-CI (P = 0.758), or IRP-4s (P = 0.375) of primary peristalsis, but significantly reduced basal UES pressure (P = 0.037) (Table 1 and Fig. 1). The DCI after MRS was similar between menthol infusion and the placebo (P = 0.568).

Figure 1. Upper esophageal sphincter (UES) pressures between menthol and the placebo in patients with ineffective esophageal motility (each point represents an individual patient). Menthol significantly reduces UES pressure than the placebo (*P = 0.037).

Table 1 . Esophageal Primary Peristalsis Between Menthol and the Placebo in Ineffective Esophageal Motility Patients

Primary peristalsis	Menthol	Placebo	P-value
LES parameters
Basal pressure (mmHg)	21.5 ± 2.3	18.7 ± 1.9	0.321
IRP-4s (mmHg)	6.3 ± 0.8	7.1 ± 0.8	0.375
EGJ-CI (mmHg∙cm)	30.5 ± 3.0	31.6 ± 4.3	0.758
UES parameters
Basal pressure (mmHg)	51.1 ± 7.7	65.9 ± 8.2	0.037
Esophageal body parameters
DCI (mmHg∙s∙cm)	268.8 ± 53.0	232.8 ± 32.1	0.471
DL (sec)	6.7 ± 0.6	6.8 ± 0.2	0.583
Total break length (cm)	7.3 ± 1.0	7.6 ± 0.9	0.852
Frequency (%)	21.5 ± 7.2	14.0 ± 3.4	0.251
MRS DCI (mmHg∙s∙cm)	217.2 ± 47.0	188.9 ± 51.6	0.568

LES, lower esophageal sphincter; IRP-4s, 4-second integrated relaxation pressure; EGJ-CI, esophagogastric junction contractile integral; UES, upper esophageal sphincter; DCI, distal contractile integral; DL, distal latency; MRS, multiple rapid swallows.

Data are presented as mean ± SEM.

Secondary Peristalsis Between Menthol and the Placebo

The results of secondary peristalsis between the administration of menthol infusion and the placebo are presented in Table 2. Menthol infusion significantly decreased the frequency of secondary peristalsis than the placebo (P = 0.002) (Fig. 2). Menthol infusion had no effect on IRP-4s of secondary peristalsis when compared with the placebo (Table 2). There was no difference for DCI, DL or total break length of secondary peristalsis between menthol infusion and the placebo (Table 2).

Figure 2. Effects of acute administration of menthol on peristaltic frequency of esophageal secondary peristalsis in patients with ineffective esophageal motility (each point represents an individual patient). Menthol significantly reduces peristaltic frequency than the placebo (*P = 0.002).

Table 2 . Secondary Peristaltic Parameters Between Menthol and the Placebo in Ineffective Esophageal Motility Patients

Secondary peristalsis	Menthol	Placebo	P-value
Frequency (%)	36.0 ± 6.1	50.0 ± 6.4	0.002
DCI (mmHg∙s∙cm)	273.5 ± 85.1	195.0 ± 37.1	0.262
DL (sec)	8.4 ± 0.9	8.0 ± 0.7	0.292
IRP-4s (mmHg)	9.8 ± 1.7	8.5 ± 1.0	0.271

DCI, distal contractile integral; DL, distal latency; IRP-4s, 4-second integrated relaxation pressure.

Data are presented as mean ± SEM.

Although IEM is considered as a minor disorder of esophageal peristalsis, it remains to be most common abnormal manometric in clinical practice. This study prospectively evaluated the effects of acute administration of menthol on esophageal peristaltic physiology in IEM. Although our study demonstrated that most of peristaltic parameters were not affected by the administration of menthol, menthol significantly reduced the triggering of secondary peristalsis in response to rapid air injections in patients with IEM. Our results are consistent to prior study demonstrating that direct infusion of menthol into the esophagus could attenuate peristaltic frequency of secondary peristalsis in healthy adults.⁸ In addition, menthol infusion significantly decreased basal pressure of UES in patients with IEM, which was also observed in healthy adults.⁸

A previous study using conventional manometry demonstrated that impaired triggering of secondary peristalsis was found in patients with IEM, and was more frequently detected in patients with severe IEM.¹³ The explanation for such findings is plausible due to the fact that the defective triggering of secondary peristalsis is more relevant to aberrant esophageal sensation or in combination of both sensory afferents and motor neurons of the reflex arc,¹⁴ which can be supported by previous work that identified a significant impairment in distension threshold for secondary peristalsis in IEM despite similar motility parameters of secondary peristalsis between those patients and healthy controls.¹³ A recent study using HRM has also shown that there was a significant defect in the triggering of secondary peristalsis particularly in patients with IEM, suggesting that IEM per se can be clinically relevant to impaired distension-induced secondary peristalsis.¹⁵

Earlier studies utilizing conventional manometry demonstrated that menthol can ameliorate esophageal spasm in patients with diffuse esophageal spasm⁷ and healthy control.¹⁶ Another study has observed that menthol may increase the risk of acid reflux due to its effects on decreasing LES pressure.⁶ It appears that activation of TRPM8 receptor in the esophageal via menthol infusion has certain and various clinical impact on esophageal peristalsis. Subsequently, a recent study applied HRM to investigate whether esophageal instillation of menthol can affect esophageal peristalsis in health adults.⁸ This work revealed in healthy adults that direct menthol infusion into the esophagus could reduce basal UES pressure and distension-induced secondary peristaltic frequency by rapid air distension.⁸ The implication has therefore suggested that activating TRPM8 receptors from menthol infusion modulated the triggering of secondary peristalsis in the human esophagous. Along with these findings, current work also confirming decreased triggering of secondary peristalsis after menthol infusion in IEM patients may support the notion that the sensorimotor interaction between TRPM8 activation and triggering secondary peristalsis appears to equally present despite the presence of esophageal hypomotility. Therefore, the current study extended previous physiological notion by demonstrating that esophageal infusion of menthol has similar impact on triggering secondary peristalsis in patients with IEM as compared to healthy adults.

Secondary peristalsis can be physiologically triggered by different intra-esophageal stimuli including air, balloon, or water infusion.^17,18 The intrinsic reflex that modulates secondary peristalsis includes a vagal afferent pathway in which mucosal and intramuscular mechanoreceptors contribute to achieve the peristalsis.^19,20 Additionally, esophageal peristalsis can be also mediated by local neuromuscular reflex inside enteric nervous system and vasovagal reflex.²¹ Therefore, lack of effects on esophageal motor characteristics of primary and secondary peristalsis subsequent to menthol infusion may re-emphasize the evidence that intact esophageal peristaltic integrity consists of multiple components including central and peripheral neuromuscular coordination, and such modulation could be far beyond the activation of TRPM8 receptors from direct menthol infusion.

Our study has shown that menthol did reduce basal UES pressure, which is in consistence with a previous work in healthy adults.⁸ It was well established that the modulation of UES pressure is controlled by the nucleus tractus solitaries as afferent part and nucleus ambiguous as motor role via branches of the glossopharyngeal and vagus nerves.²² The explanation for the current finding may infer that TRPM8 activation by menthol infusion could potentially involve with central sensitization and modulates neurophysiological pathways which subsequently influences basal UES pressure.

Our study may have some clinical implications. Since menthol physiologically reduces UES pressure and triggering of secondary peristalsis, it may have potential therapeutic benefits in patients with hypertensive UES as well as those with aberrant esophageal sensation such noncardiac chest pain²³ by relieving esophageal sensations and symptoms. Further study is therefore needed to confirm whether applying menthol could have clinical utility in patients with perceptive esophageal disorders such as functional chest pain and disorders of upper esophageal sphincter processes such as globus syndrome. Furthermore, due to the lack of the impact on esophageal smooth muscle contractions and LES metrics, it is plausible that menthol can be used to reduce symptom burden in patients with reflux symptoms and functional esophageal disorders without exacerbating gastroesophageal reflux.

There are some limitations of this study that need to be acknowledged. First, the catheter we used did not allow the measurement of bolus transport and clearance because of water-perfused catheter without impedance sensors. Second, we did not measure the effect of different menthol dosage on esophageal peristaltic parameters; however, current dosage of menthol was able to produce a significant effect on the frequency of secondary peristalsis and basal UES pressure. Third, the cold sensation via menthol infusion made this study difficult to be blinded to the patients, which may potentially confound our data due to central mediated effects on esophageal peristalsis and reflux. Fourth, we observed that menthol infusion reduced basal UES pressure; however, more accurate measurements of such parameters can be done with high resolution pharyngeal manometry. Finally, although the study applied esophageal infusion once to determine its effects on esophageal motility, it may be better to determine whether increased duration of using available menthol medication has any clinical impact on esophageal physiology.

In conclusion, this work has revealed that infusion of menthol into the esophagus appears to decrease triggering of secondary peristalsis as induced by rapid air distension in patients with IEM. Our data support novel evidence that inhibitory modulation of menthol on esophageal peristaltic effectiveness in response to rapid air distension can be present not only in healthy adults 8 but also in patients with IEM. Finally, these findings have physiological implication in that esophageal activation of TRPM8 receptors by menthol may attenuate mechanosensitivity of secondary peristalsis in response to rapid air distension despite the presence of esophageal hypomotility.

A part of this study was presented at the Digestive Disease Week (DDW Virtual) in 2023.

This study was supported by a grant, MOST 109-2314-B-303-011-MY3, from the Ministry of Science and Technology, Taiwan. The funding sources had no role in the design and conduct of the study, the collection, management, analysis, interpretation of the data, and the preparation, review, or approval of the manuscript.

None.

Study concept and design: Jui-Sheng Hung and Chien-Lin Chen; statistical analysis: Jui-Sheng Hung and Wei-Yi Lei; acquisition, analysis, or interpretation of data: Jui-Sheng Hung, Wei-Yi Lei, Tso-Tsai Liu, Chih-Hsun Yi, Ming-Wun Wong, Shu-Wei Liang, and Chien-Lin Chen; drafting of the manuscript: Jui-Sheng Hung and Chien-Lin Chen; critical revision of the manuscript for important intellectual content: all authors; administrative, technical, or material support: Chien-Lin Chen; and study supervision: Chien-Lin Chen.