Inhibition of gastric perception of mild distention by omeprazole in volunteers

Abstract

AIM: To evaluate the effects of omeprazole on gastric mechanosensitivity in humans.

METHODS: A double lumen polyvinyl tube with a plastic bag was introduced into the stomach of healthy volunteers under fluorography and connected to a barostat device. Subjects were then positioned so they were sitting comfortably, and the minimal distending pressure (MDP) was determined after a 30-min adaptation period. Isobaric distensions were performed in stepwise increments of 2 mmHg (2 min each) starting from the MDP. Subjects were instructed to score feelings at the end of every step using a graphic rating scale: 0, no perception; 1, weak/vague; 2, weak but significant; 3, moderate/vague; 4, moderate but significant; 5, severe discomfort; and 6, unbearable pain. After this first test, subjects received omeprazole (20 mg, after dinner) once daily for 1 wk. A second test was performed on the last day of treatment.

RESULTS: No adverse effects were observed. Mean MDP before and after treatment was 6.3 ± 0.3 mmHg and 6.2 ± 0.5 mmHg, respectively. One subject before and 2 after treatment did not reach a score of 6 at the maximum bag volume of 750 mL. After omeprazole, there was a significant increase in the distension pressure required to reach scores of 1 (P = 0.019) and 2 (P = 0.017) as compared to baseline. There were no changes in pressure required to reach the other scores after treatment. Two subjects before and one after omeprazole rated their abdominal feeling < 1 at MDP, and mean (± SE) abdominal discomfort scores at MDP were 0.13 ± 0.09 and 0.04 ± 0.04, respectively. Mean scores induced by each MDP + 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 (mmHg) were 1.1 ± 0.3, 2.0 ± 0.4, 2.9 ± 0.5, 3.3 ± 0.4, 4.6 ± 0.3, 5.2 ± 0.3, 5.5 ± 0.2, 5.5 ± 0.3, 5.7 ± 0.3, and 5.4, respectively. After omeprazole, abdominal feeling scores for the same incremental pressures over MDP were 0.3 ± 0.1, 0.8 ± 0.1, 2.0 ± 0.4, 2.8 ± 0.4, 3.8 ± 0.4, 4.6 ± 0.4, 4.9 ± 0.3, 5.4 ± 0.4, 5.2 ± 0.6, and 5.0 ± 1.0, respectively. A significant decrease in feeling score was observed at intrabag pressures of MDP + 2 mmHg (P = 0.028) and + 4 mmHg (P = 0.013), respectively, after omeprazole. No significant score changes were observed at pressures ≥ MDP + 6 mmHg.

CONCLUSION: Although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gastric distension.

Key Words: Functional dyspepsia, Acid exposure, Ome-prazole, Barostat test, Mechanosensitivity

INTRODUCTION

According to Rome III, the classification for functional gastrointestinal disorders published in 2006, functional dyspepsia (FD) is defined as the presence of one or more dyspepsia symptoms (postprandial fullness, early satiation, epigastric pain, or epigastric burning) that originate from the gastroduodenal region in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms[1]. Alteration of gastric motility, visceral hypersensitivity, impaired accommodation of meals, gastritis induced by Helicobacter pylori (H. pylori) infection, and dysfunction of the central nervous system have all been implicated in the pathophysiology of FD[2-4]. Duodenal acidification increases proximal gastric mechanosensitivity, induces proximal gastric relaxation, and seems to inhibit the proximal gastric accommodation to a meal[5]. Hypersensitivity not only to acid in the duodenum but also gastric distension has been proposed among the possible mechanisms of FD. Thus, the mechanism by which decreased duodenal acid exposure affects symptoms of dyspepsia warrants investigation.

Omeprazole, a proton pump inhibitor that strongly decreases acid secretion, has been prescribed in the treatment of FD worldwide. This is the best first-line treatment when compared with ranitidine, cisapride, and placebo for primary care of H. pylori-negative dyspepsia patients[6,7]. However, changes in patients’ perceptions of gastric distention after omeprazole administration have yet to be clarified. The gastric barostat test has been reported to be the gold standard method for evaluating gastric perception[8-11]. In the present study, we examined the effects of omeprazole on mechanosensitivity in humans using the barostat test.

MATERIALS AND METHODS

Study subjects

Ten healthy volunteers were recruited (8 men, 2 women; mean age, 31.6 ± 2.1 years; range, 23 to 41 years). None of the subjects had any history of gastrointestinal disease, nor were they taking any medications. Per individual interviews, no subjects had any dyspepsia symptoms (postprandial fullness, early satiation, epigastric pain, or epigastric burning). A check for H. pylori infection was not requested. Written informed consent was obtained from each participant. The ethics committee of Aichi Medical University approved all the study protocols (No. 369-3).

Gastric barostat

The barostat system was set up as reported previously[12]. After the patient had fasted for 12 h, a double lumen polyvinyl tube with an adherent finely folded plastic bag (Mui Scientific, Mississauga, Ontario, Canada) was introduced through the mouth into the stomach under fluorography. The polyvinyl tube was then connected to a barostat device (Distender series II TM; G and J Electronics, North York, Ontario, Canada). The bag was unfolded by inflation with 300 mL of air and was positioned in the proximal stomach with the subject in a recumbent position, after which the bag was deflated. Subjects were then positioned so they were sitting comfortably with their knees bent (80°) and trunk upright.

Gastric sensitivity to intragastric bag distension

After a 30-min adaptation period, minimal distending pressure (MDP) was determined by increasing the intrabag pressure by 1 mmHg every 3 min until a volume of 30 mL was reached. Gastric perception of distention by a barostat device was examined[12]. Isobaric distensions were performed in stepwise increments of 2 mmHg (2 min each) starting from the MDP while the corresponding intragastric volume was recorded continuously. Subjects were instructed to score feelings in the upper abdomen at the end of every distending step using a graphic rating scale that included verbal descriptors, as follows: 0, no perception; 1, weak/vague; 2, weak but significant; 3, moderate/vague; 4, moderate but significant; 5, severe discomfort; and 6, unbearable pain. The endpoint of each sequence of distensions was established at an intrabag volume of 750 mL or when the subject reported unbearable pain (score 6).

Effects of omeprazole on the barostat test

This study was investigated the effects of omeprazole (Omepral^®; AstraZenca, Osaka, Japan) on the barostat test. After the first barostat test, 10 volunteers received omeprazole (20 mg, once after dinner) as the medication for 1 wk. The second barostat study was performed on the morning after the last medication.

Statistical analysis

Data are expressed as mean ± SE. Statistical evaluation was performed using one way-analysis of variance. Values of P < 0.05 were considered statistically significant. Analyses were performed using a personal computer with Office Excel 2003 software (Microsoft, Redmond, WA, United States), and Analyse-it Software (Analyse-it Software, Ltd., Road Leeds, United Kingdom).

RESULTS

No adverse effects were observed with omeprazole. Oral intubation with subsequent positioning of the barostat bag was well-tolerated by all subjects. The mean MDP before and after omeprazole was 6.3 ± 0.3 mmHg and 6.2 ± 0.5 mmHg, respectively. One subject at baseline and 2 after omeprazole did not reach discomfort scores of 6 at the maximum bag volume of 750 mL.

The distention pressures (mmHg) required to induce scores of weak/vague (score 1, n = 10), weak but significant (score 2, n = 10), moderate/vague (score 3, n = 10), moderate but significant (score 4, n = 10), severe discomfort (score 5, n = 10), and unbearable pain (score 6, n = 9) were 3.0 ± 0.5, 5.2 ± 0.7, 7.0 ± 1.0, 8.6 ± 0.9, 11.1 ± 0.8, and 13.5 ± 0.9, respectively, at baseline. After 1 week of daily omeprazole, the distension pressure required to induce the same scores (n = 10 for scores 1 to 4; n = 9, score 5; n = 8, score 6) were 4.6 ± 0.4, 7.8 ± 0.6, 9.4 ± 0.9, 10.4 ± 1.0, 13.8 ± 1.8, and 15.3 ± 1.0, respectively. The distended pressure needed to reach scores of 1 (P = 0.019) and 2 (P = 0.017) (Figure 1) increased significantly after omeprazole. No changes in pressure were demonstrated for other scores after treatment.

Figure 1 Intragastric pressure by a barostat device at each score of upper abdominal feeling. The distention pressure required to induce a weak/vague feeling (score 1) in the upper abdomen increased from 3.0 ± 0.5 mmHg over the minimal distending pressure (MDP) at baseline to 4.6 ± 0.4 mmHg over the MDP after omeprazole, P = 0.019. The distention pressure to induce a weak but significant feeling (score 2) increased from 5.2 ± 0.7 mmHg to 7.8 ± 0.6 mmHg, P = 0.017. The n sizes for each data point are indicated on the graph.

Eight subjects scored 0 for the MDP at baseline and 9 scored 0 for the MDP after omeprazole. The mean discomfort scores (± SE) at MDP before and after omeprazole were 0.13 ± 0.09 and 0.04 ± 0.04, respectively.

The mean scores induced by each MDP + 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 mmHg were 1.1 ± 0.3 (n = 10), 2.0 ± 0.4 (n = 10), 2.9 ± 0.5 (n = 10), 3.3 ± 0.4 (n = 10), 4.6 ± 0.3 (n = 10), 5.2 ± 0.3 (n = 8), 5.5 ± 0.2 (n = 5), 5.5 ± 0.3 (n = 3), 5.7 ± 0.3 (n = 2), and 5.4 (n = 1), respectively. After omeprazole, the abdominal feeling scores for the same incremental pressures over MDP were 0.3 ± 0.1 (n = 10), 0.8 ± 0.1 (n = 10), 2.0 ± 0.4 (n = 10), 2.8 ± 0.4 (n = 10), 3.8 ± 0.4 (n = 10), 4.6 ± 0.4 (n = 10), 4.9 ± 0.3 (n = 8), 5.4 ± 0.4 (n = 5), 5.2 ± 0.6 (n = 3), and 5.0 ± 1.0 (n = 2), respectively. A significant decrease in the feeling score was observed at intrabag pressures of MDP + 2 mmHg (P = 0.028) and + 4 mmHg (P = 0.013), respectively, after omeprazole (Figure 2). No significant score changes were seen at pressures ≥ MDP + 6 mmHg.

Figure 2 Score of upper abdominal feeling during gastric distension by a barostat device. The mean scores at the intrabag pressures of minimal distending pressure (MDP) + 2 mmHg and + 4 mmHg were decreased from baseline after omeprazole: 1.1 ± 0.3 vs 0.3 ± 0.1, P = 0.028; and 2.0 ± 0.4 vs 0.8 ± 0.1, P = 0.0132, respectively. No significant changes were observed at pressures > MDP + 4 mmHg. The n sizes for each data point are indicated on the graph.

DISCUSSION

In this study, we have shown for the first time the inhibitory effect of 1 wk of treatment with omeprazole on perception of mechanical distension by a barostat device. Namely, a significant increase was observed in the pressure required to induce a weak/vague feeling (score 1) and a weak but significant feeling (score 2). In other words, the perceived intensity of MDP + 2 and + 4 mmHg were significantly decreased after omeprazole treatment.

We recruited normal volunteers who were paid for their participation, and not all participants scored a weak/vague abdominal feeling (score 1) at intrabag pressure of MDP, indicating that the results obtained in the present study are limited to dyspepsia-free normal subjects.

The mechanisms by which omeprazole decreases perceptions of discomfort associated with gastric distension remain unknown. Omeprazole is a proton pump inhibitor that strongly decreases acid secretion. In a previous report of 5-d treatment with omeprazole at a similar dose (20 mg) to the present study, the number of hours with intragastric pH greater than 4 during a 24-h period was found to be 10.5 h[13]. Omeprazole has been reported to be most effective in patients who rated epigastric pain or heartburn as their most bothersome symptom[6,7]. Visceral hypersensitivity as well as gastric dysmotility, impaired accommodation to the meals, H. pylori-induced gastritis, and dysfunction of the central nervous system have all been implicated in the pathophysiology of FD[2-4]. Hypersensitivity to gastric distension and acid has especially been demonstrated in patients with FD. After the first report that gastric distension-induced perception was significantly increased in subjects with FD compared with controls in 1991[14], it has been reported that the hypersensitivity against distension might present in 34% to 66% of patients with FD[15]. In addition, duodenal acidification-induced dyspeptic symptoms occur more significantly in patients with FD than in healthy volunteers[16].

A growing set of evidence has clarified the role of acid on dyspeptic symptoms and mechanosensitivity. First, acid infusion into the stomach induced dysmotility-like predominant dyspeptic symptoms in healthy Japanese control subjects[17]. Second, intraluminal infusion of hydrochloric acid affected sensitization of stomach mucosal mechanoreceptors[18]. Next, distal esophageal infusion also increased gastric sensitivity to distension[19]. Finally, intraduodenal acid infusion increased fundic compliance, decreased the tone and phasic contractile activities of the fundus, and increased proximal gastric mechanosensitivity[5,20,21]. These data suggest that the presence of acid in the upper gut might enhance mechanosensitivity. This putative mechanism has been supported by animal studies. Protons evoke multiple currents in primary afferent neurons that are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential vanilloid-1 (TRPV1) ion channels have been most thoroughly studied[22-24]. Taken together, it is speculated that an omeprazole-induced decrease in acid secretion followed by the downregulation of chemoreceptors might suppress distension-induced mechanosensitivity, resulting in the reduced perception of gastric distension demonstrated in the present study.

In this study, the inhibitory effect of omeprazole on perception induced by intragastric bag distension was demonstrated only with mild distension stimulus and weak feeling in the abdomen in normal volunteers. The precise reasons for these limited effects are unclear. Jones et al[22] demonstrated that both TRPV1 and ASIC3 knock-out mice were significantly less sensitive to colon distension, with an average response magnitude only 58% and 50% of controls, respectively. The data may suggest that afferent nociceptive signal transfer occurs mainly via a mechanoreceptor, rather than a chemoreceptor at moderate and severe distension.

It is well-known that gut infection is one of the risk factors for functional gastrointestinal disorders such as irritable bowel syndrome and FD[25]. Visceral hypersensitivity after infection has been reported in both animals[26] and humans[27]. Proton pump inhibitors have been reported to have potential anti-inflammatory effects apart from acid suppression[28]. Therefore, it is possible that the omeprazole-induced decreased perception of gastric distension might be mediated by the anti-inflammatory action of omeprazole.

In conclusion, although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gastric distension, suggesting that the drug might be effective in the treatment of FD.

COMMENTS

Background

Hypersensitivity to gastric distension has been proposed among the possible mechanisms of functional dyspepsia (FD). Omeprazole has been prescribed in the treatment of FD. They examined the effects of omeprazole on mechanosensitivity in humans.

Research frontiers

The gastric barostat test is the gold standard method for evaluating gastric perception. They examined the effects of omeprazole on mechanosensitivity in humans using the barostat test.

Innovations and breakthroughs

Omeprazole is a proton pump inhibitor that strongly decreases acid secretion. The data suggest that suppression of acid secretion may decrease mechanosensitivity of the proximal stomach as well as dyspeptic symptoms.

Applications

Although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gastric distension.

Terminology

These studies used the gastric barostat test in which a plastic bag with a double lumen polyvinyl tube was introduced into the stomach under fluorography. The tube was connected to a barostat device, which is a computer-controlled pump. Isobaric distensions were performed in stepwise increments. This method is the gold standard for evaluating gastric perception.

Peer review

This is a good descriptive study in which authors evaluate the effects of omeprazole on gastric mechanosensitivity in humans. The results are interesting and suggest that omeprazole decreases mechanosensitivity to mild gastric distension.