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Keywords:

  • gastric accommodation;
  • sumatriptan;
  • transpyloric flow;
  • ultrasonography

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Sumatriptan, a 5HT1 receptor agonist, inhibits antral motor activity, delays gastric emptying and relaxes the gastric fundus. The aim of this study was to characterize the effect of sumatriptan on transpyloric flow and gastric accommodation during and immediately after ingestion of a liquid meal using duplex sonography. Ten healthy subjects were investigated twice on separate days. In random order either sumatriptan 6 mg (Imigran® 0.5 mL) or a placebo were given s.c. 15 min before ingesting 500 mL of a meat soup. The subjects were examined during the 3-min period before ingestion of the liquid meal, the 3-min spent drinking the meal and 10 min postprandially. Sumatriptan caused a significant widening of both the gastric antrum (P=0.02) and the proximal stomach (P=0.01) 10 min postprandially as compared with placebo. It caused no significant differences in time to initial gastric emptying (P=0.2), but significantly delayed commencement of peristaltic-related transpyloric flow (P=0.04). Sumatriptan had no significant effect on mean abdominal symptom scores, but after sumatriptan there was a significant negative correlation between width of postprandial antral area and postprandial nausea and between width of postprandial antral area and postprandial bloating. We therefore conclude that sumatriptan causes a postprandial dilatation of both the distal and the proximal stomach with no change in dyspeptic symptoms nor in length of time to first gastric emptying. Time to commencement of peristaltic-related emptying is delayed.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Gastric emptying requires coordinated motor activity of the proximal stomach, the gastric antrum, the pylorus and the proximal duodenum.1 The coordination is afforded by extrinsic and intrinsic neuronal reflexes, including the enteric nervous system. Serotonin, or 5-hydroxytryptamine (5HT), may act as a neurotransmitter and has been demonstrated immunohistochemically in the myenteric plexus of the stomach.2 It causes relaxation of the stomach wall and inhibition of gastric emptying. Sumatriptan, a selective 5HT1 receptor agonist, acts on vascular 5HT1 receptors and is used in the treatment of migraine in man.

Coulie et al.3 found that sumatriptan caused a significant increase in the gastric half emptying time for both liquids and solids in healthy subjects and also increased the lag phase for the emptying of both solids and liquids as revealed by scintigraphy. They attrtibuted the effects of sumatriptan on gastric emptying to the prolongation of the lag phase. For liquids this marked prolongation of the lag phase could be an effect of sumatriptan on pyloric tone and antropyloroduodenal coordination.

Using a gastric barostat, Tack et al.4, 5 demonstrated that administration of sumatriptan caused an immediate and profound relaxation of the gastric fundus and an inhibition of phasic contractility. Thus, larger gastric volumes could be accommodated before thresholds for perception of discomfort were reached.

Using duplex sonography antroduodenal motility6, 7 and transpyloric flow of gastric contents can be visualized simultaneously.8[9]–10 The technique allows second by second monitoring of antral contractions and transpyloric flow.

The aim of the present study was to investigate the effect of sumatriptan on antral and proximal stomach areas and transpyloric flow using duplex sonography.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Study design

The study was conducted as a double-blind, placebo-controlled, cross-over study. All participants gave written, informed consent to participate in the trial. The study was approved by the Regional Ethics Committee and conducted in accordance with the Declaration of Helsinki.

Subjects

Ten healthy students, five women and five men, participated in the study. Their median age was 24 years (range 20–27 years). Their heights (mean ± SD) were 172 ± 7 cm. Their weights were 68 ± 11 kg. One of the males was a smoker. The criteria for exclusion from the study were: subjects with dyspeptic symptoms, pregnant or lactating women, subjects younger than 18 or older than 65 years of age, subjects suffering from sulfa allergy, cardiovascular diseases, hemiplegical, ophtalmoplegical or basilar migraine, epilepsy, kidney failure and/or liver failure and subjects currently using ergotamine.

Test substances

The test drugs were administrated subcutaneously using an injection pen. Sumatriptan and placebo were both transparent liquids contained in identical glass ampullas designed for the pen. Thus, it was impossible to differentiate sumatriptan from placebo by the look of the test substances. The sumatriptan ampulla contained 0.5 mL of sumatriptan (6 mg) (Imigran®, Glaxo/Wellcome, Oslo, Norway). The placebo ampulla contained 0.5 mL of a 0.9% solution of NaCl.

Test meal

A liquid meal of commercial meat soup (Toro® clear meat soup; Rieber & Søn A/S, Bergen, Norway), 2 cubes L−1, was prewarmed to 37 °C. 500 mL of this soup was ingested gradually over 3 min. The meal contained 1.8 g protein, 0.9 g fat and 1.1 g carbohydrate (20 kcal.). Osmolarity was 350 mOsm kg−1 H2O. Fat, protein and carbohydrate were all soluble in water. In addition the soup contained insoluble seasoning (0.4 g L–1). The seasoning had been ground, and the maximal size of the small insoluble particles was 0.2 mm. In healthy subjects previously investigated by us, ingestion of 500 mL of this soup induced antral contractions at a frequency of 3 min–1, i.e. typical fed state peristalsis.

Apparatus

A duplex scanner (Vingmed System Five, Horten, Norway), with a 5-MHz curved array probe was used. This scanner allowed real-time ultrasound images of antral motility and flow velocity curves of the Doppler recordings to be visualized simultaneously. For quantitative measurements of flow velocity and timing, a pulsed Doppler mode was used. Quantitative measurements of antral area, fundal diameter and sagittal area of the proximal stomach were calculated automatically using the built-in caliper and calculation program of the ultrasound scanner. Real-time ultrasound images and velocity curves were recorded on video tapes.

Measurements

Distal stomach  The width of the antral area was measured in a vertical section in which the antrum, the superior mesenteric vein and the aorta were visualized simultaneously. The outer profile of the muscularis propria was outlined and the width calculated automatically. The values given were the average of two measurements performed one after the other.

Proximal stomach  A proximal gastric area in a sagittal section was outlined by tracing from the top margin of the fundus and 7 cm downwards along the axis of the stomach as described by Gilja et al.7, 11 A fundal diameter was chosen as the second measurement and defined as the maximal diameter in an oblique frontal section, kept within 7 cm along the axis of the proximal stomach. Measurements of the proximal stomach were performed 10 min postprandially.

Transpyloric flow  The study of the antropyloroduodenal region was performed with the ultrasound probe positioned at the level of the transpyloric plane with the antrum, the pylorus and the proximal duodenum visualized simultaneously. The common chamber was defined as a volume entity created by a simultaneous relaxation of the proximal duodenum, pylorus and antrum, allowing liquid contents within the volume to be retained or passed back and forth across the pylorus. The sample volume of the pulsed Doppler was positioned across the pylorus, and the angle between the Doppler beam and the transpyloric direction of flow was always <60°. With the probe in this position we registered time to the occurrence of the following test parameters:

(i)  First gastric emptying, defined as the first occurrence of gastric emptying after the start of drinking the soup. An episode of gastric emptying was defined as flow across the pylorus with a mean velocity of more than 10 cm sec–1 lasting more than 1 s.

(ii)  Peristaltic-related transpyloric emptying defined as gastric emptying associated with propulsive antral contractions. If no antral contractions were seen during the observation period, time to total peristaltic-related transpyloric emptying was for the statistical analysis set as if occurring at the end of registration.

(iii)  Peristaltic-unrelated transpyloric emptying, defined as transpyloric emptying of common chamber contents, not associated with visible antral contractions.

Abdominal symptoms  Abdominal symptoms in the fasting state and 10 min postprandially were scored using a Visual Analogue Scale (VAS). In the postprandial registration the subjects were asked to report all abdominal symptoms sensed following soup ingestion. The symptoms registered were the sense of epigastric pain/discomfort, nausea, bloating and hunger. They were graded from 0 to 100, where 0 equalled no symptoms and 100 represented intolerable symptoms. Total symptom score was the subject’s own evaluation of the total abdominal discomfort during the examination (ingestion period + 10 min postprandially) graded in the same way as the individual symptoms from 0 to 100.

Adverse effects  Subjective adverse effects were assessed 10 min postprandially by using separate 100 mm VAS for pain at injection point, numbness, nausea, muscle stiffness, dizziness, flushing, feeling of heaviness, chest pain, exhaustion and tiredness. The subjects were to report all adverse effects sensed after injection of the test substance.

Procedure

The subjects were investigated twice with sumatriptan or placebo in a randomized order with an interval of at least two days between each investigation. The subjects were randomly allocated into two blocks of five; one for those who received active drug on the first day and one for those who received the placebo. The investigations took place between 08.00 and 10.00 hours after an overnight fast. First, the subjects were asked to fill in the VAS for abdominal symptoms in the fasting state. The subjects were then seated in an arm chair with a frontal thigh-to-abdomen angle of approximately 120°. Fasting motility pattern (to avoid phase III and late phase II of the migrating motor complex, MMC) and the width of antral area was measured. Sumatriptan 6 mg (Imigran® 0.5 mL) or placebo were given s.c. 15 min before ingesting the meat soup. The duplex scanning was performed in the antropyloroduodenal position 3 min before the ingestion of 500 mL of the meat soup and continued during the 3 min drinking process and 10 min postprandially, or longer if no emptying was seen by then. In this period, we recorded time to first gastric emptying, to peristaltic-related and to peristaltic-unrelated transpyloric flow and to dyspeptic symptoms. Antral area, fundal diameter and fundal area were measured 10 min postprandially. The measurements were performed between antral contractions while the subjects held their breathing in expiration. The ultrasound examination was performed by one investigator (TH). The subjects registered their postprandial abdominal symptoms and adverse effects on the VAS immediately after finishing the experiments.

Statistical analysis

Values for measured variables were given as mean ± SD. Parametric tests were applied to data that followed a normal distribution, whereas on the data that was not normally distributed nonparametric tests were performed (SPSS® for Windows version 6.1). Almost all motility data were normally distributed whereas all symptomatic/adverse data were not. Two-sided P-values < 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

The subjects started to drink the soup approximately 15 min after injection of the test substances (876 ± 81 vs. 913 ± 42 s, P=0.22). No difference in mean drinking time (189 ± 17 vs. 192 ± 19 s, P=1.00) was noted.

Ten minutes postprandially the area of the proximal stomach (sagittal section) was significantly wider after injection of sumatriptan than after placebo (Table 1, Fig. 1). The fundal diameters showed no significant difference (Table 1).

Table 1.   Width of proximal and distal stomach areas, time to first gastric emptying and time to peristaltic-related transpyloric flow in healthy subjects Thumbnail image of
image

Figure 1 Effect of sumatriptan on width of proximal stomach 1. 0 min postprandially in ten healthy volunteers, sagittal section.

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Before the meal all the subjects showed a MMC phase of I or early II. The subjects displayed no difference in width of fasting antral area between sumatriptan and placebo (Table 1). Ten minutes after the meal the width of the antral area was significantly wider with sumatriptan compared to placebo (Table 1, Fig. 2).

image

Figure 2.  Effect of sumatriptan on width of antral area 10 min postprandially in ten healthy volunteers.

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No significant difference in time to first gastric emptying was seen after sumatriptan compared to that after placebo (Table 1, Fig. 3). The time to peristaltic-related flow was significantly delayed after sumatriptan compared to placebo (Table 1, Fig. 4). In the time period between first gastric emptying and peristaltic-related flow, peristaltic-unrelated flow was seen.

image

Figure 3.  Effect of sumatriptan on time to first gastric emptying across the pylorus of a liquid meal in ten healthy volunteers.

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image

Figure 4.  Effect of sumatriptan on time to peristaltic-related flow across the pylorus after a liquid meal in ten healthy volunteers.

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No significant differences were found between sumatriptan and placebo in total abdominal symptom score neither before (9.4 ± 16.17 vs. 4.06 ± 8.78 mm, P=0.47) nor after soup ingestion (6.5 ± 8.03 vs. 10.8 ± 25.16 mm, P=0.75). Sumatriptan caused no significant differences in time to symptom occurrence: (440.0 ± 325.27 vs. 227.67 ± 141.17 s, P=0.22). There were no significant differences in the individual abdominal symptom scores after sumatriptan or a placebo (Table 2).

Table 2.   Abdominal symptoms before and after soup ingestion in healthy subjects Thumbnail image of

After sumatriptan significant negative correlations were found between width of postprandial antral area and postprandial nausea (r=–0.77, P=0.01), and between width of postprandial antral area and postprandial bloating (r=–0.79, < 0.01). Statistically significant correlations between motility data and symptoms were otherwise not found (results not shown).

Sumatriptan showed significantly higher scoring for the following adverse effects as compared to the placebo: pain at injection point, numbness, muscle stiffness and flushing. For the rest of the adverse effects there were no significant differences (Table 3).

Table 3.   Adverse effects in healthy subjects. Mean score (mm) on a 100-mm visual analogue scale Thumbnail image of

After sumatriptan, a significant negative correlation was found between width of postprandial antral area and the adverse effect nausea (r=–0.77, < 0.01). Statistically significant correlations between motility data and adverse effects were otherwise not found (results not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

In healthy subjects, administration of sumatriptan increased the width of postprandial areas of the antrum and the proximal stomach compared to placebo. Moreover, sumatriptan delayed the onset of peristaltic-related flow, but left the time to initial gastric emptying unchanged. The fact that sumatriptan caused a postprandial dilatation of both the proximal and the distal stomach suggests a more general relaxatory effect of the drug.

Sumatriptan increased the sagittal area of the proximal stomach, but not the transverse diameter. This finding is similar to what we have found in previous studies on the proximal stomach using ultrasound. We think that when filling the stomach, the area in the sagittal section will increase more than the transverse diameter due to the normal configuration and placement of the stomach.

Tack et al.4 administrated sumatriptan in the interdigestive state in man and demonstrated a immediate and profound relaxation of the gastric fundus as measured by a gastric barostat. The increased width of the proximal stomach after a meal in the present study indicates that a similar relaxation as seen in the interdigestive state also occurs postprandially. The increased stomach areas both distally and proximally, and the delay in the onset of peristaltic-related emptying in the postprandial state are consistent with a delay in gastric emptying as shown radioscintigraphically by Coulie et al.3 and Houghton et al.12 suggesting a general inhibitory effect of sumatriptan on GI motility.

Using radioscintigraphy, sumatriptan has been found to induce a lag phase for the gastric emptying of liquids.3 Coulie et al.3 define this lag phase as the time period needed for the first 5% of activity to evacuate out of the stomach. In the present study we found no differences in time to start of gastric emptying of liquids after sumatriptan as compared to that after placebo. What differed was the time interval until commencement of peristaltic-related flow. During this interval duplex sonography revealed that small volumes left the stomach by peristaltic-unrelated flow. Owing to constant variation of the pyloric diameter, the Doppler technique did not allow quantification of this flow volume. Net gastric emptying during the peristaltic-unrelated flow period could therefore not be determined. Thus, we cannot deduce from this study whether peristaltic-unrelated flow belongs to the lag phase or the emptying phase of gastric emptying as determined by scintigraphy. The results need not be contradictory, however. Doppler signals only give velocity and duration of flow, whereas scintigraphy gives quantitative measurements. Second by second monitoring of gastric emptying by duplex sonography is probably a more sensitive method for registering early emptying of small initial volumes than techniques such as radioscintigraphy and breath tests. Our results therefore suggest that gastric emptying starts equally as early with sumatriptan as with placebo, but may quantitatively be reduced with sumatriptan.

Hausken et al.13 suggest that the initial peristaltic-unrelated emptying may constitute one mechanism by which the duodenum ‘tastes’ the gastric content. Thereby it may regulate gastric tone, gastric emptying and fed state peristalsis. Following the administration of sumatriptan, this regulating mechanism may be altered as suggested by sumatriptan’s relaxatory effects and time to peristaltic-related flow.

In spite of a wider stomach both distally and proximally, we recorded no significant differences in scoring of meal-related abdominal symptoms between sumatriptan and placebo. After sumatriptan we found significantly negative correlations between width of postprandial antral area and postprandial nausea and between width of prostprandial antral area and bloating. The findings are consistent with those of Tack et al.14 who found that sumatriptan caused larger volumes to be accommodated by the stomach before thresholds for discomfort were reached.

Gilja et al.11 found a defective accommodation of the proximal stomach postprandially in patients with functional dyspepsia (FD). Recently Tack et al.15 reported that in FD patients the impaired relaxation could be normalized by sumatriptan, leading to an improvement in symptoms. As sumatriptan causes a dilatation of the distal and proximal stomach after a meal, a beneficial effect of an antral- and fundus-relaxing drug in patients with FD might be anticipated.

The mechanism by which sumatriptan influences gastric motor activity is not known. Several central and/or peripheral actions can be involved. One possibility is that sumatriptan acts centrally. Sumatriptan, however, penetrates the blood–brain barrier poorly,16 and moreover, it relaxes the isolated guinea pig stomach.17 These facts argue against a central action. The relaxatory effect of sumatriptan on the stomach suggests activation of inhibitory pathways. Coulie et al.18 found that activation of the 5HT1 receptor by sumatriptan results in an inhibition of the gastric fundus tone and that this effect is partially mediated through activation of a nonadrenergic noncholinergic (NANC) mechanism, involving nitric oxide as the inhibitory neurotransmitter. Nitric oxide acts also as a NANC inhibitory transmitter in the antrum19 and in the pylorus.20 Based on studies conducted by Novitol et al.21 epigastric symptoms might be due to increased gastric wall tension. Gastric relaxation by sumatriptan could reduce wall tension and thereby improve epigastric symptoms.

Pain at injection point, numbness, muscle stiffness, flushing and heaviness were adverse effects related to sumatriptan. All the adverse effects are known from migraine therapy. They were all mild and transient.

Some problems were associated with duplex sonography of transpyloric flow and peristalsis. Individual anatomic variations sometimes made it difficult to visualize the pyloric channel and the proximal duodenum in one single section. In addition, the sample volume of the pulsed Doppler, which must be positioned precisely across the pylorus, easily lost its position by respiration and movements. Subcutaneous fat and abdominal gas may impair the image quality. None had to be excluded in our study for these reasons.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Sumatriptan causes a postprandial dilatation of both the distal and the proximal stomach without any change in dyspeptic symptoms nor in time to first gastric emptying. Time to commencement of peristaltic-related transpyloric flow, however, is delayed.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References
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