SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Although delayed gastric emptying is often found in functional dyspepsia, a causal role for delayed emptying in inducing symptoms has not been demonstrated.

Aim  To investigate the influence of delaying gastric emptying rate in healthy volunteers on the occurrence of meal-related symptoms.

Methods  Fourteen healthy subjects (six men, mean age 23 ± 1) underwent gastric emptying studies twice using the 14C octanoic acid and 13C glycin breath test after pre-treatment with saline or sumatriptan 6 mg s.c. Breath samples were taken before meal and at 15-min intervals for a period of 360 min postprandially. At each breath sampling, the subject was asked to grade the intensity (0–6) of four dyspeptic symptoms.

Results  Sumatriptan pre-treatment significantly delayed solid but not liquid gastric emptying (t1/2 respectively 159 ± 11 vs. 112 ± 9 min, P < 0.005 and 134 ± 11 vs. 116 ± 12 min, N.S.). Sumatriptan significantly decreased the mean cumulative symptom score (21.3 ± 5.5 vs. 8.0 ± 2.6, P = 0.01), as well as scores for each individual symptom.

Conclusion  A moderate delay in gastric emptying in health is not associated with an increase of meal-related symptoms. This observation argues against a causal role for delayed gastric emptying in the pathogenesis of dyspeptic symptoms.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Delayed gastric emptying is considered a major pathophysiological mechanism underlying symptoms in functional dyspepsia and idiopathic gastroparesis.1–12 Several studies have investigated the relationship between delayed gastric emptying and symptom pattern and severity. Depending on the study, the percentage of dyspeptic patients with delayed gastric emptying is ranging from 25% to 50%.1–12Most studies failed to find a relationship between delayed gastric emptying and symptom pattern,1–9 but recent large-scale studies showed that patients with delayed gastric emptying for solids are more likely to report postprandial fullness, nausea and vomiting.10–12

The relationship between symptom pattern and the presence of delayed emptying suggests a possible pathophysiological role for delayed gastric emptying in eliciting dyspeptic symptoms like fullness, nausea and vomiting. However, this relationship is not necessarily causal, and it is conceivable that a hitherto unclarified mechanism induces both delayed emptying and symptoms like fullness, nausea and vomiting. Furthermore, patients with delayed gastric emptying are usually treated with gastroprokinetic drugs, but evidence from the studies with prokinetics that their symptomatic benefit is related to enhancement of gastric emptying is lacking.1, 2, 13–15

The aim of the present study was to investigate the effect of delaying gastric emptying on postprandial symptom severity in healthy controls. We used sumatriptan, a drug with well described effects on solid gastric emptying rate, as a pharmacological tool to delay gastric emptying.16

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study subjects

Fourteen healthy volunteers (six men, mean age 23 ± 1 years) participated in the study. None of the healthy subjects had symptoms or a history of gastrointestinal disease or drug allergies, nor were they taking any medication. Written informed consent was obtained from each participant and the study protocol had been approved by the Ethics Committee of the University Hospital.

Gastric emptying breath test with assessment of meal-related symptoms

Gastric emptying rates for solids and liquids were determined by using the 14C octanoic acid and 13C glycin breath test.8, 12, 17, 18 The test meal consisted of 180 g of white bread (six slices), three eggs, the yolk of which were doped with 74 kBq of 14C octanoid acid sodium salt (DuPont; NEN Research, Boston, MA, USA) and 300 mL of water. All meals were consumed within a 10-min period. The total caloric value of the test meal was 575 kcal.

Breath samples were taken before meal and at 15-min intervals for a period of 360 min postprandially. At each sampling point, the subject exhaled into a tube for measuring exhaled 13C.

At each breath sampling point, the subject was instructed to grade the intensity of four different symptoms (fullness, bloating, nausea and epigastric discomfort), using a graphic rating scale that combined verbal descriptors on a scale graded from 0 to 6. Descriptors indicated that a score of 0 represented no perception; 1 represented a vague perception; 2 represented a mild perception; 3 and 4 represented vague and definite perception of a moderate sensation respectively; 5 represented discomfort and 6 represented a severe sensation.19

Studies on the influence of sumatriptan on gastric emptying and meal-related symptoms in healthy controls

Fourteen healthy subjects underwent two gastric emptying breath tests with assessment of meal-related symptoms after an overnight fast, approximately 1 week apart. At the start of the meal, 0.5 mL NaCl 0.9% or sumatriptan 6 mg (Imitrex; Glaxo N.V., Brussels, Belgium) were administered subcutaneously in a double-blind, randomized, cross-over design. The order of saline and sumatriptan treatment was randomized by drawing cards from a box of cards determining the sequence. A study nurse who was otherwise not involved in the study administered the medication. Half of the subjects received saline first; the other half received sumatriptan first.

Data analysis

The 13C breath content was determined by on-line gas chromatographic purification-isotope ratio mass spectrometry (ABCA; Europe Scientific, Crewe, UK). For both carbon labels, CO2 production was assumed 300 mmol/m2 of body surface per hour. The body surface area was calculated by the weight–height formula of Haycock et al.20 The results of the 13CO2 breath tests were expressed as the percentage 13CO2 excreted per hour by calculating procedures described elsewhere.8, 12, 17, 18 Gastric half-emptying times (t1/2) for solids and liquids and lag times (tlag) for solids were calculated from the 13CO2 content of breath samples as previously described.8, 12, 17, 18 Symptom scores were obtained before and 4 h after the standardized meal. For each symptom, a meal-related severity score was obtained by adding scores at all time-points. A cumulative meal-related symptom score was obtained by adding individual symptom severity scores.

From the placebo data, the upper limit of normal for solid and liquid half-emptying time were determined as the 95th percentile. After sumatriptan pre-treatment, the number of subjects with a gastric half-emptying time above the 95th percentile for solids or liquids was determined. Results are expressed as mean ± S.E.M. Student's t-test was used to compare results after different pre-treatments. A P-value <0.05 was considered significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Half-emptying times and lag times for solids were 112 ± 9 and 66 ± 7 min respectively. Administration of sumatriptan significantly prolonged the half-emptying times (159 ± 11 min, P < 0.005) and the lag times (110 ± 10 min, P < 0.01) for solids. The half-emptying time for liquids was not significantly altered by sumatriptan (116 ± 12 vs. 134 ± 11 min, P = 0.18). The upper limit of normal for solid and liquid emptying were 157 and 189 min respectively. After saline, one patient had both solid and liquid half-emptying times outside of the normal range. After sumatriptan, eight patients had a half-emptying time which was outside the normal range (one for liquid, five for solids and one for both).

The delay in gastric emptying of solids was not accompanied by an increase in symptom score. Administration of sumatriptan 6 mg s.c. significantly decreased the mean cumulative symptom score (21.3 ± 5.5 vs. 8.0 ± 2.6, P = 0.01) (Figure 1a).

image

Figure 1.  Influence of sumatriptan 6 mg s.c. on solid gastric emptying rate and meal-related symptoms in healthy controls. (a) Sumatriptan delayed solid gastric emptying rate and induced a significant decrease in the severity of meal-related symptoms (* P < 0.05 vs. placebo). (b) Influence of sumatriptan 6 mg s.c. on individual meal-related symptoms (* P < 0.05 vs. placebo).

Download figure to PowerPoint

Analysis of the severity scores of the different symptoms showed that the subjects reported a significant lower score after administration of sumatriptan for the occurrence of bloating (P < 0.001), postprandial fullness (P = 0.001), epigastric discomfort (P < 0.001) and nausea (P = 0.004) (Figure 1b). There was no correlation between the change in gastric emptying rate, considering lag time or half-emptying time, and the change in symptom severity, for overall symptom severity as well as for changes in individual symptom severity. Sumatriptan altered the intensity, but not the time-sequence of meal-induced symptoms (Figure 2).

image

Figure 2.  Influence of sumatriptan on the severity of meal-related symptoms and their evolution in a 4-h postprandial window (numbers stayed low up to 6 h, and the plot was shortened for clarity). Sumatriptan significantly decreased the severity of postprandial fullness and bloating, but did not change the time-course of these symptoms in relation to meal ingestion. Differences between placebo and sumatriptan were significant for postprandial fullness at individual time points from 0 to 90 min postprandially, and for bloating at individual time points from 0 to 105 min postprandially.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The role of delayed gastric emptying in the pathogenesis of dyspeptic symptoms remains controversial.21–24 Several studies have established that delayed gastric emptying is present in a subset of patients with unexplained dyspeptic symptoms1–12 and most large-scale studies found a relationship between the presence of delayed emptying and the dyspeptic symptom pattern.10–12 These observations suggest a possible pathophysiological role for delayed gastric emptying in eliciting dyspeptic symptoms like fullness, nausea and vomiting. However, the symptomatic benefit of prokinetic drugs in dyspeptic patients is not correlated with the improvement in gastric emptying rate13–15, and large clinical trials with the strong prokinetic macrolide ABT-229 were unequivocally negative with regard to symptom improvement.25, 26 Hence, the pathophysiological role of delayed gastric emptying remains to be established.

A strong case for pathophysiological relevance of a functional abnormality in symptom generation is made when induction or mimicking of the underlying disturbance in healthy subjects induces these symptoms. Several studies have used nutritional, physical or pharmacological interventions which delayed gastric emptying rates in healthy subjects.27–36 Although not specifically designed to evaluate changes in meal-related symptoms, none of these studies reported the induction of dyspepsia-like symptoms in the participants.

In the present study, we studied the influence of sumatriptan on the gastric emptying rate of a high-caloric meal, and on the occurrence of epigastric meal-related symptoms in healthy controls. In keeping with a study in healthy controls, overall symptom scores were very low (on average 21 of a maximum of 408). Administration of sumatriptan induced a moderate delay in gastric emptying. Gastric emptying rates for solids were significantly delayed, and half of the patients had emptying rates outside the normal range. However, this was not associated with an increase in epigastric symptoms. This observation confirms the lack of strict causality between gastric emptying rate and the occurrence of dyspeptic symptoms.

Moreover, the occurrence of individual symptoms like bloating, fullness, nausea and discomfort was significantly inhibited after administration of sumatriptan. It is conceivable that these observations are related to the relaxatory effect of sumatriptan on the proximal stomach.37 Recent studies have established the role of tension-type mechanoreceptors in perception from the proximal stomach.38–40 Relaxation of the proximal stomach, as induced by sumatriptan, results in a shift of the intragastric volume to higher values that are needed before tension receptors are stimulated by the distension37 and this might account for the lower epigastric perception scores obtained after sumatriptan administration in the present study. Previous studies in healthy volunteers suggested that the effect of sumatriptan on gastric sensitivity was attributable to an effect on gastric tone, and not by an antinociceptive action of the drug.37 Nevertheless, modulation of perception by a site of action on the afferent sensorial pathway cannot be entirely excluded. An action at a central level seems less likely, since the drug poorly penetrates the blood brain barrier.41

The postprandial epigastric sensations recorded by the healthy subjects in the present study are probably not representative of meal-related symptoms in dyspepsia. Overall, the intensity scores were low and the very low levels of discomfort or nausea scoring illustrate that unpleasant sensations did not really occur. The study therefore does not allow any predictions on a therapeutic effect of sumatriptan for meal-related symptoms in functional dyspepsia. The study also does not preclude symptomatic effects due to extreme delay in gastric emptying, as can be observed in gastroparesis patients.

In summary, we observed that moderately delaying gastric emptying in health by pre-treatment with sumatriptan 6 mg s.c. is not associated with an increase of meal-related symptoms. This observation argues against a causal role for delayed gastric emptying in the pathogenesis of dyspeptic symptoms.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

No external funding was received for this study.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Corinaldesi R, Stanghellini V, Raiti C, et al. Effect of chronic administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in patients with idiopathic gastroparesis. Gut 1987; 28: 3005.
  • 2
    Jian R, Ducrot F, Ruskone A, et al. Symptomatic, radionuclide and therapeutic assessment of chronic idiopathic dyspepsia. A double-blind placebo-controlled evaluation of cisapride. Dig Dis Sci 1989; 34: 65764.
  • 3
    Talley NJ, Shuter B, McCrudden G, et al. Lack of association between gastric emptying of solids and symptoms in nonulcer dyspepsia. J Clin Gastroenterol 1989; 11: 62530.
  • 4
    Scott AM, Kellow JE, Shuter B, et al. Intragastric distribution and gastric emptying of solids and liquids in functional dyspepsia. Lack of influence of symptom subgroups and H. pylori-associated gastritis. Dig Dis Sci 1993; 38: 224754.
  • 5
    Bortolotti M, Bolondi L, Santi V, et al. Patterns of gastric emptying in dysmotility-like dyspepsia. Scand J Gastroenterol 1995; 30: 40810.
  • 6
    Koskenpato J, Kairemo K, Korppi-Tommola T, et al. Role of gastric emptying in functional dyspepsia: a scintigraphic study of 94 subjects. Dig Dis Sci 1998; 43: 11548.
  • 7
    Quartero AO, De Wit NJ, Lodder AC, Numans ME, Smout AJ, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta- analysis. Dig Dis Sci 1998; 43: 202833.
  • 8
    Maes BD, Ghoos YF, Hiele MI, Rutgeerts PJ. Gastric emptying rate of solids in patients with nonulcer dyspepsia. Dig Dis Sci 1997; 42: 115862.
  • 9
    Talley NJ, Verlinden M, Jones M. Can symptoms discriminate among those with delayed or normal gastric emptying in dysmotility-like dyspepsia? Am J Gastroenterol 2001; 96: 14228.
    Direct Link:
  • 10
    Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996; 110: 103642.
  • 11
    Perri F, Clemente R, Festa V, et al. Patterns of symptoms in functional dyspepsia: role of Helicobacter pylori infection and delayed gastric emptying. Am J Gastroenterol 1998; 93: 20828.
    Direct Link:
  • 12
    Sarnelli G, Caenepeel P, Geypens B, Janssens J, Tack J. Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol 2003; 98: 7838.
    Direct Link:
  • 13
    Kellow JE, Cowan H, Shuter B, et al. Efficacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther 1995; 9: 15360.
  • 14
    Sturm A, Holtmann G, Goebell H, Gerken G. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion 1999; 60: 4227.
  • 15
    Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, Talley NJ. Efficacy of cisapride and domperidone in functional dyspepsia: a meta-analysis. Am J Gastroenterol 2001; 96: 68996.
  • 16
    Coulie B, Tack J, Maes B, Ghoos Y, De Roo M, Janssens J. Sumatriptan, a selective 5-HT1 receptor agonist, induces a lag phase for gastric emptying of liquids in man. Am J Physiol 1997; 272: G9028.
  • 17
    Ghoos YF, Maes BD, Geypens BJ, et al. Measurement of gastric emptying rate of solids by means of a carbon labeled octanoic acid breath test. Gastroenterology 1993; 104: 16407.
  • 18
    Maes BD, Ghoos YF, Geypens BJ, et al. Combined carbon-13-glycin/carbon-14-octanoic acid breath test to monitor gastric emptying rates of liquids and solids. J Nucl Med 1994; 35: 82431.
  • 19
    Notivol R, Coffin B, Azpiroz F, Mearin F, Serra J, Malagelada JR. Gastric tone determines the sensitivity of the stomach to distension. Gastroenterology 1995; 108: 3306.
  • 20
    Haycock G, Schwartz G, Wisotsky D. Geometric method for measuring body surface area: a height–weight formula validated in infants, children and adults. J Pediatr 1978; 93: 6266.
  • 21
    Quigley EM. Symptoms and gastric function in dyspepsia – goodbye to gastroparesis? Neurogastroenterol Motil 1996; 8: 2735.
  • 22
    Stanghellini V, Tosetti C, Corinaldesi R. Symptoms and gastric functions in dyspepsia – goodbye to gastroparesis or to inadequate studies? Neurogastroenterol Motil 1997; 9: 2034.
  • 23
    Tack J, Peeters TL. What comes after macrolides and other motilin stimulants? Gut 2001; 49: 31718.
  • 24
    Camilleri M. Motilin agonists and dyspepsia: throwing out the baby with the bath water. Gut 2002; 51: 612.
  • 25
    Talley NJ, Verlinden M, Snape W, et al. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial. Aliment Pharmacol Ther 2000; 14: 165361.
  • 26
    Talley NJ, Verlinden M, Geenen DJ, et al. Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial. Gut 2001; 49: 395401.
  • 27
    Fone DR, Horowitz M, Maddox A, Akkermans LM, Read NW, Dent J. Gastroduodenal motility during the delayed gastric emptying induced by cold stress. Gastroenterology 1990; 98 (5 Pt 1): 115561.
  • 28
    Houghton LA, Mangnall YF, Read NW. Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 1990; 31: 12269.
  • 29
    Bergmann JF, Chassany O, Petit A, Triki R, Caulin C, Segrestaa JM. Correlation between echographic gastric emptying and appetite: influence of psyllium. Gut 1992; 33: 10423.
  • 30
    Tjeerdsma HC, Smout AJ, Akkermans LM. Voluntary suppression of defecation delays gastric emptying. Dig Dis Sci 1993; 38: 8326.
  • 31
    Levein NG, Thorn SE, Wattwil M. Dopamine delays gastric emptying and prolongs orocaecal transit time in volunteers. Eur J Anaesthesiol 1999; 16: 24650.
  • 32
    Geboes KP, Maes B, Luypaerts A, et al. Magnesium chloride slows gastric emptying, but does not affect digestive functions. Aliment Pharmacol Ther 2002; 16: 15717.
  • 33
    Sninsky CA, Davis RH, Clench MH, Thomas KD, Mathias JR. Effect of lidamidine hydrochloride and loperamide on gastric emptying and transit of the small intestine. A double-blind study. Gastroenterology 1986; 90: 6873.
  • 34
    Fone DR, Horowitz M, Read NW, Dent J, Maddox A. The effect of terminal ileal triglyceride infusion on gastroduodenal motility and the intragastric distribution of a solid meal. Gastroenterology 1990; 98: 56875.
  • 35
    Nowak A, Jonderko K, Kaczor R, Nowak S, Skrzypek D. Cigarette smoking delays gastric emptying of a radiolabelled solid food in healthy smokers. Scand J Gastroenterol 1987; 22: 548.
  • 36
    Savage AP, Adrian TE, Carolan G, Chatterjee VK, Bloom SR. Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers. Gut 1987; 28: 16670.
  • 37
    Tack J, Coulie B, Wilmer A, Andrioli A, Janssens J. Effect of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000; 46: 46873.
  • 38
    Piessevaux H, Tack J, Wilmer A, Coulie B, Geubel A, Janssens J. Perception of changes in wall tension of the proximal stomach in man. Gut 2001; 49: 2038.
  • 39
    Distrutti E, Azpiroz F, Soldevilla A, Malagelada JR. Gastric wall tension determines perception of gastric distension. Gastroenterology 1999; 116: 103542.
  • 40
    Caldarella MP, Azpiroz F, Malagelada JR. Antro-fundic dysfunctions in functional dyspepsia. Gastroenterology 2003; 124: 12209.
  • 41
    Sleight AJ, Cervenka A, Peroutka SJ. In vivo effects of sumatriptan (GR 43175) on extracellular levels of 5-HT in the guinea pig. Neuropharmacology 1990; 29: 51113.