Dr J. Tack, Department of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: email@example.com
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.
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
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.
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.
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).
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).
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.