A placebo-controlled trial of the 5-HT1A agonist R-137696 on symptoms, visceral hypersensitivity and on impaired accommodation in functional dyspepsia.

Acute studies suggested a therapeutic benefit for fundus-relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long-term studies are lacking. R-137696 is a serotonin-1A (5-HT(1A)) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R-137696 on symptoms in FD with VH or IA. Randomized, double-blind, placebo-controlled, parallel group study of 4 weeks R-137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty-three patients (33 VH and 20 IA), 18 men, mean age 40 +/- 13 years were recruited. Twenty-four received placebo and 29 received R-137696. In VH patients, both placebo and R-137696 improved total symptom scores, with a tendency for superiority of placebo (-1.12 vs-0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R-137696 had no significant influence on total or individual symptom scores (-0.08 and -0.27). In VH, both placebo and R-137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R-137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4-week administration of the fundus-relaxing 5-HT(1A) agonist R-137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.

Gastric hypersensitivity induced by oesophageal acid infusion in healthy volunteers.

Distal oesophageal acid exposure has been shown to increase visceral sensitivity of the proximal oesophagus via central sensitization. Here we evaluated whether acidification of the distal oesophagus also affects the sensorimotor function of the proximal stomach. A gastric barostat study combined with a 30-min acid (HCl 0.15 mol L(-1)) or saline infusion in the distal oesophagus was performed in 18 healthy volunteers. Gastric and cutaneous sensitivity was assessed before and up to 2 h after the start of infusion. Directly after acid infusion, but not after saline, the threshold for discomfort decreased (-6.4 +/- 1.7 vs 0.4 +/- 0.4 mmHg; P = 0.028) and distension-induced symptoms increased significantly compared with the baseline (122 +/- 49% vs -3 +/- 9%). Cutaneous sensitivity remained unaffected by acid infusion. In contrast, when the infused liquid was aspirated 3 cm more distally, at the level of the lower oesophageal sphincter, the effect of acid infusion on gastric sensitivity was abolished and the increase in distension-induced symptoms was reduced (61 +/- 24%). Distal oesophageal acid infusion induces visceral hypersensitivity without affecting somatic sensitivity arguing against a similar mechanism of central sensitization as observed in non-cardiac chest pain. As reduction of the acid load to the stomach prevented this effect, our findings indicate that either gastric and/or duodenal acidification is involved. It should be emphasized though that aspiration from distal oesophagus may have attenuated the effect by reducing the acid-exposed area or by reducing the contact time.

Impaired drinking capacity in patients with functional dyspepsia: intragastric distribution and distal stomach volume.

The water drink test is a good tool to evoke dyspeptic symptoms. To what extent these symptoms are related to altered gastric distribution is not clear. Therefore, we determined gastric volumes after a drink test using SPECT. After a baseline scan 20 healthy volunteers (HV) and 18 patients with functional dyspepsia (FD) underwent a drink test (100 mL min(-1)) followed by five scans up to 2 h. Dyspeptic symptoms were scored before every scan. A Wilcoxon signed rank test (P < 0.05) and a mixed effects model were used for statistical analyses. Fasting volumes were significantly higher in FD compared to HV for total, proximal and distal stomach (P < 0.001). Functional dyspeptic patients ingested significantly less water (P < 0.001) and had an impaired filling of the distal part of the stomach (P = 0.001) after the drink test. In FD, bloating (prox. 80%, dist. 56%), pain (prox. 87%, dist. 62%) and fullness (prox. 80%, dist. 59%) were determined more by proximal stomach volume rather than distal stomach volume. These data suggest that drinking capacity is mainly determined by antral volume, with a reduced antral filling in FD compared to HV. The persisting symptoms of bloating, pain and fullness in FD are predominantly associated with proximal stomach volume.

Review article: a critical view on impaired accommodation as therapeutic target for functional dyspepsia.

Several important pathophysiological mechanisms have been identified in functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accommodation. Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been rather disappointing in general. These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involving other regions of the proximal gut or by the increasing insight that central mechanisms may play an important role. Future studies of impaired accommodation should take these considerations into account.

Fundic accommodation assessed by SPECT scanning: comparison with the gastric barostat.

BACKGROUND: Recently, single photon emission computed tomography (SPECT) scanning was described as a non-invasive technique to assess fundic accommodation. However, in contrast with the barostat, no intragastric distending force is applied during SPECT scanning. We hypothesised that in the absence of a barostat balloon, SPECT scanning largely detects the volume effect of the ingested meal and is a rather insensitive tool to detect fundic relaxation. METHODS: After an overnight fast, healthy volunteers underwent a barostat study and SPECT scanning on two separate days to assess: (1) meal induced fundic accommodation (Nutridrink, 200 ml, 300 kcal); and (2) gastric relaxation to 1 mg intravenous glucagon. RESULTS: Fasting fundic volumes (145 (8) v 280 (32) ml; p=0.001) and average postprandial volume (329 (10) v 571 (53) ml; p=0.001) were significantly lower measured with SPECT compared with the barostat study. Meal induced fundic relaxation (183 (10) v 289 (46) ml; p=0.050) and the postprandial/fasting volume ratio (2.32 (0.10) v 2.27 (0.29); p=0.892) did not differ significantly between SPECT scanning and the barostat. However, no correlation could be determined between accommodation volumes measured by both techniques. In contrast with meal induced relaxation, the glucagon induced increase in fundic volume (19 (5) v 406 (56) ml; p=0.007) and post/pre glucagon ratio (1.16 (0.03) v 3.02 (0.54); p=0.046) were significantly lower when measured by SPECT scanning compared with the barostat. CONCLUSION: SPECT scanning detects changes in postprandial volume but is less suitable than the gastric barostat in detecting changes in gastric tone. Our study therefore questions its role as a tool to detect impaired accommodation and warrants further validation of this technique.

Impaired drinking capacity in patients with functional dyspepsia: relationship with proximal stomach function.

BACKGROUND & AIMS: Impaired fundic accommodation to a meal and hypersensitivity to distention are increasingly recognized as important mechanisms underlying functional dyspepsia (FD). In the present study, we evaluated whether a drink test can predict such abnormalities and thus represent a noninvasive tool to study proximal stomach motor function. METHODS: Healthy volunteers (HV), nonconsulters with mild dyspeptic symptoms (MS), and patients with FD filled out a disease-specific questionnaire and underwent a drink test with either water or with a high calorie fluid. The maximal ingested volume and the subsequent symptoms were meticulously recorded. In addition, all subjects underwent a gastric barostat study assessing meal-induced relaxation and sensation to distention. RESULTS: Drinking capacity was not significantly related to any particular dyspeptic symptom. FD were able to consume less water (893 +/- 70 mL) and caloric liquid (767 +/- 50 mL) compared with HV (water, 1764 +/- 120 mL; caloric liquid, 1308 +/- 96 mL) or MS (water, 1645 +/- 120 mL; caloric liquid, 973 +/- 45 mL). Approximately half of the FD had an abnormal water or Nutridrink test compared with 9% of MS and 4% of HV. Furthermore, FD developed significantly more symptoms than MS or HV after both drink tests. The drinking capacity did not predict impaired fundic accommodation or visceral hypersensitivity. CONCLUSIONS: FD, but not MS, have an impaired drinking capacity to both water and a nutrient liquid. The drinking capacity is not related to a specific dyspeptic symptom and does not predict proximal stomach motor function.