G. Karamanolis

Promotility Medications - Now and in the Future

Gastrointestinal promotility drugs stimulate smooth muscle contractions to enhance gastric emptying and small and large bowel transit. Currently available drug classes with prokinetic properties include antidopaminergic agents, serotonergic agents, and motilin-receptor agonists. Due to moderate prokinetic effects, poor symptomatic responses and the presence of adverse effects, there is a clear need for new classes of prokinetics. Several newer prokinetic drugs and drug classes are currently under evaluation. Selecting candidate agents and designing the appropriate therapeutic trials is hampered by the lack of insight in the pathophysiology of motility-related symptoms. As gastrointestinal motor disorders are chronic, relapsing, and remitting disorders, it seems desirable that studies with candidate prokinetic drugs establish a long-term efficacy and not only short-term effects on gastrointestinal functions.

Perception of dysphagia: lack of correlation with objective measurements of esophageal function

Background  The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically‐induced esophageal hypocontractility, and in patients with gastro‐esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM).

Role of endogenous opioids in the control of gastric sensorimotor function

Abstract  Endogenous opioids have been implicated not only in the process of feeding but also in the control of gastric sensitivity and gastric motor responses, and impairment of antinociceptive opioid pathways has been hypothesized to contribute to the pathogenesis of functional dyspepsia. Our aim was to study the effect of suppression of endogenous opioid action by naloxone on gastric sensorimotor function in healthy volunteers. During intravenous administration of saline or naloxone (0.4 mg intravenous bolus followed by continuous infusion 20 μg kg−1 h−1), sensitivity to gastric distension, gastric accommodation and fundic phasic contractility were evaluated by barostat in 15 subjects. Nutrient tolerance and meal‐related symptoms were assessed using a satiety drinking test (n = 13), and solid and liquid gastric emptying were evaluated by breath test (n = 14). Naloxone did not influence gastric compliance and sensitivity. No effect on preprandial gastric tone was found but meal‐induced accommodation was significantly inhibited by naloxone (P = 0.031). Subjects receiving naloxone demonstrated a higher motility index before (20.8 ± 2.4 vs 28.0 ± 1.9 mL s−1, P = 0.007) and after (15.2 ± 2.0 vs 22.7 ± 1.5 mL s−1, P = 0.0006) the meal. Naloxone significantly decreased the amount of food ingested at maximum satiety (715.4 ± 77.7 vs 617.3 ± 61.3 mL, P = 0.03). No effect of naloxone on gastric emptying was observed and intensity of postprandial symptoms was unchanged. These observations suggest that endogenous opioids are involved in the control of gastric accommodation and phasic contractility but not in the control of sensitivity to gastric distension or gastric emptying in healthy volunteers.

Oesophageal tone and sensation in the transition zone between proximal striated and distal smooth muscle oesophagus

Abstract  Previous studies have shown that the proximal striated muscle oesophagus is less compliant and more sensitive than the distal smooth muscle oesophagus. Conventional and high resolution manometry described a transition zone between striated and smooth muscle oesophagus. We aimed to evaluate oesophageal tone and sensitivity at the transition zone of oesophagus in healthy volunteers. In 18 subjects (seven men, mean age: 28 years) an oesophageal barostat study was performed. Tone and sensitivity were assessed using stepwise isobaric distensions with the balloon located at transition zone and at distal oesophagus in random order. To study the effect induced on transition zone by a previous distension at the distal oesophagus and vice versa, identical protocol was repeated after 7 days with inverted order. Initial distension of a region is referred to as ‘naïf’ distension and distension of a region following the distension of the other segment as ‘primed’ distension. Assessment of three oesophageal symptoms (chest pain, heartburn and ‘other’) was obtained at the end of every distension step. Compliance was significantly higher in the transition zone than in the distal oesophagus (1.47 ± 0.14 vs 1.09 ± 0.09 mL mmHg−1, P = 0.03) after ‘naif’ distensions. This difference was not observed during ‘primed’ distensions. Higher sensitivity at transition zone level was found in 11/18 (61%) subjects compared to 6/18 (33%, P < 0.05) at smooth muscle oesophagus. Chest pain and ‘other’ symptom were more often induced by distention of the transition zone, whereas heartburn was equally triggered by distension of either region. The transition zone is more complaint and more sensitive than smooth muscle oesophagus.

Influence of naloxone on rectal sensorimotor function in health

Abstract  Abnormal rectal motor physiology and visceral hypersensitivity are implicated in the pathogenesis of irritable bowel syndrome. Endogenous opioids are involved in both the regulation of gut motility and the processing of sensory information. Our aim was to study the effect of suppression of endogenous opioid function by naloxone on rectal sensorimotor function in health. Eighteen healthy subjects participated in a rectal barostat study. Sensorimotor function was evaluated during two consecutive stepwise distensions separated by 30 min of basal tone recording, and with perception scoring on a 0–6 graded scale. Naloxone was administered, after 15 min of basal tone measurements, as an intravenous bolus (0.4 mg), followed by continuous infusion (20 μg kg−1 h−1) in a placebo‐controlled, single‐blinded and randomized fashion. Naloxone did not alter rectal sensitivity. Comparison of visual analogue scale scores between naloxone and saline did not reveal altered intensities of pain or discomfort. Compared to the baseline distension, a significant adaptive increase in compliance occurred during the second distension after saline (7.8 ± 0.7 vs 11.0 ± 0.6 mL mmHg−1, P = 0.0016). This dynamic change in rectal compliance did not occur after naloxone administration (8.8 ± 0.7 vs 10.1 ± 0.8 mL mmHg−1, ns). Low intensity tonic distension induced a rectal adaptive relaxation, which was absent after naloxone. Naloxone does not alter rectal sensitivity but abolishes rectal adaptation in response to repeated balloon distention. These observations suggest that the endogenous opioid system is involved in control of rectal tone rather than rectal sensitivity.

Role of duodenal mucosal nerve endings in the acid‐induced duodenogastric sensorimotor reflex: Effect of benzocaine in healthy humans

Duodenal acid exposure induces a duodenogastric reflex resulting in gastric relaxation, inhibition of antral motility, and sensitization of the proximal stomach to distension. Duodenal hypersensitivity to acid has been identified as a potential pathogenic mechanism in functional dyspepsia. The nature and localization of the duodenal acid‐sensitive receptors are still elusive. We hypothesize that acid directly activates superficial afferent nerve endings in the duodenal mucosa, triggering the duodenogastric reflex.