Triptans and gastric accommodation: pharmacological and therapeutic aspects

Abstract

In the past decade, several studies have reported a significant delay of gastric emptying induced by the anti-migraine agent sumatriptan (a 5-hydroxytryptamine (5-HT)_1B/D receptor agonist) in healthy human beings. In patients with functional dyspepsia, sumatriptan improves gastric accommodation after food consumption and reduce perception of gastric distension, hence relieving epigastric symptoms. Recent studies have established that impaired accommodation after food consumption is a major patho-physiological mechanism in functional dyspepsia and restoration of accommodation is considered to be a potential therapeutic target. The precise site of action of sumatriptan in humans is at present unknown, although recent studies carried out using a canine model indicate that sumatriptan exerts its action on gastric accommodation through 5-HT_1B receptors, since both GR127935 and SB216641 (respectively, non selective 5-HT_1B/D and selective 5-HT_1B receptor antagonists) fully antagonised the effects of sumatriptan. Gastric relaxation and enhanced accommodation to a distending stimulus seem to be a class effect of triptans, since it occurs not only with sumatriptan, but also with second-generation triptans (rizatriptan and naratriptan), at least in a canine model. In dyspeptic patients, administration of triptans would be able to restore gastric accommodation after a meal and to improve symptoms of early satiety, confirming the therapeutic potential of 5-HT_1B/D receptor agonists in functional dyspepsia.

Introduction

The term gastric accommodation describes the ability of the stomach to adapt itself following the ingestion of a meal. This response provides an appropriate gastric reservoir for food and enables volume increases without a rise in gastric pressure. It involves at least two responses: “receptive relaxation” [1], which allows the stomach to accept a load without a significant rise in gastric pressure, and “adaptive relaxation” [2], which modulates gastric tone in response to the specific properties of the food ingested. Normally, the proximal stomach relaxes in response to food ingestion in order to act as a reservoir and to enable an increase in gastric volume. Impaired gastric accommodation has recently been shown as a common finding in patients with functional dyspepsia [3], [4]. Thus, restoration of gastric accommodation is proposed as a potential therapeutic target in dyspepsia [4].

The patho-physiological mechanisms responsible for functional dyspepsia include psycho-social factors and alterations in motility and visceral sensation. Approximately 50% of patients with functional dyspepsia have motor disorders, such as impaired fundic relaxation, antral dilation and/or hypomotility, small bowel dysmotility, or abnormal duodenogastric reflexes [5], [6], [7], [8]. Tack et al. [9] have recently proposed the following relationship between gastric physiology and symptoms:

• delayed gastric emptying associated with post-prandial fullness, nausea and vomiting;

• impaired gastric (fundic) accommodation associated with early satiety and weight loss;

• visceral hypersensitivity associated with epigastric pain, belching and weight loss.

This classification, although simplistic, has the advantage of underlining the fact that subgroups of dyspeptic patients may considerably differ in the pathophysiology of their symptoms.

In the past decade, many efforts have been made in order to extend our therapeutic armamentarium for dyspepsia, because the available drugs (mainly prokinetics) often do not provide adequate control of symptoms. Tack et al. [10] reported that, in healthy volunteers, sumatriptan, the anti-migraine agent caused significant relaxation of the gastric fundus and enabled the accommodation of considerably larger volumes before thresholds for perception or discomfort were reached during iso-volumetric distension. The fact that perception thresholds were altered by sumatriptan in response to iso-volumetric, not isobaric, distension suggests that the effect of sumatriptan was determined by the change in gastric tone rather than by an effect on visceral sensitivity. These observations provide a rationale for testing sumatriptan as means for relieving symptoms in dyspeptic patients with defective post-prandial gastric accommodation.

Different hypothesis have been put forward to explain the effect of sumatriptan. Recently, it was demonstrated that 5-hydroxytryptamine (5-HT)-induced relaxations of the guinea pig stomach are mediated through activation of a 5-HT₁-like receptor [11]. Some authors also considered 5-HT_1P receptors, since their presence is reported in enteric neurons [12], and suggested that sumatriptan might act via this receptor subtype [10] (see, however, Section 2).

The aim of the present review is to consider published evidence on the mechanisms involved in the action of triptans on gastric motility/visceral sensitivity, to consider possible new avenues for drug development for relieving symptoms in the subset of patients with functional dyspepsia and impaired gastric accommodation.