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Progress with Novel Pharmacological Strategies for Gastro-oesophageal Reflux Disease

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Abstract

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs).

Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs.

GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD.

Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date.

The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis.

In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid μ-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardio-vascular, urinary and respiratory adverse effects.

Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans.

A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.

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Acknowledgements

The original work of the authors was supported by funds from the Universities of Pavia and Bologna. The authors have no conflicts of interest to declare.

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  1. Department of Physiological and Pharmacological Sciences, University of Pavia, Piazza Botta 11, I-27100, Pavia, Italy

    Marcello Tonini

  2. Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy

    Roberto De Giorgio

  3. Department of Pharmacology, University of Bologna, Bologna, Italy

    Fabrizio De Ponti

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  1. Marcello Tonini
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Correspondence to Marcello Tonini.

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Tonini, M., De Giorgio, R. & De Ponti, F. Progress with Novel Pharmacological Strategies for Gastro-oesophageal Reflux Disease. Drugs 64, 347–361 (2004). https://doi.org/10.2165/00003495-200464040-00001

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