Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain

Abstract

Objective. Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhibitors (PPIs). Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 (TRPV1) antagonists. Aim. To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients. Material and methods. Enrolled patients had NERD and a partial PPI response (moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks' PPI therapy). Fourteen patients (21–69 years, 9 women) were block-randomized into this placebo-controlled, double-blinded, crossover study examining efficacy of a single dose (95 mg) of AZD1386. On treatment days, each participant's esophagus was stimulated with heat, distension, and electrical current at teaching hospitals in Denmark and Sweden. Heat and pressure pain served as somatic control stimuli. Per protocol results were analyzed. Results. Of 14 randomized patients, 12 were treated with AZD1386. In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [–3%, 95% confidence interval (CI), –22;20%], distension (–11%, 95% CI, –28;10%), or electrical current (6%, 95% CI, –10;25%). Mean cutaneous heat tolerance increased by 4.9°C (95% CI, 3.7;6.2°C). AZD1386 increased the maximum body temperature by a mean of 0.59°C (95% CI, 0.40–0.79°C), normalizing within 4 h. Conclusions. AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response, whereas it increased cutaneous heat tolerance. TRPV1 does not play a major role in heat-, mechanically and electrically evoked esophageal pain in these patients. ClinicalTrials.gov identifier: D9127C00002.

Key Words::

• esophagus
• GERD
• heartburn
• heat
• NERD
• pain
• PPI
• reflux
• regurgitation
• sensitivity
• TRPV1

Acknowledgements

We thank research nurses Len Jaremo, Gunilla Näslin, Karen-Marie Marstal, and Corinna Schmidt for their role in acquiring the data.

Declaration of interest: Personal interests: ALK has received a travel grant from AstraZeneca. MÅ and MBH are employees of AstraZeneca. LN was an employee of AstraZeneca during the conduct of this study. JG and FHJ have no competing interests. MS and PFJ have served as consultants for AstraZeneca. AMD has served as a consultant for AstraZeneca, Pfizer, and Perdue. Funding interests: This study was funded by AstraZeneca. The “Obelske Family Foundation” and “Hertha Christensen Foundation” are acknowledged for funding Mech-Sense and hence this project. Writing support (language revision) was provided by Michael Molloy-Bland, PhD, of Oxford PharmaGenesis^™ Ltd and funded by AstraZeneca R&D, Mölndal, Sweden.