Study protocol for a randomised double-blinded, sham-controlled, prospective, cross-over clinical trial of vagal neuromodulation for pain treatment in patients with chronic pancreatitis

Abstract

Introduction: The management of chronic pancreatitis (CP) is challenging and requires a personalised approach focused on the individual patient's main symptoms. Abdominal pain is the most prominent symptom in CP, where central pain mechanisms, including sensitisation and impaired pain modulation, often are involved. Recent clinical studies suggest that vagal nerve stimulation (VNS) induces analgesic effects through the modulation of central pain pathways. This study aims to investigate the effect of 2 weeks transcutaneous VNS (t-VNS) on clinical pain in patients with CP, in comparison to the effect of sham treatment.

Methods and analysis: Twenty-one patients with CP will be enrolled in this randomised, double-blinded, single-centre, sham-controlled, cross-over study. The study has two treatment periods: A 2-week active t-VNS using GammaCore device and a 2-week treatment with a sham device. During both treatment periods, the patients are instructed to self-administer VNS bilaterally to the cervical vagal area, three times per day. Treatment periods will be separated by 2 weeks. During the study period, patients will record their daily pain experience in a diary (primary clinical endpoint). In addition, all subjects will undergo testing which will include MRI, quantitative sensory testing, cardiac vagal tone assessment and collecting blood samples, before and after the two treatments to investigate mechanisms underlying VNS effects. The data will be analysed using the principle of intention to treat.

Ethics and dissemination: The regional ethics committee has approved the study: N-20170023. Results of the trial will be submitted for publication in peer-reviewed journals.

Trial registration number: The study is registered at www.clinicaltrials.gov: NCT03357029.

Keywords: chronic pain; clinical trials; gastrointestinal disease; transcutaneous electrical nerve stimulation; viscera.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Mode of action of transcutaneous vagal nerve stimulation (t-VNS). (1) Pain arises in the periphery, for example, pancreas and a signal is sent to the spinal cord. This leads to the ascending activation of the spinal neurons (2). In the brain, pain is processed in higher cortical centres (3). t-VNS, it is expected to block the perception of pain in the cerebral cortex, by stimulating nucleus tractus solitarius and thereby decrease glutamate level. Simultaneously, the net-descending inhibition will be activated as a result of top-down input from cortex and the limbic system (4).

Figure 2

Schematic flow chart of the interventional study design enabling comparison of the modulatory effect to self-administered of transcutaneous vagal nerve stimulation (t-VNS) in patients with chronic pancreatitis. Patients with chronic pancreatitis will be randomly assigned to one of two double-blinded treatments: (1) 2 weeks of t-VNS, 2 weeks of washout and 2 weeks of sham treatment; or (2) 2 weeks of sham treatment, 2 weeks of washout and 2 weeks of t-VNS. Evaluation of the two treatments will be assessed by collecting pain diary, pain questionnaires, MRI scan, blood sample, cardiac vagal tone (CVT) and pain assessments. quantitative sensory testing (QST).

Figure 3

Standard Protocol Items: Recommendations for Interventional Trials figure. BPI-SF, Brief Pain Inventory—Short Form; CVT, cardiac vagal tone; PGIC, Patient Global Impression of Changes Questionnaire; QST, quantitative sensory testing; VNS, vagal nerve stimulation.