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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.

SUBMITTER: Muthulingam JA

PROVIDER: S-EPMC6720238 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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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.

Muthulingam Janusiya Anajan JA Olesen Søren Schou SS Hansen Tine Maria TM Brock Christina C Drewes Asbjørn Mohr AM Frøkjær Jens Brøndum JB

BMJ open 20190823 7

<h4>Introduction</h4>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 th ...[more]

PMID: 31603076

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Project description:Background & aimsChronic abdominal pain is the primary symptom of chronic pancreatitis, but unfortunately it is difficult to treat. Vagal nerve stimulation studies have provided evidence of anti-nociceptive effect in several chronic pain conditions. We investigated the pain-relieving effects of transcutaneous vagal nerve stimulation in comparison to sham treatment in chronic pancreatitis patients.MethodsWe conducted a randomised double-blinded, sham-controlled, crossover trial in patients with chronic pancreatitis. Patients were randomly assigned to receive a two-week period of cervical transcutaneous vagal nerve stimulation using the gammaCore device followed by a two-week sham stimulation, or vice versa. We measured clinical and experimental endpoints before and after each treatment. The primary clinical endpoint was pain relief, documented in a pain diary using a visual analogue scale. Secondary clinical endpoints included Patients' Global Impression of Change score, quality of life and Brief Pain Inventory questionnaire. Secondary experimental endpoints included cardiac vagal tone and heart rate.ResultsNo differences in pain scores were seen in response to two weeks transcutaneous vagal nerve stimulation as compared to sham treatment (difference in average pain score (visual analogue scale): 0.17, 95%CI (-0.86;1.20), P = 0.7). Similarly, no differences were seen for secondary clinical endpoints, except from an increase in the appetite loss score (13.9, 95%CI (0.5:27.3), P = 0.04). However, improvements in maximum pain scores were seen for transcutaneous vagal nerve stimulation and sham treatments as compared to their respective baselines: vagal nerve stimulation (-1.3±1.7, 95%CI (-2.21:-0.42), P = 0.007), sham (-1.3±1.9, 95%CI (-2.28:-0.25), P = 0.018). Finally, heart rate was decreased after two weeks transcutaneous vagal nerve stimulation in comparison to sham treatment (-3.7 beats/min, 95%CI (-6.7:-0.6), P = 0.02).ConclusionIn this sham-controlled crossover study, we found no evidence that two weeks transcutaneous vagal nerve stimulation induces pain relief in patients with chronic pancreatitis.Trial registration numberThe study is registered at NCT03357029; www.clinicaltrials.gov.

Project description:ObjectiveTo evaluate the effectiveness of transcranial direct current stimulation alone and in combination with cognitive behavioural management in patients with non-specific chronic low back pain.DesignDouble blind parallel group randomised controlled trial with six months' follow-up conducted May 2011-March 2013. Participants, physiotherapists, assessors, and analyses were blinded to group allocation.SettingInterdisciplinary chronic pain centre.Participants135 participants with non-specific chronic low back pain >12 weeks were recruited from 225 patients assessed for eligibility.InterventionParticipants were randomised to receive anodal (20 minutes to motor cortex at 2 mA) or sham transcranial direct current stimulation (identical electrode position, stimulator switched off after 30 seconds) for five consecutive days immediately before cognitive behavioural management (four week multidisciplinary programme of 80 hours).Main outcomes measuresTwo primary outcome measures of pain intensity (0-100 visual analogue scale) and disability (Oswestry disability index) were evaluated at two primary endpoints after stimulation and after cognitive behavioural management.ResultsAnalyses of covariance with baseline values (pain or disability) as covariates showed that transcranial direct current stimulation was ineffective for the reduction of pain (difference between groups on visual analogue scale 1 mm (99% confidence interval -8.69 mm to 6.3 mm; P=0.68)) and disability (difference between groups 1 point (-1.73 to 1.98; P=0.86)) and did not influence the outcome of cognitive behavioural management (difference between group 3 mm (-10.32 mm to 6.73 mm); P=0.58; difference between groups on Oswestry disability index 0 point (-2.45 to 2.62); P=0.92). The stimulation was well tolerated with minimal transitory side effects.ConclusionsThis results of this trial on the effectiveness of transcranial direct current stimulation for the reduction of pain and disability do not support its clinical use for managing non-specific chronic low back pain.Trial registration Current controlled trials ISRCTN89874874.

Project description:Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP.40 patients with CP will be enrolled. Patients are randomised to receive 8?h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4?weeks. To improve blinding, 1?mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8?weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP.The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences.The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).

Project description:ObjectiveTo perform a pilot study to assess the efficacy of intraneural facilitation, a novel manual technique, in the treatment of carpal tunnel syndrome (CTS).DesignPatients with clinical and electrodiagnostic evidence of CTS were randomized into intraneural facilitation or sham groups.SettingElectrodiagnostic laboratory in a university medical center.ParticipantsPatients referred to our electrodiagnostic laboratory were screened based on nerve conduction studies that were diagnostic for distal median neuropathy at the wrist or CTS. A total of 14 participants were enrolled; 4 participants withdrew prior to randomization, with the remaining 10 participants (N=10) divided equally between treatment and control groups. There was a 9:1 female-to-male sex ratio and average duration of symptoms was 28.5 months.InterventionsTreatment was performed twice weekly for 3 weeks.Main outcome measuresPrimary outcomes were the Boston Carpel Tunnel Questionnaire (BCTQ) and Boston Functional Status Scale at enrollment and at 1 week and 3 months after completion of intervention. A secondary outcome was ultrasonography (US) of the median nerve performed at baseline and 1 week after intervention.ResultsTen participants completed the trial, 5 each in the treatment and 5 each in the sham groups. The total percentage change in BCTQ and Boston Functional Status Scale scores decreased at baseline, 1 week, and 3 months after intervention. However, there was no difference between control and intraneural facilitation group. Within-group differences showed nonstatistically significant differences for all the groups except for the BCTQ questionnaires after 3 months of intraneural facilitation therapy was completed (P=.043) compared with baseline. Between-group differences showed large effects for the BCTQ questionnaires (d=1.933) and wrist to forearm ratio (WFR) 1 week after completion of intervention.ConclusionsThis pilot study suggests that intraneural facilitation might improve symptoms and possibly function but did not improve median nerve cross-sectional area or WFR in CTS at follow-up evaluation 3 months after completion of intervention.

Project description:BackgroundPercutaneous peripheral nerve stimulation is an analgesic technique involving the percutaneous implantation of a lead followed by the delivery of electric current using an external pulse generator. Percutaneous peripheral nerve stimulation has been used extensively for chronic pain, but only uncontrolled series have been published for acute postoperative pain. The current multicenter study was undertaken to (1) determine the feasibility and optimize the protocol for a subsequent clinical trial and (2) estimate the treatment effect of percutaneous peripheral nerve stimulation on postoperative pain and opioid consumption.MethodsPreoperatively, an electrical lead was percutaneously implanted to target the sciatic nerve for major foot/ankle surgery (e.g., hallux valgus correction), the femoral nerve for anterior cruciate ligament reconstruction, or the brachial plexus for rotator cuff repair, followed by a single injection of long-acting local anesthetic along the same nerve/plexus. Postoperatively, participants were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator in a double-masked fashion. The dual primary treatment effect outcome measures were (1) cumulative opioid consumption (in oral morphine equivalents) and (2) mean values of the "average" daily pain scores measured on the 0 to 10 Numeric Rating Scale within the first 7 postoperative days.ResultsDuring the first 7 postoperative days, opioid consumption in participants given active stimulation was a median (interquartile range) of 5 mg (0 to 30) versus 48 mg (25 to 90) in patients given sham treatment (ratio of geometric means, 0.20 [97.5% CI, 0.07 to 0.57]; P < 0.001). During this same period, the average pain intensity in patients given active stimulation was a mean ± SD of 1.1 ± 1.1 versus 3.1 ± 1.7 in those given sham (difference, -1.8 [97.5% CI, -2.6 to -0.9]; P < 0.001).ConclusionsPercutaneous peripheral nerve stimulation reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery.Editor’s perspective

Project description:Chronic non-specific low back pain is the most common medical problem for which patients seek complementary and alternative medical treatment, including bee venom acupuncture. However, the effectiveness and safety of such treatments have not been fully established by randomized clinical trials. The aim of this study is to determine whether bee venom acupuncture is effective for improving pain intensity, functional status and quality of life of patients with chronic non-specific low back pain.This study is a randomized, double-blinded, sham-controlled clinical trial with two parallel arms. Fifty-four patients between 18 and 65 years of age with non-radicular chronic low back pain experiencing low back pain lasting for at least the previous three months and ? 4 points on a 10-cm visual analog scale for bothersomeness at the time of screening will be included in the study. Participants will be randomly allocated into the real or sham bee venom acupuncture groups and treated by the same protocol to minimize non-specific and placebo effects. Patients, assessors, acupuncturists and researchers who prepare the real or sham bee venom acupuncture experiments will be blinded to group allocation. All procedures, including the bee venom acupuncture increment protocol administered into predefined acupoints, are designed by a process of consensus with experts and previous researchers according to the Standards for Reporting Interventions in Clinical Trials of Acupuncture. Bothersomeness measured using a visual analogue scale will be the primary outcome. Back pain-related dysfunction, pain, quality of life, depressive symptoms and adverse experiences will be measured using the visual analogue scale for pain intensity, the Oswestry Disability Index, the EuroQol 5-Dimension, and the Beck's Depression Inventory. These measures will be recorded at baseline and 1, 2, 3, 4, 8 and 12 weeks.The results from this study will provide clinical evidence on the efficacy and safety of bee venom acupuncture in patients with chronic non-specific low back pain.This study is registered with the United States National Institutes of Health Clinical Trials Registry: NCT01491321.

Dataset Information

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.

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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.

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