Central Mechanisms of Calmare: an fMRI Trial

Pilot one-treatment and extended 10-treatment studies are carried out on participants with peripheral neuropathy comparing traditional TENS and Calmare stimulation protocols using a double-blind apparatus. Resting fMRI scans are obtained before and after the treatment, as well as after most of the pain has returned.

Study Overview

• Status: Completed
• Conditions: Peripheral Neuropathy
• Intervention / Treatment: Device: Calmare; Device: TENS

Detailed Description

Pain can be either useful or harmful. Acute pain conveys information to the brain about real or potential damage that can productively lead to avoidance or treatment of the damage. However, chronic pain, which extends beyond these useful purposes, becomes a potentially debilitating inconvenience. Estimations based on surveys report that as many as 33% of Americans suffer from chronic pain, with a significant portion being unable to successfully manage it.

The current means to treating chronic pain include: surgery, drug therapy, physical therapy, psychological intervention, and others. Unfortunately, despite these options, many people continue to suffer from a chronic pain condition. Neuropathic pain, or pain caused by nervous system damage, is particularly hard to treat. Drug therapy and surgery have relatively low success rates and undesirable side effects. Thus, there is a need for additional research and new treatment methods for neuropathic pain patients.

The Calmare device was designed as one such means to treat chronic neuropathic pain. It works through electrostimulation of the skin near the pain site, and, according to recent studies, has significantly reduced chronic neuropathic pain in most subjects (Majithia et al., 2016).

Previous studies of Calmare effectiveness have defined the success of treatment as the reduction of reported pain levels by the patient. Though useful, these studies fail to provide an objective measurement of pain reduction and fail to discover the mechanisms by which it occurs. In addition, previous studies have been unable to perform a true double-blind experiment in which the placebo effect was entirely accounted for. The pilot study takes a step toward filling this gap by performing a double blind, randomized single-treatment trial comparing Calmare efficacy to traditional transcutaneous electrical nerve stimulation (TENS) efficacy. The ten-treatment study examines the durability of the pain relief for 12 weeks after the treatment period.

The goal of these studies is two-fold: first, to use fMRI before and after a full therapeutic Calmare treatment course to determine the extent to which Calmare affects the connectivity of the pain centers of the brain, and second, to determine whether traditional TENS or Calmare is more effective in reducing neuropathic chronic pain. The Calmare treatment is administered in a double-blind fashion with neither the technician, nor the subject knowing whether the TENS or the Calmare is being administered. The investigator's hypothesis is that Calmare therapy decreases subject pain through a central mechanism that will be manifest in decreased functional connectivity of the brain's pain centers. The degree to which this happens is determined by comparing the decrease in pain intensity, as reported by the patient, with the difference in fMRI BOLD temporal correlations between pain centers.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Utah
    • Provo, Utah, United States, 84602-1018
      • BYU MRI Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• They must have suffered from a diagnosed peripheral neuropathy (diabetic, chemotherapy induced, or other) for a minimum of 6 months.
• At the time of the study they must experience pain greater than or equal to 5 on a visual analog pain scale from 0-10, with 0 being "no pain" and 10 being "the worst imaginable pain."

Exclusion Criteria:

• pregnancy
• a history of epilepsy or brain damage
• presence of a serious psychiatric disorder (e.g. schizophrenia, manic-depressive psychosis, primary major depression)
• multiple sources of chronic pain (e.g. a chronic pain condition other than a peripheral neuropathy or more than one site of neuropathies)
• a skin condition that would prevent application of skin electrodes
• latex allergy
• severe arrhythmia or any form of equivalent heart disease
• history of myocardial infarction or ischemic heart disease within the past 6 months
• celiac plexus block or other neurolytic pain control treatment within the past 4 weeks
• state of active withdrawal from drugs and/or alcohol
• ineligible for fMRI due to metal implants, etc.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Calmare; Single- or ten-dose treatments on consecutive weekdays, 30 minutes each.	Device: Calmare; Skin is stimulated with an electrical voltage via electrode pads, variably distorted sine wave at ~47 Hz.
Active Comparator: Traditional TENS; Single- or ten-dose treatments on consecutive weekdays, 30 minutes each.	Device: TENS; Skin is stimulated with an electrical voltage via electrode pads, 300 micro-second rectangle pulse at 47 Hz.; Other Names: Traditional TENS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analaog Scale (VAS) Pain Score Changes	Change from baseline in VAS score, which is marked on a line labeled 0 on the left (no pain) and 10 on the right (the most exquisite pain imaginable).	The intra-subject change in VAS score from pre-Rx baseline a) after the 30-minute treatment and b) again the next day (pilot), or a) after each of the ten 30-minute treatments and b) 6- and 12-weeks from end of treatment (extended)
Washington Neuropathic Pain Scale (WNPS) Pain Score Changes	Change from baseline in each of ten WNPS scores, which are marked boxes have integral values of 0 on the left (no pain) and 10 on the right (the most exquisite pain imaginable).	The intra-subject change in ten WNPS pain scores from baseline after the 30-minute Rx and again the next day (pilot) or after each of the ten 30-minute Rxs and 6- and 12-weeks from end of Rx period (extended)
Changes in resting fMRI Correlations	Change in temporal correlations of resting fMRI signals from 93 cerebral regions of interest.	Intra-subject changes in fMRI signals from baseline (taken immediately before first Rx) obtained 30 minutes after first Rx (pilot) or 10th Rx (extended) and again 24 hours later (pilot) or 6-weeks later (extended).

Collaborators and Investigators

• Sponsor: Brigham Young University
• Collaborators: Sorenson Legacy Foundation; Brigham Young University MRI Research Facility
• Investigators: Principal Investigator: David D Busath, M.D., Brigham Young University

Publications and helpful links

General Publications

• Majithia N, Smith TJ, Coyne PJ, Abdi S, Pachman DR, Lachance D, Shelerud R, Cheville A, Basford JR, Farley D, O'Neill C, Ruddy KJ, Sparadeo F, Beutler A, Loprinzi CL. Scrambler Therapy for the management of chronic pain. Support Care Cancer. 2016 Jun;24(6):2807-14. doi: 10.1007/s00520-016-3177-3. Epub 2016 Apr 4.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): November 15, 2017
• Study Completion (Actual): November 15, 2017

Study Registration Dates

• First Submitted: January 21, 2020
• First Submitted That Met QC Criteria: January 23, 2020
• First Posted (Actual): January 27, 2020

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 23, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Idiopathic; diabetic; chemotherapy-induced
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: F15130

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No