The Effect of Remote Electrical Neuromodulation (REN) on Conditioned Pain Modulation (CPM) in Migraine and Fibromyalgia

September 21, 2026 updated by: Theranica

A Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Effect of a REN Wearable Device on Conditioned Pain Modulation (CPM) in Patients With Migraine and/or Fibromyalgia

Migraine and Fibromyalgia (FM) are chronic pain disorders characterized by altered central pain processing and impaired endogenous pain inhibition. FM presents with widespread musculoskeletal pain, fatigue, sleep disturbance, and cognitive symptoms and is strongly associated with central sensitization. Migraine similarly involves dysfunction of central inhibitory and descending pain modulation, with evidence of abnormal cortical excitability, impaired sensory habituation, and alterations in pain-related evoked potentials.

Conditioned Pain Modulation (CPM) is a measure of the body's endogenous pain-inhibitory mechanism, based on the phenomenon whereby the pain evoked by one painful stimulus (the test stimulus) is reduced by the concurrent application of a second, remote nociceptive stimulus (the conditioning stimulus). It is widely regarded as a proxy for the function of descending pain-modulatory pathways.

CPM is used as an experimental biomarker of descending pain inhibition across chronic pain conditions, including fibromyalgia and migraine. Studies consistently demonstrate reduced inhibitory responses in both migraine and fibromyalgia compared with healthy controls, indicating a robust deficit in descending pain modulatory systems. Combining a contact heat test stimulus (TS) with a cold pressor conditioning stimulus (CS) is a widely used and validated CPM paradigm.

Nerivio, a Remote Electrical Neuromodulation (REN) device, is a non-invasive, non-pharmacological therapy indicated for the acute and preventive treatment of migraine. The REN device is worn on the upper arm and delivers peripheral electrical stimulation to activate CPM-related descending inhibitory pathways and reduce migraine pain. This distal stimulation approach is designed to activate CPM-related circuits by recruiting brainstem pain-regulatory centers and modulating central nociceptive processing.

This randomized, double-blind, placebo-controlled trial is designed to assess the effect of a single REN session on CPM and cortical pain processing in adults with migraine or fibromyalgia. Using a standardized CPM induction protocol, the study will evaluate changes in behavioral CPM responses, before, during, and after REN vs. sham stimulation in patients with migraine or fibromyalgia. This study aims to clarify whether REN enhances descending pain inhibition and pain processing in populations with impaired endogenous pain modulation.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The Nerivio device is a prescription use, self-administered device for use in the home environment for the acute and/or preventive treatment of migraine above the age of 8 years old. It is a wireless, wearable, battery-operated stimulation unit controlled by a smartphone software application.

The study hypothesis is that the REN wearable can induce the CPM mechanism, leading to a reduced pain response to a painful stimulus, and that the reduced pain response following REN stimulation will be larger than following Placebo (sham) stimulation, similar to the standard CPM response demonstrated by exposure to cold water. The placebo device will be identical to the active Nerivio device in its appearance and administration, differing only in the electrical waveform which is designed to activate the CPM mechanism (REN) or not (Placebo).

Pain levels will be measured using standard Numeric Rating Scale (NRS) between 0 and 10.

This hypothesis will be tested using Active or Sham devices as the Conditioned Stimuli (CS), with a heat stimulus serving as the Test Stimulus (TS) for pain induction.

Where:

TS is a painful stimulation (heat on the arm) P1 is the pain response to TS (baseline P2 is the pain response to TS following a standard CS (hand in cold water) P5 is the pain response to TS 15 minutes following a REN treatment (stimulation on the upper arm) CPM1 is the difference between TS pain response following the standard CS (cold water) and the pain response to the TS alone (CPM1 = P2-P1) CPM4 is the difference between TS pain response following the standard CS (cold water) and the pain response following 15 minutes after REN treatment (CPM4 = P5-P1)

The study hypothesis is that REN will lead to a larger CPM response than the placebo stimulation. That is, the CPM response following REN (CPM4 REN = P5 REN - P1 REN) will be larger than the CPM response following Placebo (CPM4 Placebo = P5 Placebo - P1 Placebo), relative to the standard CPM response to cold water in each arm:

H0: (CPM4 REN - CPM1 REN) - (CPM4 Placebo - CPM1 Placebo) = 0 H1: (CPM4 REN - CPM1 REN) - (CPM4 Placebo - CPM1 Placebo) ≠ 0

In other words:

H0: (P5 REN - P2 REN) - (P5 Placebo - P2 Placebo) = 0 H1: (P5 REN - P2 REN) - (P5 Placebo - P2 Placebo) ≠ 0

The analysis will compare REN and Placebo as CS across various TS, relative to the effect of cold water - a defined, well-established CS for CPM induction.

The study design includes the following:

Setting of Test Stimulus (TS): Participant will undergo thermal pain stimulus. 10-second thermal stimulus will be applied to the volar forearm using a contact thermode. Pain levels from repeated TS applications will be collected using NRS. This pain level is defined as P1.

Standard Conditioning Stimulus (Cold water hand immersion). TS will be applied under the presence of Conditioning Stimulus (CS). The participant's hand & wrist will be immersed for up to 30 seconds in a plastic container filled with cold water at 8-10°C. Pain levels from repeated TS applications will be collected using NRS. This pain level is defined as P2. CPM1 will be calculated by comparing P2 to P1.

Randomization procedure

Following completion of the baseline CPM assessment, qualified participants will be randomized to either:

  • Active REN group
  • Placebo (Sham) group

A break of 15 minutes will be taken prior to starting the treatment phase to eliminate the CPM effect by cold water.

A device (REN or Placebo) will serve as the Conditioning Stimulus, and treatment will be conducted for 45 minutes. TS will be applied and pain levels will be collected using NRS from repeated TS applications at mid treatment (P3; 20 minutes into treatment), end of treatment (P4; 40 minutes into treatment), and post treatment (P5; 15 minutes following the end of the treatment).

Interim analysis will be performed following the recruitment of 40 participants,

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
120

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Israel
      • Haifa, Israel
        • Recruiting
        • Rambam Health Care Campus
        • Contact:
          • Yelena Granovsky, PhD
          • Phone Number: +97247772065
        • Principal Investigator:
          • Yelena Granovsky, PhD
  • United States
    • New Jersey
      • Bridgewater, New Jersey, United States, 08807
        • Not yet recruiting
        • Theranica Bio-Electronics Inc
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

- Adults diagnosed with migraine and/or fibromyalgia above 18 years old.

For migraine:

  • Has been diagnosed with migraine according to the ICHD-3 diagnostic criteria for migraine
  • Experiencing 6-24 headache days per month
  • Uses up to 1 prescribed preventive medication for migraine
  • Did not make any changes to their migraine medications treatment in the month prior to the study enrollment.

For Fibromyalgia:

  • Has been diagnosed with FM according to the ACR 2010/6 diagnostic criteria for FM with disease duration for at least 6 months prior to study enrolment.
  • Did not make any changes to their FM medications in the month prior to the study enrollment.
  • Naïve to the Nerivio device.
  • Must be able and willing to comply with the protocol.
  • Provides written informed consent form.

Exclusion Criteria:

  • Has an implanted electrical and/or neurostimulation device (e.g., cardiac pacemaker or defibrillator, vagus nerve neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator cochlear implant, sphenopalatine ganglion stimulator bladder stimulator, or occipital nerve stimulator).
  • Patients with severe depression.
  • Patients with known epilepsy. Use of any analgesics (OTC or prescribed) 24 hours prior to the study enrollment.
  • Use of Cannabis within 10 days prior to the study enrollment.
  • Use of opioids 2 months prior to the study enrollment.
  • Pregnant or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Active REN treatment

This arm will use the active REN device as the Conditioned Stimulus (CS) to the thermal Test Stimulus (TS) that will be applied at 20, 40, and 60 minutes following the initiation of the treatment with the Active REN device.
Device: Remote Electrical Neuromodulation (REN) device

Nerivio is a Remote Electrical Neuromodulation (REN) Device. It is approved for the acute and/or preventive treatment of migraine from the age of 8 and above.

Other Names:
  • Nerivio
Placebo Comparator: Placebo REN treatment

This arm will use the Placebo device as the Conditioned Stimulus (CS) to the thermal Test Stimulus (TS) that will be applied at 20, 40, and 60 minutes following the initiation of the treatment with the Placebo device.
Device: Remote Electrical Neuromodulation (REN) device

Nerivio is a Remote Electrical Neuromodulation (REN) Device. It is approved for the acute and/or preventive treatment of migraine from the age of 8 and above.

Other Names:
  • Nerivio

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Between-groups (Active vs Placebo) difference in mean change of Conditioned Pain Modulation (CPM) activity from post-treatment (CPM4) to baseline (CPM1), measured by Numeric Rating Scale (NRS, 0-10).
Time Frame: 1 hour

Difference between the Active and Placebo groups in the mean change of pain levels following Test Stimulus (TS) at 15 minutes post-treatment with the REN wearable as the Conditioned Stimulus (CS) versus pain levels following Test Stimulus (TS) under cold water as Conditioned Stimulus (CS):

(CPM4 REN - CPM1 REN) - (CPM4 Placebo - CPM1 Placebo) = (P5 REN - P2 REN) - (P5 Placebo - P2 Placebo)

The pain range is between 0 to 10. CPM4 is the difference between the pain level with REN as CS and pain prior treatment without Conditioned Stimulus (CS). CPM1 is the difference between the pain level with Cold Water as Conditioned Stimulus (CS) and pain prior treatment without Conditioned Stimulus (CS). Thus, the expected value is a negative number and higher number means higher CPM activity.
1 hour

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Between-groups difference in mean change of pain levels from post-treatment Test Stimulus (P5) to baseline Test Stimulus (P1), measured by Numeric Rating Scale (NRS, 0-10).
Time Frame: 1 hour

Difference between the Active and Placebo REN groups in the mean change of pain levels following Test Stimulus at 15 minutes post-treatment with REN as Conditioned Stimulus (CS) and baseline pain levels following Test Stimulus only, without Conditioned Stimulus (CS):

(P5 REN - P1 REN) vs. (P5 Placebo - P1 Placebo)

The pain range is between 0 to 10. the higher the number, the higher the pain. The expected value is a negative number and higher number means higher CPM activity.
1 hour
Between-group difference in mean change of pain levels following Test Stimulus (TS) under cold water as Conditioned Stimulus (CS) (P2) to baseline Test Stimulus only (P1), measured by Numeric Rating Scale (NRS, 0-10).
Time Frame: 15 minutes

Difference between the Active and Placebo REN wearable groups (prior randomization) in the mean change of pain levels following Test Stimulus under cold water as Conditioned Stimulus (CS), and baseline pain levels following Test Stimulus only (P2-P1), This comparison will determine the CPM response of the participants PRIOR to randomization.

CPM1 REN vs CPM1 Placebo = (P2 REN - P1 REN) vs (P2 Placebo - P1 Placebo)

The pain range is between 0 to 10. the higher the number, the higher the pain. The expected value is a negative number and higher number means higher CPM activity.
15 minutes

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Temporal buildup of Conditioned Pain Modulation (CPM) - Between-groups (Active vs Placebo) difference in mean change of CPM activity from mid (20 minutes) and end of treatment (40 minutes) to baseline, measured by Numeric Rating Scale (NRS, 0-10).
Time Frame: 40 minutes

Between-group difference (Active vs. Placebo) in mean change of pain levels at mid-treatment following Test Stimulus (at 20 minutes from initiation of REN treatment; P3) and at end of REN treatment following Test Stimulus (at 40 minutes from initiation of REN treatment; P4) to baseline pain levels following Test Stimulus only (P1),

(P3 REN - P1 REN) vs (P3 Placebo - P1 Placebo) (P4 REN - P1 REN) vs (P4 Placebo - P1 Placebo)

The pain range is between 0 to 10. the higher the number, the higher the pain. The expected value is a negative number and higher number means higher CPM activity.
40 minutes

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Theranica

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Alit Stark Inbar, PhD, Theranica

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 23, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 31, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 8, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 21, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 25, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 25, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 21, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • TCH-016

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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