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

NCT07841509 | Recruiting FDA Device

• 1 other identifier: TCH-016
• Study Type: interventional
• Target: 120
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Migraine; Fibromyalgia; Conditioned Pain Modulation

Keywords

Remote Electrical Neuromodulation; Nerivio

Outcome Measures

Primary Outcomes (1)

• 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).

  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 Outcomes (2)

• 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).

  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).

  15 minutes

Other Outcomes (1)

• 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).

  40 minutes

Study Arms (2)

Active REN treatment

ACTIVE COMPARATOR

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

Placebo REN treatment

PLACEBO COMPARATOR

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

Interventions

Remote Electrical Neuromodulation (REN) device 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.

Also known as: Nerivio

Active REN treatment; Placebo REN treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Theranica: lead

Study Sites (2)

Theranica Bio-Electronics Inc

Bridgewater, New Jersey, 08807, United States

NOT YET RECRUITING

Rambam Health Care Campus

Haifa, Israel

RECRUITING

MeSH Terms

Conditions

Migraine Disorders; Fibromyalgia

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases

Study Officials

• Alit Stark Inbar, PhD

  Theranica

  STUDY DIRECTOR

Central Study Contacts

Dagan Harris, PhD

CONTACT

+972723909763; daganh@theranica.com

Yara Asmar, BSc

CONTACT

+972723909763; yaraa@theranica.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: * A selection of identically looking Active and Placebo devices will be used to maintain blinding. Each device will be numbered with a unique randomization identification number. * No information regarding expected stimulation perception will be provided, except for the fact that stimulation intensity adjustment control will allow to adjust intensity to a "well perceived but non-painful" level. The adjustment of the intensity level for each participant will be performed by the study coordinator and the participant during the first 5-7 minutes of treatment start. * During the study visit, participants will not be asked directly any questions regarding treatment perception.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A randomized, double-blind, placebo-controlled trial

Study Record Dates

• First Submitted: September 8, 2026
• First Posted: September 25, 2026
• Study Start: June 23, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 31, 2027
• Last Updated: September 25, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); IL (1)