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

ConditionsMigraine Fibromyalgia Conditioned Pain Modulation

Trial statusRecruiting

Trial phaseNot applicable

Trial typeInterventional

Biological sexAll

Age18+

SponsorTheranica

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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.

Trial design

Design model

Parallel

Treatments tested in this trial

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.

Treatment groups

120 Participants

are divided into 2 treatment groups

Group A: Active REN treatmentActive comparator 1 intervention

Group B: Placebo REN treatmentPlacebo comparator 1 intervention

Trial outcomes

Primary outcomes

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.

Time frame

1 hour

Secondary outcomes

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).

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.

Time frame

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).

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.

Time frame

15 minutes

Other outcomes

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).

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.

Time frame

40 minutes

Sponsors and contacts

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Theranica

Lead sponsor

Source ClinicalTrials.gov

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