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

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,

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