An Open Label Study Assessing REN Treatment in Headache Management in Temporomandibular Disorders

Temporomandibular disorders (TMD) encompass a group of conditions involving the masticatory muscles, temporomandibular joint (TMJ), and associated structures. TMD is the most common cause of non-odontogenic orofacial pain and is the second most commonly occurring musculoskeletal condition. Up to 70% of the general population experiences signs and/or symptoms of TMD, with headache presenting as one of the most common manifestations. Recent studies highlight the comorbid presence of headache and TMD, hypothesizing that a relationship likely exists between the two conditions. Accordingly, a recent systematic review and meta-analysis supported a positive association between pain-related TMD, migraine, and chronic tension-type headaches. Other studies demonstrated that, among patients seeking care for headaches, the prevalence of those presenting with TMD symptoms ranged from 52-55%. Headache severity has also been associated with the number of TMD symptoms such that the prevalence of headache in TMD patients with one TMD symptom was 57%, with two symptoms was 65%, and with three or more symptoms was 73%. Notably, the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study -the largest population-based study in adults designed to identify risk factors associated with the onset and persistence of TMD - showed that prior headaches were a significant risk factor for the development of first-onset TMD symptoms9. After the development of TMD, both headache severity and frequency were shown to increase in the TMD group compared to healthy participants. Specifically, the prevalence of migraine episodes increased 10-fold in the group that developed TMD symptoms. Finally, clinical studies revealed that, when TMD is successfully treated, headache symptoms also tend to resolve, suggesting a role of TMD in the pathophysiological process.

A key mechanism underlying both TMD and migraine is the deficiency in Conditioned Pain Modulation (CPM), a descending inhibitory pathway that regulates pain processing. CPM impairment has been implicated in chronic pain states, including both migraine and TMD, contributing to their frequent co-occurrence and shared pathophysiology. Remote Electrical Neuromodulation (REN) is an emerging non-pharmacological intervention that exerts its analgesic effects by activating the CPM system, which is deficient in individuals with TMD and migraine. The Nerivio REN wearable device is FDA-cleared for acute and/or migraine prevention, in patients 8 years of age or older. It is a prescription use, self-administered device for use in the home environment at the onset of migraine headache or aura for acute treatment, or every other day for preventive treatment. By enhancing endogenous pain inhibition, REN has been shown to provide effective relief in migraine, and its application in TMD is expected to yield similar clinical benefits. Given the evidence linking CPM dysfunction to TMD pathogenesis, REN presents a promising therapeutic approach to addressing both the underlying pain dysregulation and symptom burden in affected patients.

The aim of this study is to evaluate the safety and efficacy of Nerivio Infinity for the management of headache, orofacial pain and TMD related symptoms.

This is an open-label, single arm study to determine whether REN can be utilized for the management of TMD-related pain and other symptoms. 40 participants (ages 12 years and older) with a TMD diagnosis will be enrolled. Treatment will be performed once daily for 45 minutes per treatment, for 6 weeks. Daily treatment ensures consistent neuromodulation, is expected to reduce overall pain severity, and to maintain CPM activation. TMD pathophysiology supports daily use: TMD involves central sensitization and chronic engagement of the trigeminal system, similar to migraine. Unlike migraine, where individual attacks may be separated by pain-free periods, TMD pain is often persistent or recurrent on a near-daily basis. Moreover, daily use ensures sustained neuromodulatory effects to prevent worsening of pain flares while improving functional jaw mobility. Daily use is expected to reduce overall pain severity, attack frequency, and functional impairment (aligning with migraine prevention goals). Additional acute use (as-needed adjunct to daily treatment) will be permitted and is expected to address pain flare-ups that may still occur despite daily neuromodulation.

The study will consist of two main phases:

4-week baseline phase- in which participants will report their symptoms daily via an electronic app diary (with no intervention); 6-week intervention phase- in which eligible participants perform once daily treatments using Nerivio Infinity device, and continue to report symptoms daily via the app.

Inclusion criteria

• Is of 12 years of age and older (inclusive; of any gender, race, or ethnicity)
• Meets diagnostic criteria for chronic TMD (Myalgia and/or Arthralgia) based on the Diagnostic Criteria for TMD (DC/TMD)
• Has experienced TMD pain for at least 6 months
• Has experienced TMD pain at level ≥4 on a 0-10 scale for at least 10 days of the last 30 days
• Commits to not making any changes to TMD treatment regime (medication and/or non-medication), including not adding or removing treatment, and if on any existing treatment then maintaining the same treatment type, dosage, and frequency from 3 months prior to enrollment to study completion
• Naïve to REN treatment
• Willing and able to understand and comply with all study procedures and be available for the duration of the study
• Has their own smartphone or tablet device that is connected to the internet
• Provides a signed and dated informed consent form

Exclusion criteria

• Has any of the following medical conditions:

1.1 Uncontrolled seizures/epilepsy 1.2 Benign and malignant TMJ and masticatory muscle tumors 1.3 Presence of implanted electrical device

• Has experienced facial trauma or orofacial surgery within 6 weeks prior to the Screening and Baseline Visit
• Is undergoing current active orthodontic treatment
• Currently being treated with chemotherapy or radiation therapy
• Meets the ICHD-3 diagnostic criteria for migraine with or without aura, either chronic or non-chronic migraine
• Currently taking an opioid medication, whether episodically or daily, within 30 days prior to the Screening and Baseline Visit
• Has been treated with another investigational drug or treatment within 30 days prior to the Enrollment Visit
• Taking more than one prescription drug for the treatment of pain (including all types of drugs and modalities, e.g. pill, spray, injection) Note that this criterion does not refer to drug-free based treatments (including split therapy, physical therapy, acupuncture, massage therapy, biofeedback, CBT, or transcutaneous electrical nerve stimulation) for the treatment of pain, which may be used (single or multiple treatments) as long as not changed throughout the study.
• Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude the participant's full compliance with or completion of the study