Treating Bothersome, Non-Headache Migraine Symptoms with Neuromodulation
By Leah Small
Physician review by Michael A. L. Johnson, MD
The non-headache symptoms of migraine have a major impact on quality of life. These symptoms may include photophobia (sensitivity to light), phonophobia (sensitivity to sound), osmophobia (sensitivity to smells), nausea or vomiting. For some patients, a migraine-associated symptom can be more disabling than the headache itself, significantly impacting their quality of life.These symptoms are often referred to as [migraine-associated] most bothersome symptoms (MBS).
Due to the negative impacts of non-headache migraine symptoms, the U.S. Food and Drug Administration recommends that clinical trials for acute treatments of migraine evaluate drug effectiveness in treating non-headache migraine symptoms as well as headache pain. However, MBS are understudied, which limits understanding of the causes of migraine symptoms and the availability of effective treatments.
Several neuromodulation therapies have been shown to provide both significant headache relief and resolution of migraine-associated symptoms. Neuromodulatory devices treat migraine pain by modifying nervous system activity and are available for home use.
Most common non-headache migraine symptoms
The most bothersome non-headache symptoms of migraine include nausea and vomiting, photophobia (sensitivity to light) and phonophobia (sensitivity to sound).
Photophobia is by far the most common MBS. In the large, cross-sectional, observational Migraine in America Symptoms and Treatment (MAST) study, 64.9% of respondents reported experiencing all 3 migraine symptoms. The most common MBS was photophobia (49.1%), followed by nausea (28.1%) and phonophobia (22.8%).
In multiple studies, researchers note that certain MBS are more prevalent in specific patient groups. For instance, a follow-up survey of MAST study participants found that “respondents reporting photophobia as the MBS were more likely to be men, to be obese, and to report visual aura. Those reporting nausea as the MBS were more likely to be women, to have lower incomes, and to report lower levels of treatment optimization.”
Challenges of treating the most bothersome symptoms of migraine
Though migraine is one of the most common neurological disorders worldwide, it is often ineffectively treated. Therapies for migraine tend to primarily focus on relieving headache pain and not on other associated symptoms that are just as debilitating.
Physicians often prescribe antiemetics for nausea during migraine, and triptans and non-steroidals for intermittent photophobia. However, results may vary and migraineurs could benefit from adjuvant therapies. Migraine treatments often prioritize alleviating headache pain, while equally disabling associated symptoms frequently remain underaddressed.
Neuromodulation is an effective treatment for the most bothersome symptoms of migraine
The Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM) study was the largest clinical trial to date to examine the effectiveness of external trigeminal nerve stimulation (eTNS) for the acute treatment of migraine.
The TEAM study showed that a two-hour treatment with external trigeminal nerve stimulation (eTNS) resolved and reduced migraine pain, it also resolved MBS and migraine-associated symptoms. Specifically, resolution of the most bothersome migraine-associated symptom (MBS) was 14.1% higher in the active stimulation group compared to sham (56.4% vs. 42.3%; p = 0.001). Additionally, patients receiving verum eTNS experienced significantly greater resolution across various migraine-associated symptoms compared to sham stimulation (42.5% vs. 34.1%; p = 0.044).
Researchers subsequently conducted a post hoc analysis of the TEAM study, recently published in Headache, to investigate whether eTNS offered differential therapeutic effects across specific MBS subtypes, including photophobia, phonophobia, nausea, and vomiting.
“Essentially, the question we sought to answer with this paper was, ‘Is the response to trigeminal nerve stimulation different according to different subtypes of most bothersome symptom?” said Michael A. L. Johnson, MD, one of the co-investigators.
For each type of bothersome symptom, a two-hour eTNS treatment reduced pain and symptom severity at two and 24-hours post treatment, with more variability in response from patients who reported nausea as their most bothersome symptom. However, eTNS was more effective in resolving nausea than sham stimulation.
The authors performed a heterogeneity of treatment effect analysis to evaluate how eTNS outcomes varied by MBS subtype — a novel approach in neuromodulation research. They found that eTNS produced favorable results across most subtypes, though outcomes for patients with nausea as their MBS showed greater variability, aligning with prior evidence suggesting this group may be more treatment-resistant.
“MBS are very understudied,” noted Deena Kuruvilla, MD, the study’s principal investigator. The authors concluded that their post hoc analysis model should serve as a foundation for future research assessing the therapeutic impact of migraine-associated symptoms—an often overlooked and under-recognized aspect of migraine. “Clinicians tend to focus on treating headache pain, while MBS can be much more disabling for people with migraine. This study confirms that we, as clinicians, should be treating migraine as the complex, multi-symptom brain disorder that it is.”
