Increased Treatment Opportunities for Trigeminal Autonomic Cephalalgias

By Dara G. Jamieson, MD

Synopsis: Trigeminal autonomic cephalalgias (TACs) include cluster headache, paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms. They are female-predominant primary headache disorders that coexist with migraines and mood disorders. Indomethacin is underused in those TACs that are specifically indomethacin responsive. Noninvasive vagus nerve stimulation for TACs is well-tolerated and more effective for prevention than as an acute treatment.

Sources: Moskatel LS, Ogunlaja O, Zhang N. Prevalence, demographics, comorbidities, and treatment patterns of patients with the trigeminal autonomic cephalalgias: A retrospective analysis of United States electronic health records. BMC Neurol. 2025;25(1):299.

Fernandes CS, Ashraf U, Goadsby PJ. Neuromodulation in trigeminal autonomic cephalalgias: 11-year experience of non-invasive vagus nerve stimulation. Cephalalgia. 2025;45(9):3331024251370339.

Moisset X. Vagus nerve stimulation for trigeminal autonomic cephalalgias: Evidence, challenges and future directions. Cephalalgia. 2025;45(9):3331024251370318.

The International Classification of Headache Disorders, Third Edition, labels cluster headache, paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA) as trigeminal autonomic cephalalgias (TACs).

Moskatel et al analyzed the prevalence, demographics, comorbidities, and treatment patterns of these primary headache disorders using data from the Epic Cosmos electronic health record platform. The authors identified 152,727 patients with cluster headaches, 59,312 with paroxysmal hemicrania, 19,321 with hemicrania continua, and 6,291 with SUNCT. The five-year prevalence rates per 100,000 were highest for cluster headache (56.7), followed by paroxysmal hemicrania (22.0), hemicrania continua (7.2), and SUNCT (2.3). Although all TACs are female-predominant, with prevalence peaking in late middle age, the rates in women were highest with hemicrania continua and were lowest with cluster headaches.

The overlapping diagnosis of migraine was associated with paroxysmal hemicrania in 35.1% of patients, cluster headache in 36.4% of patients, SUNCT in 37.2% of patients, and hemicrania continua in 51.8% of patients. Depression and anxiety are comorbid conditions in primary headache disorders, and especially in TACs occurring in women. Patients with SUNCT had the highest incidence of cerebrovascular disease (10.4%), while patients with cluster headaches had the highest rates of nicotine (20.1%), alcohol (4.7%), and cannabis (3.9%) use disorders.

A significant proportion of patients received medical treatment for their TACs, with 75.5% of cluster headache patients and 86.1% of hemicrania continua patients using prescribed medications. Steroids, gabapentin, and topiramate were used for prevention and triptans were used for abortive treatment of cluster headaches. Indomethacin was notably underused to treat the specifically indomethacin-responsive TACs, which are paroxysmal hemicrania (6,533 [14.7%]) and hemicrania continua (7,762 [46.6%]). Limitations of this epidemiological study include potential diagnostic inaccuracies because of the reliance on electronic health records and the possibility of misdiagnosis among patients.

Alternative, non-drug treatment of TACs has been explored. Fernandes et al evaluated the effectiveness and tolerability of treating patients with TACs using noninvasive vagus nerve stimulation (nVNS). Seventy-four patients with cluster headaches, 10 patients with paroxysmal hemicrania, 15 patients with hemicrania continua, four patients with SUNCT, three patients with SUNA, and two patients with undifferentiated TAC were treated between January 2014 and February 2025. The nVNS device was applied to the pain side of the neck for two vagal nerve stimulations through the skin of two minutes each up to three times a day for preventive treatment. The device was used as needed for acute treatment of TACs.

A clinically meaningful treatment response with nVNS occurred if the patient reported a decrease in the frequency or duration, or both, of their TAC attacks after a minimum of eight weeks of using nVNS. Overall, 70 patients considered nVNS to be useful over a median time using nVNS of 47 (interquartile range [IQR], 18-66) months. The median time of use in patients who did not find nVNS useful was seven (IQR, 4-12) months. The majority of patients (59 [84%]) found the treatment useful as a preventive treatment and 33 patients (47%) also found it useful as acute treatment. The median number of stimulations per day for preventive treatment was six (IQR, 6-9).

The adverse events (AEs) reported in 23 patients were mild and self-limiting. The most common AEs were self-limiting neck discomfort and facial pain ipsilateral to the site of stimulation. Fifty-nine (55%) patients withdrew from using nVNS, including 11 patients (19%) who had considered it initially useful. Reasons for discontinuation included lack of efficacy (59%), AEs (10%), and access problems (12%).

The findings of the study showed that nVNS generally is more effective as a preventive treatment than as an acute treatment, with 65% of patients finding it useful, at least initially. The authors concluded that nVNS is a safe, tolerable, and effective option, particularly for preventive treatment in all TACs, noting that cluster headaches predominated in the study. All groups of TAC patients considered nVNS more useful as a preventive treatment, while cluster headache and SUNCT/SUNA patients also considered it useful as an acute treatment.

Moisset wrote an editorial reviewing the data on the use of various neuromodulatory devices in headache disorders. However, barriers, such as cost and limited access to the devices, hamper their widespread use. He also noted the high rate of treatment discontinuation in the study by Fernandes et al, with more than half of the patients (59 out of 108) ceasing to use nVNS. He cautioned that in clinical trials involving treatment of TACs, the placebo response to treatment can be particularly high, emphasizing the importance of well-designed randomized controlled treatment trials.

Commentary

TACs are particularly debilitating primary headaches that often are underrecognized and undertreated. They pose particular treatment challenges related to ineffective and poorly tolerated medical treatment. Even when the TAC is specifically responsive to indomethacin, the medication is underused. However, indomethacin may cause gastrointestinal AEs, especially at the higher doses that would be expected to be beneficial in reducing headache frequency and severity. Other preventive medications that also are effective for migraine prevention are used non-specifically for TAC, often with unimpressive results. The comorbidities of patients with TACs, who often are in their 50s and 60s, may limit the use of acute abortive medications that risk vascular complications. Treatments beyond the usual medications need to be explored.

Neuromodulatory treatment of TACs may circumvent some of the problems associated with acute and preventive medications. In an 11-year study, nVNS was found to be well-tolerated and more effective as a preventive treatment than as acute treatment for TACs. However, although most patients with TACs found the device to be useful for preventive treatment, the discontinuation rate was more than half, even though the AEs associated with nVNS were not especially bothersome, especially compared to the disability associated with the headaches. The reason for both high satisfaction and high discontinuation rates includes a decrease in efficacy over time, potentially related to an initial placebo response. More research is needed for patients affected by these incapacitating headache disorders, especially when the response to medications and neuromodulatory devices still is inadequate. Despite treatment results that were less impressive than one would wish, neuromodulatory devices do expand the available treatments for these debilitating and medically refractory primary headaches.

Dara G. Jamieson, MD, is Clinical Associate Professor of Neurology, Weill Cornell Medical College.