Reversion from chronic migraine to episodic migraine: A new outcome measure

Migraine can be easily separated into two subtypes based on headache frequency; that is, episodic migraine (EM) and chronic migraine (CM). Over the years, our understanding of migraine chronification has largely improved (1). Patients with CM are more likely to have depression, anxiety, asthma, and circulation problems than those with EM (2). Cutaneous allodynia, non-cephalic pain, fibromyalgia, and chronic low back pain are also more common in CM (3–5). Also, neuroimaging studies on CM demonstrate structural changes in brain regions involved in pain processing and affective regulation (6,7). Compared with EM, CM is associated with higher disabilities, socioeconomic burdens, and medical costs (1,2,7).

It is estimated that the annual incidence of transition from EM to CM is 2.5–3.1% (8,9), and the risk factors of migraine chronification include overuse of acute medications, ineffective acute treatment, obesity, depression, and stressful life events (7). Considering the huge disease burden of CM, the goals of treatment for EM should include preventing transformation to CM. In contrast, the American Migraine Prevalence and Prevention (AMPP) study reported that about 26% patients with CM reverted to EM over 2 years (10). The results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) study showed 49.9% reverted to EM during 3-month follow-up (5). One earlier study of ours also showed that up to 65% of patients remitted from chronic daily headache (mainly CM) in two years (11). Seemingly, CM is not a stable diagnosis during follow-up, although these epidemiological studies did not mention how many participants were on migraine preventive treatment. However, this outcome measure “reversion from CM to EM” has never been tested in clinical trials.

Studies focusing on CM treatment are not as common as on EM, and the results are less optimal (12,13). Before the era of CGRP monoclonal antibodies (mAbs), only topiramate and onabotulinumtoxinA demonstrated efficacy in CM (14–16); and the latter was effective only in CM but not in EM (16–18). In real-world practice, traditional preventive medications for EM are commonly prescribed to patients with CM (18). CGRP mAbs showed positive results as prophylactic treatment for CM (13). However, as for EM, the clinical trials for CM also used mean reduction of monthly migraine days and proportions of 50% reduction of monthly migraine days as their co-primary endpoints (13,19).

In this volume of Cephalalgia, Lipton et al. (20) conducted a post-hoc analysis of erenumab, a human monoclonal antibody blocking the CGRP receptor, for the preventive treatment of CM to test, for the first time, this new outcome measure – reversion from CM to EM. It is defined as < 45 headache days per 12 weeks in this study. They found 54.1% of patients with CM reverted to EM in the first 12 weeks after treatment, and 96.8% of these patients maintained the status quo of EM for further 64 weeks. Patients who did not revert to EM through the first 12 weeks still had a more than 75% probability of achieving persistent EM reversion for 24 weeks. Overall, two-thirds of patients with CM who completed 64-week erenumab treatment reverted to EM in long-term follow-up, and the reversion rate to EM is numerically higher in patients receiving 140 mg than 70 mg. This proof-of-concept study demonstrated both the short-term and long-term efficacy of erenumab on “reversion of CM to EM” in patients with CM.

Since most of the suggested primary and secondary outcome measures are similar for the clinical trials between EM and CM regarding the preventive treatment (19,21). “Reversion of CM to EM” is at least specific for CM. Moreover, from the patients’ perspective, “reversion of CM to EM” is more intuitive than mean reduction of migraine days. On the other hand, there are still issues for this outcome measure. For example, as the authors clearly demonstrated, patients with headache frequency close to the boundary between EM and CM (i.e. 15 days) are more likely to reach this outcome measure. Another issue is that patients with CM are frequently associated with several co-morbid conditions and chronic pain disorders (5), and for patients with certain conditions it may be more difficult to attain “reversion to EM”. These comorbid conditions are frequently excluded in clinical trials of CM. Nevertheless, this new outcome measure is worth testing for the other existing CM treatments, such as onabotulinumtoxinA, topiramate, and other CGRP mAbs based on their published clinical trials or in clinical settings in the future.