Abstract
Background
The definition of chronic migraine has long been debated. Recently, it was suggested to define subjects with at least 8/migraine days as chronic migraine; that is, incorporating so-called high frequency episodic migraine (eight or more migraine days but less than 15 headache days per month).
Methods
We addressed the possible problems that might arise based on this proposal accounting for clinical, pathophysiological, impact and public health aspects.
Results and conclusions
Defining chronic migraine on the basis of headache frequency alone does not account for clinical and pathophysiological aspects, as well as for the impact of chronic migraine in terms of disability and quality of life. Moreover, it is potentially harmful for patients in terms of allocation of resources. These issues are discussed in the present manuscript, and we support the idea of defining high frequency episodic migraine as an independent entity as a viable path to follow.
Migraine is a highly disabling disease that involves 14% of the global population, with a higher prevalence in women than men, and is a leading driver of disability among populations (1). The definition of chronic migraine (CM) has been debated among researchers for a long time. The International Classification of Headache Disorders-3 (ICHD-3) differentiates CM from episodic migraine (EM), setting the threshold at 15 headache days/month in the last 3 months, of which at least 8 days have migraine-like features. Chalmer and colleagues compared CM patients with high frequency episodic migraine patients (HFEM, defined as eight or more migraine days but less than 15 headache days per month) regarding the number of lifelong and previous year attacks, use of triptans, comorbidities, and social parameters. They found that the two groups were similar for the selected variables, concluded that they are equally disabled, and proposed that they could be merged into the same category (2). However, Chalmer and colleagues did not report data on headache frequency in the two groups, which might therefore be either greatly different (e.g. 8–10 vs. 22–24 headache days/month) or little different (e.g. 12–13 vs. 16–18 headache days/month). They therefore proposed to expand the CM definition to HFEM, to grant HFEM patients access to the appropriate treatment options that have been available so far only for CM patients. This conclusion however poses several problems dealing with clinical and pathophysiological aspects, as well as with disability and quality of life (QoL) outcomes, economic and public health issues.
Migraine chronification occurs mostly as a gradual process and fluctuations in the frequency of the attacks are common (3), which makes it very hard to set a definite border between HFEM and CM. Serrano and colleagues have described these natural fluctuations and demonstrated that transitions between CM and EM are common (4). Evolutions from EM to CM are more frequent, probably also due to medication overuse that may lead to migraine chronification (5). At the same time 75% of CM patients remit to EM mostly because of the use of preventive therapies (5).
Changes in clinical features, rather than headache frequency alone, could better address the mechanism of chronification. This is accurately detected through CM-specific pathogenic mechanisms including the presence of TTH-like pain, reduced pain threshold, and cutaneous allodynia, which may underline the activation of different pathogenic mechanisms. CM shares with TTH the activation of the trigeminal nucleus caudalis (6). Aside from the primary central mechanisms, the peripheral sensitization of the dural, pial, and meningeal arteries might be an important contributor to migraine pathogenesis (7), activating the trigeminal nucleus in a way similar to myofascial trigger points in TTH. The TTH-like episodes in patients with CM might be mild migraines without accompanying symptoms, as suggested by their response to triptans (6). Medication overuse and increasing headache frequency can further contribute to decreasing the characteristic migraine features, leading to the emergence of TTH-like ones (6). Transition from EM to CM is also associated with a pain sensitization-driven decreased pain threshold, and derangement of top-down pain modulation that induces increased susceptibility to external noxious stimuli, aggravating the trigeminal sensitization and generating a vicious cycle (8). Future studies refining the specific mechanisms of CM will likely contribute to define diagnostic criteria based on pathophysiology rather than numerical thresholds.
Disability and QoL measures across LFEM, HFEM and CM patients.
Notes: All one-way ANOVAs were significant at p < .001 level with two-tailed testing. All Bonferroni post-hoc test were significant at p < .001 level, except for WHODAS-12 post-hoc analysis between HFEM and CM, where the significance was p = .001. Data herein reported are a secondary analysis of Raggi A, et al. (9).
LFEM: low frequency episodic migraine; HFEM: high frequency episodic migraine; CM: chronic migraine; MIDAS: migraine disability assessment; WHODAS-12: 12-item WHO disability assessment schedule; MSQ: migraine specific quality of life; MSQ-RR: MSQ-role restriction; MSQ-RP: MSQ-role prevention; MSQ-EF: MSQ-emotional function.
Following the proposal of Chalmer and colleagues, if the category of CM is to include those that are now defined as HFEM, then the amount of persons that may require access to specific prophylactic treatments is reasonably expected to increase. This would make the cost of migraine disorders rise dramatically. As shown in a manuscript reporting data from the International Burden of Migraine Study (10), the total annual healthcare cost associated with CM was €2436, versus €743 for EM. Analytically, the cost of acute treatment in CM and EM patients was €369 and €134 per year (i.e. around €31 and €11 per month) respectively, whereas the cost of prophylaxis (including botulinum toxin injections) was €132 and €54 per year (i.e. around €11 and €4.5 per month). Therefore, the increase in healthcare costs due to the addition of new and expensive treatments for a too-large audience would not be compensated by a reduction in the consumption of acute medications, and of total costs including indirect or public health system costs. A concrete risk, for insurance-based systems, is that such treatments might be cost-effective only for the portion of the population with higher salaries, where indirect cost reduction could compensate for the DMMD cost; for universal coverage systems, there is a risk of a hyper-selection of the most severe, and therefore less numerous, cases. The current position taken in the UK by the National Institute for Health and Care Excellence on September 2019 (11), which did not approve erenumab for the prophylaxis of either CM or EM, is based on the lack of a clear cost-effectiveness compared to available treatments. Thus, if the idea of the equivalence between HFEM and CM is followed, the actual risk is that the target for specific clinical and public health interventions is not correctly identified: This, instead of facilitating all patients, would damage particularly those more in need in the case of rationalization of resources.
In conclusion, arbitrarily classifying migraine by frequency alone may support treatment decisions but does not allow the clear identification of distinct subsets of patients that are more in need, with public health implication we all should be aware of. Furthermore, both pathophysiological evidence and clinical aspects suggest the specificity of ICHD-3-defined CM, and at the moment they do not seem to encourage the assimilation of HFEM into the same diagnostic group. The same indication can be derived from the analysis of disability and QoL measures, as discussed above on data from an Italian sample. Based on the data herein presented, the alternative hypothesis that was also accounted by Chalmer and colleagues; that is, to pursue new studies and research able to define HFEM as an independent entity, may be a viable path to follow (1). Only then we will be able to look into treatment priority targets aiming to intercept the chronification process and its overall burden from a perspective of economic, personal and social sustainability of new therapeutic options (12,13).
Footnotes
Public health relevance
CM and HFEM are not only different in terms of headache frequency, but also in terms of clinical and pathophysiological aspects, as well as in terms of impact on patients and public health relevance.
Merging these two entities may potentially lead to dangerous consequences for patients if resource allocation is reduced, with the risk that new emerging preventive treatments are not made available to those patients that are more in need.
Declaration of conflicting interests
AR, MG, ML, RO declared no conflicts of interest in respect of this manuscript; DD has received honoraria as speaker or for participating in advisory boards from Novartis, Teva, and Eli Lilly; SS received honoraria as speaker or for participating in advisory board from Abbott, Allergan, Eli Lilly, Novartis, and Teva; PM received honoraria as speakers bureau and advisory boards from Allergan, Eli Lilly, Novartis, and Teva; royalties from Springer, SpringerNature, and travel grants from the European Medicine Agency. PM serves as Editor-in-chief of The Journal of Headache and Pain and Section Editor, Medicine, SpringerNature Comprehensive Clinical Medicine, and serves as EU expert for the European Medicine Agency. He is the Immediate Past-President of the European Headache Federation. SS serves as Associate Editor of The Journal of Headache and Pain and is Treasurer of the European Headache Federation. AR serves as Associate Editor of BioMed Research International.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
