Todd J. Schwedt, MD

Chronic migraine (CM), a severe and disabling neurologic disease, occurs with a worldwide prevalence of about 2%.

 The International Classification of Headache Disorders (ICHD)-3 beta defines CM as 15 or more headache days per month over at least 3 months’ time, with at least 8 days per month on which headaches and associated symptoms meet diagnostic criteria for migraine.

 CM has a significant negative impact on individuals and society; 90% of persons with CM have moderate or greater levels of migraine-related disability.

 The total average cost of CM is estimated at $7750 per person annually-4.4 times greater than the cost of episodic migraine (EM)-with the majority of the cost due to loss of productive time.

Why EM transforms to CM is not fully understood, but many risk factors have been identified.

 Among the proposed mechanisms is that a higher frequency of migraine attacks produces sensitization of the trigeminal system and affected neuronal networks, reducing the overall threshold for activation. To further investigate this proposed mechanism, a recent large longitudinal observational study examined the effect acute treatment response has on transformation to CM.

The study followed selected participants from the American Migraine Prevalence and Prevention Study. From that study, 5681 individuals meeting ICHD 2 criteria for EM, determined by standardized survey, were identified and followed for 1 year. Variables collected included sociodemographic data, headache frequency, disability due to migraine, depression, and acute treatment type and efficacy.

Treatment efficacy was assessed using a validated self-administered survey (the Migraine-Treatment Optimization Questionnaire) that grades the acute treatment into 1 of 4 response categories: very poor, poor, moderate, or maximum treatment efficacy. At 1 year, participants who had transformed to CM were identified. Multivariate modeling was used to calculate the overall risk of self-reported efficacy of acute treatments on conversion to CM.

The results showed that 3.1% of participants transformed from EM to CM. Participants who were graded as having very poor response to acute treatment were at significantly higher risk for developing CM compared with those who had maximum acute treatment response. Across all 3 models used, adjusting for sociodemographic, headache frequency/disability, and acute medication class, very poor response to treatment remained a consistent marker for progression to CM (OR=3.39, 95% CI, 1.98-5.8; OR=2.39, 95% CI, 1.33-4.28; OR=2.55, 95% CI, 1.42-4.61, respectively).

Overall, this suggests that individuals with very poor acute treatment response had roughly 2.5- to 3.5-fold greater odds of developing CM. Those with moderate or better acute treatment efficacy did not have a significant increased risk.

A weakness of this study’s observational design is that it cannot demonstrate a direct casual effect. It’s possible that very poor acute treatment response may be a marker for more severe/resistant disease and may not be a cause for the transformation to CM. Although this possibility cannot be excluded, the authors did adjust for headache days/month and headache-related disability and very poor treatment response remained a significant risk for transformation (OR=2.39, 95% CI, 1.33-4.28).

Among the types of acute treatments, no single medication class was associated with a higher risk of transformation to CM. Although the study was not designed for head-to-head treatment comparisons, individuals who used triptans were more likely to have a moderate or maximum acute treatment response and patients who used NSAIDs or simple analgesics were less likely to be in the high efficacy categories.

Overall, the study provides supporting evidence that efficacy of acute medication matters beyond just treating a single migraine and may have an impact on the risk of developing worsened disease. Although the individual effectiveness of acute medications was not addressed in this study, that has been addressed in a recent 

 Ineffective acute migraine treatment is associated with a 2.5- to 3.5-fold increased risk of transformation to chronic migraine.

Global prevalence of chronic migraine: a systematic review. 

2. Headache Classification Committee of the International Headache Society (IHS). 

The International Classification of Headache Disorders, 3rd edition (beta version). 

Headache impact of chronic and episodic migraine: results from the American Migraine Prevalence and Prevention study. 

4. Munakata J, Hazard E, Serrano D, et al. 

Economic burden of transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) study. 

6. Lipton RB, Fanning KM, Serrano D, et al. 

Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. 

7. Marmura MJ, Silberstein SD, Schwedt TJ. 

The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. 

Articles

Efficacy of acute medication matters beyond just treating a single migraine. It may increase the risk of worsened disease.

Poor Acute Treatment May Lead to Chronic Migraine

Migraine is a prevalent and often debilitating condition with highly variable individual responses to prophylactic therapy. Selecting an effective prophylactic treatment for an individual patient often is a process of trial and error, without clear clinical factors to guide selection of effective therapy.

Several recent studies have examined whether patient description of headache “direction” may predict treatment response, specifically to onabotulinumtoxinA (Botox) injections.

The association between headache directionality and response to Botox was first published in a triple-blinded prospective and retrospective study in 2006.

This study examined a variety of neurologic symptoms associated with migraine, in both episodic and chronic forms, in responders and nonresponders to 100 units of Botox given for migraine prophylaxis. In the prospective portion of the study, 27 of the 42 patients were categorized as either “clear responders” or “clear nonresponders” based on patient headache logs between weeks 4 and 12 after initial injection.

Between these 2 groups, factors such as presence of aura, photophobia, phonophobia, nausea, vomiting, neck muscle tenderness, and presence of cutaneous allodynia were not correlated with response to onabotulinumtoxinA. However, the description of perceived direction of the origin of the headache was the sole characteristic studied that correlated strongly with response.

Subjects with migraine who described their headache as 

 or a perceived buildup of pressure “as if their skull was about to split open,” were much more likely to be nonresponders. None of the patients with exploding headache were described as responding to Botox in the prospective portion of the study, and those with exploding headaches comprised 89% of the nonresponders in the retrospective portion.

 or “assaulted by external forces, typically described as crushing, clamping or stubbing,” and 

 or “eye popping pain,” were more likely to report response to Botox. Of the responders in the prospective and retrospective portions, 93% and 84%, respectively, described their headache as being either imploding or ocular.

A follow-up study confirmed the correlation with description of headache directionality and Botox response in a retrospective study of 82 patients with subjects meeting International Classification of Headache Disorders 2 (ICHD2) diagnostic criteria for migraine.

 Patients who had received Botox for migraine prophylaxis were interviewed, and a number of clinical characteristics, including headache directionality, were recorded. Patients who had a self-reported drop in headache days by more than 66% were considered responders; less than 33%, nonresponders; and between 33% and 66%, questionable responders.

Those who described their headaches as imploding or ocular accounted for the majority of responders (70%). Those who described their headache as exploding accounted for the majority of nonresponders (78%).

However, obtaining a consistent description of the direction of a patient’s headache may not be straightforward. In an attempt to standardize assessment of directionality, a recent study examined different methods of determining headache directionality in an outpatient women’s health clinic for patients who met ICHD2 criteria for migraine.

 The study compared 3 methods of determining headache direction: (1) a pictorial representation of their headache,(2)  a standardized survey designed to allow the patient to express directionality, and (3) a clinician’s blinded assessment using standardized questions.

Surprisingly, the study demonstrated poor concordance among the different methods, with descriptions of directionally varying widely within subjects when the different methods of assignment were used. The authors suggest that this may be the result of most patients’ unfamiliarity with the concept of headache directionality given that physicians question this infrequently. This represents a potentially significant challenge in using the approach clinically.

While the description of headache directionality may help clinicians better select patients with migraine who may respond to Botox or potentially other prophylactic therapies, the best way to determine this in a consistent manner is as of yet unclear. Furthermore, why the description of the direction from which the pain originates would be predictive in treatment response and what this tells us about the potential pathophysiology also are unknown.

It’s hypothesized that those patients who describe their headaches as imploding may have more involvement of extracranial nociceptors and therefore may have more response to therapies that are directed at extracranial targets, such as Botox. While this cultivates many intriguing questions, further investigations are needed.

1. Jakubowski M, McAllister PJ, Bajwa ZH, et al. 

Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A.

Migraine prophylaxis with botulinum toxin A is associated with perception of headache.

3. Files JA, Schwedt TJ, Mayer AP, et al. 

Imploding and exploding migraine headaches: comparison of methods to diagnose pain directionality.

Knowing the direction of the headache's origin, while clinically difficult to ascertain on a consistent basis, has shown some predictive value for migraines.

Todd J. Schwedt, MD

Articles

Poor Acute Treatment May Lead to Chronic Migraine

Imploding or Exploding: Headache Direction May Help Select Treatment