The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.
Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.
The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.
Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.
When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.
Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.
A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).
The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.
Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.
Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.
The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.
Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.
For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.