This month we will discuss "migraine plus" conditions: menstrual migraine as well as migraine-associated symptoms, including allodynia, photophobia, and nausea.
Migraine is one of the most common and disabling conditions worldwide, and it is three times more likely to be found in women than men. This is even more so during reproductive years, where many women experience hormonally triggered migraine attacks. Although some women will experience migraine exclusively perimenstrually, most women who experience menstrual migraine attacks also will have migraine attacks that are not hormonally triggered. It is often challenging to find the correct acute treatment for specific kinds of migraine attacks, and many women will describe specific acute medications as more effective for their nonmenstrual or "regular" migraine attacks compared with their perimenstrual attacks. The study by MacGregor and colleagues investigated the use of ubrogepant and compared its effect between these two subtypes of attacks.
This trial was an extension of the initial phase 3 trial of ubrogepant, called ACHIEVE II. Initial investigators enrolled over 700 patients into an open-label extension, and the participants were randomly assigned 1:1:1 to their "usual care," 50 mg ubrogepant, or 100 mg ubrogepant. Participants were blinded to the dose of ubrogepant even though they knew that they were taking ubrogepant or their standard acute medication. The purpose of the "usual care" arm was not to collect efficacy results; rather, it was for safety, specifically to evaluate the long-term hepatic safety with ubrogepant.
Participants were allowed to treat up to eight migraine attacks per 4-week interval. The duration of the trial was 52 weeks, and a second dose of medication was allowed, identical to the initial dose. Women in this trial recorded their menstrual start date and whether they treated menstrually related attacks. An attack was considered menstrually related if the headache was within a 5-day window of the onset of menstruation. Of the 734 women enrolled in the intention-to-treat population, 354 reported at least one menstrual cycle start date with a headache day. Efficacy outcome measures included pain freedom at 2 hours post-dose, pain relief at 2 hours post-dose, absence of photophobia, phonophobia, and nausea at 2 hours post-dose, normal function at 2 hours post-dose, and use of rescue medication within 24 hours of the initial dose. All information was collected via an electronic diary.
There was no statistically significant difference between 2-hour pain freedom outcomes of menstrual and nonmenstrual migraine attacks, although there was a numerically higher mean percentage of menstrual attacks that was not statistically significant. This was noted for both doses of ubrogepant. This was also the case for 2-hour pain relief; the migraine-associated symptoms of photophobia, phonophobia, and nausea; for functional disability; and the use of a rescue medication. Among all outcomes it appears that both doses of ubrogepant are equally effective for both menstrual and nonmenstrual migraine attacks. On the basis of this evidence, clinicians may be able to consolidate different acute medications for different migraine subtypes and consider the use of this calcitonin gene-related peptide (CGRP) antagonist for all the patient's attacks.
Allodynia is a condition whereby a nonpainful stimulus is perceived as painful. In the context of migraine, this often will occur in the head and neck region and as a result of the chronification of migraine — headache frequency increasing to > 15 days per month. One significant risk factor for the development of chronic migraine is medication overuse, when an acute medication for migraine is used more often than its recommended use. Pijpers and colleagues sought to determine whether the presence of allodynia was predictive for the prognosis of chronic migraine complicated by medication overuse.
This study was a subset of the Chronification And Reversibility of Migraine (CHARM) study, a randomized, double-blind, placebo-controlled trial that aimed to investigate whether treatment with botulinum toxin A was of added value in addition to withdrawal therapy in chronic migraine patients with medication overuse headache. Diagnoses were made in consultation with headache experts and confirmed by a headache diary. Exclusion criteria were: (1) other primary headache or neurologic disorders; (2) other chronic pain disorders with medium to high pain intensity or requiring pain medication; (3) major psychiatric disorders other than depression; (4) major cognitive, behavioral, or oncologic disorders; (5) contraindications for treatment or inability to adhere to the study protocol; (6) (planned) pregnancy or breastfeeding; (7) use of ergots, opioids, or barbiturates; or (8) abuse of drugs in the past 12 months. Allodynia was determined by the Allodynia Symptom Checklist (ASC) .
The primary outcome was reversion from chronic to episodic migraine; secondary outcomes were > 50% reduction in monthly migraine days and reduction in number of monthly headache days. A total of 173 participants in the CHARM trial provided baseline allodynia data and were included in this current study. Participants with cutaneous allodynia were mainly women and did not differ significantly in age, number of monthly migraine or headache days, age of onset, use of acute or prophylactic treatment, or being treated with botulinum toxin.
The absence of cutaneous allodynia was predictive for good outcome after 12 weeks. For the primary endpoint, the odds for reversion from chronic migraine to episodic migraine were 2.5 times higher for participants without allodynia vs with allodynia. In all, 75.0% of participants without allodynia vs 57.4% of participants with allodynia reverted to episodic migraine. These helpful data will allow us to better predict accurately the disease process and better set expectations for our patients with chronic migraine.
In the earlier days of headache treatment, the focus for both acute and preventive medications was a decrease in the severity or frequency of pain. As time has progressed and our understanding of migraine has broadened, we now consider pain one of the many features of migraine, albeit usually the most prominent feature. The CGRP antagonist class of migraine medications has revolutionized how migraine is treated, both acutely and preventively; however, the initial studies all focused on pain-related outcomes. Alpuente and colleagues sought to better determine the effect of CGRP monoclonal antibody medications on other migraine-associated symptoms, specifically photophobia, photophobia, nausea, dizziness, and aura.
All injectable CGRP antibody medications were studied. Responses were recorded in an electronic diary. Patients were followed at 3 and 6 months and were excluded if their diary was < 80% complete; a total of 158 patients were included in this study. At 3 months, groups of patients were further divided between those who had > 50% decrease in monthly headache days and those that had < 50% reduction.
The > 50% group showed statistically significant reductions in the ratios of photophobia, phonophobia, and aura after 6 months of treatment, and, of note, these symptoms decreased at a higher rate than the reduction in headache days per month after 6 months. Rates of nausea and dizziness only reduced proportionally to the monthly headache days. For the < 50% group, there was a rebound of dizziness in between months 3 and 6, but all other outcomes decreased in proportion to the monthly headache days.
Our patients all experience symptoms other than headache pain as part of their migraine attacks. When we discuss the risks and benefits of a new treatment, we can now more accurately address many of the other associated symptoms and explain what our patients are likely to expect when starting a new medication. Similar studies have described these findings with the oral CGRP antagonists as well, and most acute migraine studies now use "most bothersome symptom" rather than pain severity as their primary outcome.