The demographic profile of this real-world population with migraine (mean age 44 years; ~ 75% female) was generally representative of the global migraine population [17, 18]. In this real-world study, over 40% of patients were classified as insufficient responders to prescribed acute treatment (based on patient self-reported achievement of headache pain freedom within 2 h post first-dose in up to three of their last five migraine attacks).
Our findings support those of other real-world studies, including Adelphi Migraine DSPs conducted using the same methodology as that used in the current study. A 2014 US Adelphi Migraine DSP found that insufficient responders to acute therapy comprised 34% of the study population [19], and the same percentage of insufficient responders to acute treatment with triptans (34%) was found in a recent analysis of data from a 2017 Adelphi Migraine DSP conducted in the USA, France, Germany, Italy, Spain, and the UK [20].
The slightly higher proportion (56%) of insufficient responders to acute treatment reported by the US AMPP longitudinal population-based study [6] is possibly due to the use of a different definition of insufficient response in that survey: pain-free response achieved < 50% of the time. Clinical trial and observational study data have consistently reported that 30–40% of people with migraine do not respond sufficiently to triptan therapy in controlled trials [21,22,23,24].
In the current study, levels of satisfaction with acute therapy were lower in insufficient responders than in sufficient responders, with insufficient responders being significantly less likely than sufficient responders to express a willingness to continue with their current prescribed acute therapy. Overall, therefore, this analysis of Japan Adelphi Migraine DSP data supports previous findings of high levels of unmet need due to an insufficient response to current acute treatment options for people with migraine [5, 25].
Further real-world evidence that people with migraine in Japan have unmet treatment needs, albeit with respect to preventive medications, was also seen in a 2019 analysis of the Japan Medical Data Center claims database. This study reported that only 15% of people identified with migraine had received preventive medication as their index migraine treatment regimen and that, among these people, discontinuation of initial preventive treatment was common (67–83%), occurred following only a short period of treatment, and was ongoing, with most (85% of discontinuers) continuing to receive no preventive treatment after discontinuation [26].
Factors associated with insufficient response to prescribed acute treatment identified in the logistic model of this analysis of real-world data from Japan included taking acute prescribed medication when/after pain started versus at first sign of migraine, seeing a neurologist rather than an internist, having cardiovascular disease, and a higher MIDAS score. Few previous studies have investigated factors associated with response to acute therapy in people with migraine, but similar findings were reported in an analysis of the 2014 US Adelphi Migraine Specific DSP data [19]. In that analysis, taking acute medication when/after pain started (vs. at first sign of migraine) and higher MIDAS total scores were also associated with insufficient response to acute treatment. The study additionally identified depression as significantly associated with insufficient response [19], a finding also reported by the US AMPP population-based study [25].
The current analysis of the Japan Adelphi Migraine DSP data found the presence of cardiovascular disease to be associated with a lower odds of an insufficient response to acute therapy. Cardiovascular disease (myocardial infarction, peripheral vascular disease, ischemic heart disease, stroke, transient ischemic attack and uncontrolled hypertension) is considered a contraindication to the use of triptans [27, 28], a widely used acute treatment for migraine [29]. In the Japan Adelphi Migraine DSP, a majority of acute prescriptions were for triptans and NSAIDs [8]; hence, this inverse association between cardiovascular disease and insufficient response to acute medication requires further study.
Other factors associated with an insufficient response to acute migraine treatment identified from clinical or population-based studies include older age, higher body mass index, greater headache severity, more headache days per month, presence of migraine-related symptoms (e.g., photophobia/phonophobia, nausea) or cutaneous allodynia, use of NSAIDs, and non-use of preventive migraine medications or triptans [6, 25, 30,31,32,33,34]. Notably, high levels of discontinuation of migraine therapies (triptans and preventive therapies), assessed using pharmacy claims data, were recently also found to be indicative of an insufficient patient response to acute treatment [35]. Conflicting findings have been reported for the influence of gender and the time of treatment administration on response to therapy [31,32,33].
The finding that early administration of acute treatment (at the first sign of a migraine attack rather than when/after the pain starts) reduced the risk of an insufficient response to such therapy has notable implications for people with migraine in Japan. Currently in Japan, prescriptions of acute medications, such as triptans, are limited to 10–14 doses/month, and routine use of opioids for treating migraine is off-label. Hence, some people with migraine will hesitate before taking acute therapy, postponing administration until the signs of a migraine attack are more pronounced, thus potentially increasing their chances of an insufficient response.
Consulting with a headache specialist rather than a non-specialist could increase a patient’s awareness of how to improve the management of their migraine attacks. For example, the patient could be encouraged to record their migraine experience (e.g., in a migraine headache diary), which could help them better control the timing of their acute medication administration. We found that seeing a neurologist rather than an internist was associated with a higher risk of insufficient response to acute treatment, which suggests both that insufficient responders may seek out the care of a headache specialist and that even people who are consulting headache specialists are struggling to adequately treat their migraine attacks.
The finding of an association between a higher MIDAS score and an insufficient response to prescribed acute treatment in the logistic model of this analysis suggests that patients with greater levels of migraine-related disability are also struggling to adequately treat their migraine attacks.
The implications of these findings, which suggest that the earlier patients receive effective acute treatment for their migraine attacks the better the impact on longer-term prognosis, warrant further study. In particular, more research is needed to clarify, for example, the differences in factors related to insufficient response to acute therapy reported between real-world studies and those of population-based and clinical studies.
We found treatment patterns to be largely similar between insufficient responders and sufficient responders to prescribed acute treatment in Japan. However, insufficient responders to acute treatment were more likely than sufficient responders to exhibit greater migraine severity, as indicated by the higher proportions of insufficient responders with a clinical diagnosis of chronic migraine or medication-overuse or tension-type headache and the greater requirements of insufficient responders for extra doses of prescribed acute medication to relieve pain symptoms or symptoms of a migraine attack. Headache-related disability was also significantly greater and HRQoL significantly lower in Japanese insufficient responders to acute treatment than in sufficient responders, and similar findings have been reported in the overall 2017 analysis of Adelphi Migraine DSP data from USA, France, Germany, Italy, Spain, and the UK [20] and in the 2014 US Adelphi Migraine DSP [19]. Comparison of the EQ-5D utility score for insufficient responders to acute therapy in the current study (0.847) with reported Japanese norms (0.950–0.899 for age range > 20–29 to < 70 years [36]) suggests that HRQoL is markedly impaired in Japanese people with migraine with an insufficient response to acute therapy.
Comparison of the Japan and US Adelphi Migraine DSP insufficient responder data reveals notably lower mean MIDAS scores in the Japanese cohort (12.7 vs. 21.0, indicating less migraine-related disability) and more frequent reports of little or no disability (69.1% vs. 31.5%) [19]. One reason for these differences could be that the proportion of insufficient responders experiencing a low frequency (0–3) of migraine headache days per month was higher in the Japanese cohort than in the corresponding US cohort (59.9% vs. 53.7%) [19]. Additionally, these findings are possibly indicative of cultural differences between Japan and the USA.
A comparison of Japan and US Adelphi Migraine DSP WPAI scores [19] indicates that migraine impacted impairment at work, overall work impairment, and usual activity to a significantly greater extent in insufficient responders than in sufficient responders in both countries. However, in the 2014 US Adelphi Migraine DSP, migraine also significantly impacted work time missed due to migraine [19]. In the 2017 analysis of Adelphi Migraine DSP data from USA, France, Germany, Italy, Spain, and the UK, significantly greater impairments in work productivity and activity were seen in insufficient responders to triptan therapy than in sufficient responders [20].
Strengths/limitations
A major strength of this study is the use of real-world data collected using a standardized methodology (as part of the Adelphi Migraine DSP [9]), thus facilitating the comparison of study findings with those from other countries. Strengths and limitations of the use of Japan Adelphi Migraine DSP data have previously been reported [8].
As all patients who participated in the Japan Adelphi Migraine DSP had a physician-confirmed diagnosis of migraine, the study findings can be considered representative of consulting patients with migraine in Japan. However, it should be noted that consulting physicians were selected on the basis of the volume of patients with migraine routinely seen and hence had high levels of experience in treating migraine attacks. These results may therefore not be generalizable to the wider population with migraine.
Another strength of the study was that the backward logistic model used to identify factors associated with insufficient response to prescribed acute treatment included not only variables previously reported as associated with treatment response (e.g., older age, female sex, greater headache severity, and presence of migraine-related symptoms) but also additional patient characteristics and treatment patterns (e.g., numbers of prescribed acute and preventive medications), MIDAS total score and other HRQoL data, and time of administration of acute treatment.
Response to acute treatment was patient reported. There is currently no standard definition for assessing response to acute treatment for migraine. However, the definition of response we used was based on a recognized efficacy endpoint in clinical trials assessing acute treatments for migraine (headache pain freedom within 2 h of acute treatment in at least four of five [80%] migraine attacks) and is one that is desirable to patients [14]. Other researchers have proposed cut-offs for response as a positive outcome (pain freedom at 2 h) in at least two of three (67%) treated attacks [37] or three of four attacks (75% [38]). Hence, we believe that the definition we used to assess response to acute treatment was appropriate.
Additional limitations of the study include that the data are cross-sectional in nature (hence, causality cannot be inferred) and that only a limited number of physicians and patients participated.
