Patient Factors in the Dose Selection of Oral Sumatriptan for Acute Migraine: A Post Hoc Analysis of Two Randomized Controlled Studies

Migraine is a common condition associated with moderate or severe headache that affects approximately 18% of women and 6% of men in the USA [1]. The burden of disease is reflected at not only the patient level, where symptoms can be debilitating [2], but also the societal level. A study using data from 2010 estimated that migraines lead to approximately 23 million outpatient and 908,000 emergency department visits each year in the USA, resulting in more than US$4 billion in healthcare costs [3]. Furthermore, an analysis of data from 2009 to 2017 showed that healthcare resource utilization by patients with migraine was 1.9 times higher than by patients without migraine [4].

There has been a trend in recent years for patients to seek greater involvement in their healthcare; as a result, they are looking for easier access to medical professionals and treatment [5]. The COVID-19 pandemic has only accelerated the use of telehealth and similar remote healthcare services, which allows for rapid and convenient access to healthcare [6, 7]. Studies have shown that not only can healthcare professionals effectively deliver migraine treatment by telehealth, they are also comfortable doing so [8‐10]. The recent emergence of on-demand digital health clinics (including those for migraine [11, 12]) has demonstrated this trend toward easier access to migraine treatment [13, 14]. In addition, self-care is available for a range of conditions via over-the-counter (OTC) medications, with a number of drugs having switched from prescription to OTC in the USA in recent decades, including diclofenac gel, fluticasone propionate, and omeprazole [15‐17]. Triptans are available OTC in some European countries [18].

Oral sumatriptan (Imitrex; GlaxoSmithKline, Research Triangle Park, NC) for the treatment of acute migraine is available at three different dose levels in the USA (25, 50, and 100 mg) [19]. All three doses have been shown to be well tolerated and effective [20, 21], and level A evidence (medications recognized as effective based on clinical evidence) supports their use in the treatment of acute migraine [22]. Although three different doses are available, no guidance regarding a particular starting dose has been established. However, the US prescribing information advises that in patients with mild-to-moderate hepatic impairment the maximum dose should be 50 mg [19]. The label states that a sumatriptan dose of 50 or 100 mg may provide greater efficacy than the 25 mg dose, but the 100 mg dose may not provide a greater effect than the 50 mg dose [19]. As a result, selection of the initial triptan dose for acute migraine is driven by prescribers based on their clinical experience and the individual experiences of the patient. Given the less personal nature of telehealth and digital health clinics, and the potential for OTC availability of triptans, determining whether there are characteristics that could aid in the selection of an initial dose could be of value.

One key aspect in the decision to select a specific treatment is patient preference, which may comprise multiple considerations. Efficacy, speed of response, formulation, tolerability, and cost are all key drivers of patient preference in treating migraine [23]. Most studies of patient preference to date, however, have focused on patients’ attitudes and wants, rather than specifics of drug treatment [23]. Therefore, it may be beneficial to provide guidance on initial oral sumatriptan dose selection for the treatment of acute migraine in nontraditional settings, such as telehealth and other remote forms of medical care, and to inform individuals who wish to participate in the decision-making process. The objective of this post hoc analysis of two clinical studies that addressed dose selection [24, 25] was to determine whether relevant clinical and demographic factors exist to guide initial dose selection of oral sumatriptan in the treatment of acute migraine.

This comprehensive analysis of migraine- and non-migraine-related clinical factors, as well as demographic characteristics, in two clinical studies failed to identify predictors of oral sumatriptan dose preference. Although sex, urologic history, and psychological history were identified in Study 1 as possibly predictive of dose preference, they did not reach statistical significance. While sex as a predictive factor is plausible, there is no rationale for urologic and psychological history impacting dose preference; thus, these findings are likely anomalous. In Study 2, duration of migraine history, headache severity, height, and medical history of endocrine or neurologic disease were identified as possibly predictive, with history of endocrine disease being statistically significant. A relationship between some of the factors identified in Study 2 and migraine is possible. However, the lack of overlap between factors identified as possibly predictive between the two studies suggests that none are clinically important.

Previous analyses have found that only features of migraine itself, including headache severity at baseline, nausea, and photophobia/phonophobia, are predictive of 2 h response to triptans; numerous demographic and clinical variables have been found to be nonpredictive [28, 29]. Here, migraine-related baseline characteristics were not strongly associated with dose preference. Only duration of migraine history and headache severity were identified as possibly predictive of dose preference, but only in Study 2, and neither reached statistical significance. Consistent with studies of response to triptans [28, 29], no other clinical or demographic characteristics seem to have any impact on oral sumatriptan dose preference.

Overall, patients preferred a higher dose of oral sumatriptan of 50 or 100 mg rather than a lower 25 mg dose. In the original studies on which this analysis was based, better pain relief and faster pain relief were the primary reasons for preferring the higher doses, and poor tolerability was the main reason for decreasing the dose [24, 25]. In clinical trials, higher doses of sumatriptan have proven more effective than a lower 25 mg dose [30], but a 100 mg dose has not been shown to be more effective than the 50 mg dose [19]. However, sumatriptan 50 mg is associated with fewer adverse events than the 100 mg dose [30]. Altogether, these findings suggest that it would be difficult to offer specific guidance on initial sumatriptan dose selection. However, an initial trial of a moderate sumatriptan dose of 50 mg would be an appropriate starting point.

A strength of this analysis is that it was based on prospective, albeit historical, clinical studies designed to ascertain patient preference for sumatriptan dose [24, 25]. Because of the prospective nature of these studies, it was conceivable to test for a wide range of possible predictive factors using several statistical and machine-learning techniques. Importantly, the analysis has identified dose level as a potential key factor in treatment selection; this factor was omitted in previous analyses [23].

Several limitations of the study should be noted. Patients in Study 1 did not explicitly express a dose preference per se but, rather, elected to change or not change their dose to a lower or higher one. In addition, this was a post hoc analysis with limited statistical power. The sample size of patients who expressed a preference for the lower 25 mg dose of oral sumatriptan was small, limiting the ability to identify potential factors predictive of a preference for this lower dose. Populations in some patient groups, including male and non-White participants, were small, which could produce spurious findings. Furthermore, since the analysis was based on older studies, assessments of modern migraine metrics (e.g., Migraine Disability Assessment Test) were not captured. Although some of the predictive candidate factors derived from the original studies may have differed if the studies were conducted more recently, many of the factors remain relevant today (e.g., migraine characteristics and physical characteristics). Finally, the analysis did not differentiate between the 50 and 100 mg doses of oral sumatriptan, as their effectiveness may not be different [19, 30].

To our knowledge, this is the first analysis to have attempted to predict factors associated with preference for different triptan doses. While most patients preferred a higher oral sumatriptan dose of 50 or 100 mg, no migraine-related clinical or demographic characteristics, alone or in combination, were consistently (across studies) or strongly (within studies) associated with preference for oral sumatriptan dose level. Guidance on sumatriptan dosing should be based on clinical trial data as well as previous treatment experience with antimigraine therapies.