Abstract
Introduction
Individuals with headache choose over-the-counter (OTC) medications to relieve pain and associated symptoms. This real-world evidence study investigated the effect of three OTC headache treatments on headache intensity and the associated impairment of cognitive and functional parameters in headache sufferers in Germany, Brazil, and Japan.
Methods
This prospective, multinational, observational eDiary-based study included adults experiencing headache for ≥ 6 months, with ≥ 2 headache episodes per month requiring treatment and using one of the three OTC headache treatments (Germany: ibuprofen 400 mg + caffeine 100 mg; Brazil: dipyrone 1 g; Japan: ibuprofen 100 mg + caffeine 40 mg). The primary endpoint was change in headache intensity (11-point numeric rating scale [NRS]) from baseline (headache onset) to 2 h post-treatment. Secondary endpoints were association between NRS scores for headache intensity and for cognitive and functional parameters and change in these parameters from baseline to 2 h post-treatment.
Results
Of the 32,623 individuals screened, 1239 were enrolled in the study, with 607 having their first headache episode treated using one of the OTC treatments. Baseline demographics and characteristics were similar across the cohorts. At 2 h post-treatment, headache intensity significantly improved, with the mean change from baseline being 3.4 (3.1, 3.7, 95% confidence interval), 4.2 (3.9, 4.5), and 3.0 (2.7, 3.3) for German, Brazilian, and Japanese cohorts, respectively. Improvement was observed in all cognitive and functional parameters. The NRS score for headache intensity significantly predicted NRS scores of all cognitive and functional parameters (P < 0.0001).
Conclusions
The study shows that headache intensity significantly affects cognitive and functional aspects, as well as overall quality of life, for sufferers globally. It confirms the effectiveness of OTC medications and suggests using headache intensity as a self-assessment tool for symptom severity, highlighting the need for new parameters in the OTC domain to improve public health benefits.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-024-00703-5.
Keywords: Real-world evidence, Headache, Migraine, Over-the-counter medication, Consumer healthcare
Key Summary Points
| Why carry out the study? |
| There is limited understanding and guidance on how headache intensity affects cognitive and functional aspects and overall quality of life of headache sufferers, particularly upon the use of over-the-counter (OTC) medications. |
| Various randomized controlled trials have demonstrated the efficacy of these OTC medications; nevertheless, their efficacy may not directly translate into their effectiveness in clinical settings. |
| What was learned from the study? |
| This real-world evidence study confirms the role of OTC medications in alleviating headache intensity and their impact on cognitive and functional abilities in a large sample of headache sufferers across Germany, Brazil, and Japan. |
| The findings of this study highlight the need for new parameters to measure symptom severity for better treatment outcomes in headache sufferers. |
Introduction
Headache disorders present diverse phenotypes, each characterized by distinct clinical features. The International Classification of Headache Disorders (ICHD-3) divides headache disorders into primary and secondary categories, encompassing various headache types including migraine, tension-type headache, and trigeminal autonomic cephalalgias. The classification also includes neuropathies, facial pain, and other specific headache conditions [1]. Altogether, they are one of the most common drivers of disability, affecting 3.1 billion individuals globally [2]; their impact on the patients goes beyond the debilitating pain, as they impair cognitive function [3, 4], productivity [5–7], and overall quality of life (QoL) [4], incurring significant global burden [8] and healthcare costs [9–11]. A multinational descriptive analysis of the real-world burden of headache, which used the “Migraine Buddy” application, revealed that over one-third of 24,763 users experienced up to five episodes of headache or migraine per month, impacting their QoL through impaired concentration, being slower in their daily activities, and missing work or social activities [4].
Headache is one of the most common causes of self-medication worldwide [12, 13] because it is considered a minor ailment [14–16], and the consulting behavior of the sufferers depends on various factors, such as pain intensity, number of accompanying symptoms, disabilities due to headache, and attack frequency [17]. A recent prospective real-world study reported that 98.3% of the 350 participants used over-the-counter (OTC) analgesics for the treatment of headache symptoms, even after being prescribed medication for headache. Among the most recommended OTC medications for self-management of headache are metamizole (dipyrone) [18, 19], aspirin, acetaminophen (paracetamol), and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen [20]. Moreover, combination medications containing caffeine [21], aspirin [22], and acetaminophen [23] are beneficial for some types of headache, particularly tension-type headache [24]. However, their use for the management of headache disorders could vary among countries due to differences in healthcare systems, regulations, and cultural practices [25].
Furthermore, the efficacy of these OTC medications, proven by various randomized controlled trials (RCTs), may not directly translate into their effectiveness in real-life settings. Real-world evidence (RWE) studies complement RCTs by providing insights into treatment effectiveness, safety, and generalizability beyond controlled environments, guiding evidence-based medicine [26]. Moreover, the guidelines for RCTs on headache disorders underscore the importance of secondary assessment of a sufferer’s cognitive and functional impairment [27, 28] because these disorders negatively impact “mental clarity,” which involves concentration, attention, reading, processing speed, and memory [3, 29]. Most previous studies assessing the effectiveness of OTC medications for cognitive and functional parameters in headache sufferers typically included small sample sizes ranging from 10 to 75 participants [3, 30–32]. This indicates a relative scarcity of RWE on how OTC headache medications directly affect cognitive and functional parameters in headache sufferers.
Considering the above, in the present study, we investigated the effect of three local active pharmaceutical ingredients (APIs) on headache intensity and the associated impairment of cognitive and functional parameters for headache sufferers in three different geographical regions, namely the European Union, Latin America, and Asia. These regions have different healthcare systems and cultural perspectives, which may influence cognitive and functional outcomes. We included large cohorts of participants experiencing headache in Germany, Brazil, and Japan and assessed the endpoints recommended by the guidelines for RCTs on migraine and tension-type headache [4, 27, 28, 33]. The primary objective was to assess the real-world impact of OTC treatments on headache intensity using the established pain numeric rating scale (NRS) score. The secondary objectives were to describe the association between headache intensity and cognitive and functional parameters, and to describe the real-life impact of OTC treatments on these parameters. The study was reported in its preliminary form at the 16th European Headache Congress (Vienna, Austria, 07–10 December 2022) [34].
Methods
Study Design
The study was a prospective, multinational, observational study conducted from 27 May 2021 to 17 October 2022. The study (21062-01) was submitted and approved by the US Institutional Review Board (IRB): Ethical and Independent (E&I) Review Services, which is now known as Salus IRB. The study was approved by local ethics committees in Germany, Brazil, and Japan. All participants provided informed consent electronically before initiation of data collection.
Study Population
Potential participants from Germany, Brazil, and Japan were pre-identified by an external vendor (SurveyEngine GmbH; https://surveyengine.com), using targeted email campaigns, internet banners, and pop-up ads to recruit a survey panel. The inclusion criteria were as follows: participants aged ≥ 18 years and experiencing headache for ≥ 6 months, with ≥ 2 headache episodes per month requiring treatment; and those using ibuprofen 400 mg + caffeine 100 mg, dipyrone 1 g, or ibuprofen 100 mg + caffeine 40 mg (henceforth referred to as the OTC treatments) available locally in Germany, Brazil, and Japan, respectively.
The participants who were using other OTC medications for headache were excluded to reduce heterogeneity that would affect multiple other formulations. Those who were currently using prescription medications for headache and/or experiencing headache secondary to a specific illness, such as cold, flu, head injury, or hangover, were also excluded.
The enrolled set consisted of all participants who provided consent and met the study inclusion and exclusion criteria. The eligible set consisted of all enrolled participants who experienced at least one headache episode within 15 days after enrollment, and their pain intensity NRS score was assessed at baseline and 2 h post-treatment on an 11-point scale ranging from 0 to 10 for all the QoL parameters. The full analysis set (FAS) consisted of all eligible participants with a qualifying headache episode, defined as the first headache episode treated with one of the OTC treatments of interest, and their headache intensity NRS score was assessed at baseline and 2 h post-treatment.
Data Collection
The data were collected prospectively using the IMPACT-TED eDiary app. The participants answered the online sign-up survey (participant eDiary provided in Supplementary appendix) to learn about the panel and provide individual or household demographics. The study consisted of the following three periods (Fig. 1): enrollment period (day 1), during which the eligibility criteria were verified; observation period, from day 1 to the day of the first headache episode or a maximum period of 15 days; and the evaluation period, which began on the day of the first headache episode and included the next 14 days (total 15 days), and the data were collected at baseline and at 2 h after taking the OTC headache medication.
Fig. 1.
Study flow chart. OTC over-the-counter, NRS numeric rating scale. Responders: ≥30% decrease in pain intensity NRS score from baseline. Recovery: ≥20% improvement in NRS score from baseline to 2 h post−treatment
The parameters that were recorded at baseline before the administration of any medication included demographics, headache type, headache intensity, pain location, additional headache-related symptoms, cognitive impact, and functional impact. The parameters that were assessed at 1.5–2.5 h post-treatment were medication taken, timing of medication administration, other non-medicinal therapeutic approaches, headache intensity, cognitive impact, functional impact, impact on school/work, and impact on daily activities.
Study Endpoints
The primary endpoint was change in headache intensity from baseline (at headache onset) to 2 h post-treatment assessment for the qualifying headache episode (defined as the first episode treated with OTC treatment only), assessed via an 11-point NRS (0 = no pain, 10 = worst pain imaginable) [27, 28, 35]. The key secondary endpoints (2a) were the associations between headache intensity NRS scores and impact on cognitive and functional parameters, assessed using an NRS (0 = no impact, 10 = severe impact): QoL components such as ability to concentrate, be attentive, and focus (cognitive parameters); ability to be productive, coordinate multiple activities, and think clearly; and energy (functional parameters) [4]. Other secondary endpoints (2b) included change in impact of headache on the functional and cognitive parameters, which were assessed from baseline to 2 h post-treatment, and the impact of headache on daily activities, including work and school [33], assessed using single-answer (yes/no) questions. The primary and secondary (2b) endpoints were analyzed for the FAS, and secondary (2a) endpoints were analyzed for the eligible set.
Responder Analysis
The participants were considered responders if the change in their headache intensity NRS score from baseline was ≥ 30%. For cognitive and functional parameters, the participants were considered responders if the change in their NRS score from baseline was ≥ 20%.
Statistical Analysis
In the absence of prior study findings, an effect size (Cohen’s d) of 0.2 (i.e., a small effect [36]) was targeted as the minimum difference of interest and used for sample size calculation. For each country cohort, a sample size of 199 headache sufferers was required to achieve 80% power with an alpha level of 5% using a paired t-test. To achieve this target, up to 332 headache sufferers were planned to be enrolled in the study (i.e., drop-out rate of 40%). Thus, up to 996 headache sufferers were planned to be enrolled across all three countries.
All data were collected by the participants using an eDiary app in real time via standard data collection measures. Baseline demographics were listed and summarized using descriptive statistics. The pain NRS scores were categorized as severe if the respondent selected a score of 7–10 [35]. NRS scores were treated as continuous data, as is typical for pain studies, although the authors recognize their fundamentally ordinal nature.
For the primary effectiveness endpoint, a paired t-test was used to assess the change in mean NRS score at 5% significance level. Between-cohort comparisons were not performed in this study. The associations between cognitive and functional parameters and headache intensity were described using scatterplots, Kendall’s tau coefficient, and Kendall’s tau independence test. For all secondary endpoint analyses, a linear mixed-effects model was used to account for both baseline covariates as fixed effects, and the repeated observations at the patient and visit levels were used as random effects to assess the mean change in NRS scores. The treatment effects were adjusted on baseline parameters as severity and were confirmed considering these potential drivers.
Sensitivity analyses were conducted to confirm pain response and its effects. The responder/non-responder analysis was performed using binary definitions of response (≥ 30% for pain intensity) and recovery (≥ 20% for cognitive and functional parameters) as defined in the responder analysis section.
Results
Overall, 32,623 participants were screened for eligibility. In total, 1239 were included in the enrolled set (426, 361, and 452 from Germany, Brazil, and Japan, respectively). Of these, 880 were included in the eligible set (293, 261, and 326, respectively), and 607 were included in the FAS (202, 209, and 196, respectively). The main reason for exclusion from the FAS was absence of a headache episode treated only with one of the OTC treatments of interest and lack of assessment of headache intensity NRS score at baseline and 2 h post-treatment (Fig. 2; Supplementary Table 1).
Fig. 2.
Flowchart describing participants’ disposition. N represents the total number of participants screened and n represents the cohorts. *Reasons for exclusion are detailed in Supplementary Table 1
The baseline demographics and characteristics of the participants in the FAS are presented in Table 1. Overall, the mean (SD) age of the participants was 40.8 (10.7) years, which was similar across the three cohorts. A higher proportion of participants were female, except in the German cohort, where an almost equal number of male and female participants were enrolled. These proportions were consistent with the enrolled and eligible sets (overall and by country). Overall, 91.4% and 73.8% of participants complained of “headache” and “migraine,” respectively. Only 27.2% of participants were diagnosed with a headache by healthcare providers, and “self-decision” was the most common (94.1%) reason for using OTC headache treatments.
Table 1.
Demographics and characteristics of participants in the full analysis set
| Characteristic | FAS | |||
|---|---|---|---|---|
| Germany n = 202 |
Brazil n = 209 |
Japan n = 196 |
Overall n = 607 |
|
| Mean (SD) age, years | 42.8 (12.0) | 37.8 (9.2) | 41.9 (10.2) | 40.8 (10.7) |
| Female, n (%) | 102 (50.5) | 163 (78.0) | 142 (72.4) | 407 (67.1) |
| Employment status, n (%) | ||||
| Employed full-time | 142 (70.3) | 100 (47.8) | 105 (53.6) | 347 (57.2) |
| Employed part-timea | 29 (14.4) | 51 (24.4) | 39 (19.9) | 119 (19.6) |
| Not currently employed | 7 (3.5) | 42 (20.1) | 41 (20.9) | 90 (14.8) |
| Student | 4 (2.0) | 6 (2.9) | 5 (2.6) | 15 (2.5) |
| Retired | 20 (9.9) | 3 (1.4) | 2 (1.0) | 25 (4.1) |
| Time period experiencing headache, n (%) | ||||
| 6 months to 1 year ago | 17 (8.4) | 38 (18.2) | 1 (0.5) | 56 (9.2) |
| ≥ 1 year to < 2 years ago | 32 (15.8) | 82 (39.2) | 9 (4.6) | 123 (20.3) |
| ≥ 2 years ago | 153 (75.7) | 89 (42.6) | 186 (94.9) | 428 (70.5) |
| Type of headache usually experienced (self-reported), n (%) | ||||
| Headache | 200 (99.0) | 203 (97.1) | 152 (77.6) | 555 (91.4) |
| Migraine | 127 (62.9) | 151 (72.2) | 170 (86.7) | 448 (73.8) |
| Unknown | 3 (1.5) | 1 (0.5) | 11 (5.6) | 15 (2.5) |
| Diagnosis of headache by healthcare provider, n (%), yes | 82 (40.6) | 31 (14.8) | 52 (26.5) | 165 (27.2) |
| Headache frequency, n (%) | ||||
| Less than once per week | 23 (11.4) | 17 (8.1) | 41 (20.9) | 81 (13.3) |
| Once per week | 73 (36.1) | 61 (29.2) | 63 (32.1) | 197 (32.5) |
| Twice per week | 67 (33.2) | 60 (28.7) | 50 (25.5) | 177 (29.2) |
| Three times per week | 29 (14.4) | 35 (16.7) | 24 (12.2) | 88 (14.5) |
| More than three times per week | 10 (5.0) | 36 (17.2) | 18 (9.2) | 64 (10.5) |
| Reason for using local OTC headache treatments, n (%) | ||||
| Doctor prescription | 18 (8.9) | 15 (7.2) | 2 (1.0) | 35 (5.8) |
| Pharmacist’s recommendationa | 125 (61.9) | 97 (46.4) | 20 (10.2) | 242 (39.9) |
| Relative’s recommendation | 102 (50.5) | 133 (63.6) | 40 (20.4) | 275 (45.3) |
| Self-decision | 191 (94.6) | 193 (92.3) | 187 (95.4) | 571 (94.1) |
| Publicity | 72 (35.6) | 124 (59.3) | 171 (87.2) | 367 (60.5) |
| Other | 11 (5.4) | 12 (5.7) | 12 (6.1) | 35 (5.8) |
a39 or fewer hours per week
FAS full analysis set, OTC over-the-counter, SD standard deviation
At baseline, the overall study population exhibited a mean (95% confidence interval [CI]) pain NRS score of 5.8 (5.6, 5.9). NRS scores were skewed toward moderate and severe pain, with 45.1% of participants reporting an NRS score of 4–6 (moderate pain) and 38.2% reporting an NRS score of ≥ 7 (severe pain). No participants were pain-free at baseline. The mean (95% CI) pain NRS score at baseline was 5.8 (5.6, 6.1), 6.5 (6.3, 6.8), and 4.9 (4.7, 5.2) in the German, Brazilian, and Japanese participants, respectively (Fig. 3). NRS scores were skewed toward moderate (51.0% and 34.4%) and severe pain (35.6% and 56.5%) for German and Brazilian participants, respectively. In the Japanese participants, baseline NRS scores were skewed toward moderate (50.5%) and mild (28.1%) pain.
Fig. 3.
Mean value and mean change in pain numeric rating scale (NRS) scores from baseline to 2 h post-treatment for participants from Germany, Brazil, and Japan in the full analysis set, considering that the first headache episode was treated using one of the over-the-counter (OTC) treatments of interest. †Change was calculated as NRS score at baseline minus NRS score at 2 h post−treatment. Positive change score indicates improvement in pain. *From paired t-test
Primary Endpoint Analysis
At 2 h post-treatment, the mean (95% CI) pain NRS score decreased from 5.8 (5.6, 5.9) to 2.2 (2.1, 2.4), with most participants (77.2%) reporting an NRS score of ≤ 3. The mean change (95% CI) in pain NRS score from baseline to 2 h post-treatment was 3.6 (3.4, 3.7), indicating a significant improvement in pain (P < 0.0001). Improvement in pain NRS scores was observed in the participants from all three countries (Fig. 3). The mean (95% CI) pain NRS score decreased from 5.8 (5.6, 6.1) to 2.4 (2.2, 2.7), from 6.5 (6.3, 6.8) to 2.3 (2.0, 2.7), and from 4.9 (4.7, 5.2) to 1.9 (1.6, 2.2) in the German, Brazilian, and Japanese participants, respectively. A majority of participants reported an NRS score of ≤ 3 (74.2%, 75.6%, and 82.1% for Germany, Brazil, and Japan, respectively). The mean change (95% CI) in pain NRS score from baseline to 2 h post-treatment was 3.4 (3.1, 3.7), 4.2 (3.9, 4.5), and 3.0 (2.7, 3.3) for German, Brazilian, and Japanese participants, respectively, indicating a significant improvement in pain (all P < 0.0001) (Fig. 3).
Overall, 24.4% of participants reported no more pain (NRS score = 0) at 2 h post-treatment. In the German, Brazilian, and Japanese cohorts, 17.3%, 29.7%, and 26.0% of participants, respectively, reported no pain at 2 h post-treatment.
Secondary Endpoint Analyses
At baseline, Kendall’s tau coefficient revealed a significant (P < 0.0001) correlation between all cognitive and functional parameters and headache intensity in all participants. At 2 h post-treatment, a significant association was observed between headache intensity and all parameters among German and Japanese participants. For Brazilian participants, a significant association was observed between the ability to concentrate and the ability to focus (Fig. 4; Supplementary Table 2).
Fig. 4.
Scatterplots showing the relationship between pain intensity numeric rating scale (NRS) score and cognitive and functional parameter NRS scores at baseline (red) and 2 h post-treatment (blue) in the eligible set in German, Brazilian, and Japanese cohorts (from left to right). On each scatterplot, the pain intensity NRS score is shown on the x-axis, and the functional/cognitive parameter NRS score is shown on the y-axis. Each axis ranges from −1 to 11
In the FAS, the mean changes in pain NRS scores from baseline to 2 h post-treatment for cognitive and functional parameters ranged from 3.5 to 3.6 and from 3.4 to 3.8 in German participants; 3.6–3.7 and 3.7–3.9 for Brazilian participants, and 3.2–3.3 and 3.4–3.6 for Japanese participants, respectively. A significant (P < 0.0001) improvement was observed for all cognitive and functional parameters from baseline to 2 h post-treatment (Fig. 5).
Fig. 5.
Cognitive and functional parameters assessed before and after headache treatment, considering all headache episodes were treated using one of the over-the-counter (OTC) treatments of interest among the participants in the full analysis set from (A) Germany (n = 495 episodes), (B) Brazil (n = 746 episodes), and (C) Japan (n = 477 episodes). NRS, numeric rating scale
At 2 h post-treatment, the number of episodes with moderate-to-severe impact (NRS score: 7–10) on all cognitive and functional parameters was reduced from that at baseline among all participants. Across all seven parameters, the proportion of participants reporting recovery of optimal functional and cognitive parameters with pain relief (NRS score = 0) was 25–30% in all three country cohorts; 80–90% of participants reported a mild impact (NRS score < 5) after 2 h of treatment.
The participants reported that their headache episodes (n = 1718) resulted in inability to attend (11.8% of total episodes) and/or impaired performance (34.2% of total episodes) at work/school. Headache episodes were also associated with missed social activities (30.1% of total episodes) and family time (23.9% of total episodes), inability to use electronic devices (39.5% of total episodes), slower performance of home duties (61.4% of total episodes), and inability to function (30.6% of total episodes). The participants who rated their headache as “severe” reported greater impact on work/school activities (Supplementary Table 3).
Sensitivity Analyses
A responder/non-responder analysis of associations between categorized NRS pain scores and changes from baseline to 2 h post-treatment revealed that > 80% of participants in each of the three cohorts experienced ≥ 30% reduction in headache intensity from baseline and were defined as “responders.” Among the responders, > 91% achieved meaningful (≥ 20%) improvement in all functional and cognitive parameters from baseline across all three cohorts (Supplementary Table 4).
There were 510 NRS pain responders; among this responder group, over 93% had recoveries in the seven cognitive and functional measures. Reduction in severity of impact was observed across all parameters in all three cohorts.
Discussion
In the present study, the participants reported impairment of all assessed cognitive and functional parameters before taking the OTC medications, and the impairment was correlated with headache intensity. Furthermore, the medications significantly reduced headache intensity and positively impacted all cognitive and functional parameters of the participants.
Additionally, the association between reduction in headache intensity and improvement in cognition and overall functioning confirmed that headache intensity was a significant predictor of all cognitive and functional parameters; an almost one-to-one relationship was also observed between headache intensity NRS score and the seven QoL parameters. All cognitive (three) and functional (four) parameters were significantly improved, with headache intensity treatment exhibiting the maximum positive impact on the participants’ ability to concentrate (cognitive) and energy (functional).
The findings of our study are consistent with the results from previous real-world and randomized studies and build on a growing evidence base, revealing the added impacts of headaches and benefits of OTC treatments. A recent 12-week-long, single-arm RWE study, based on data from wearable activity trackers and questionnaires, reported that headache has a significant negative impact on daily life and activity [17]; it also reported that OTC pain relievers are the preferred treatment choice of people experiencing headache and that self-treatment decisions are highly influenced by symptom severity [17].
A prospective, randomized, crossover study reported that the cognitive performance of individuals decreases during migraine attacks, particularly reading and processing speed, verbal memory, and learning [3]. Furthermore, an open-label, single-attack study including 28 people with acute migraine reported that sumatriptan injection 6 mg during the attack improved impaired cognitive functioning [31, 37]. Two other studies that investigated the impact of headache on cognitive performance reported an association between headache intensity and cognitive function [30, 32]. However, these studies reported conflicting opinions regarding whether the negative impact of headache intensity on cognitive function is dependent on the type of task being performed. Moore et al. concluded that headache intensity impairs general task performance, irrespective of the task complexity [32], whereas Attridge et al. concluded that the effect of headache intensity is dynamic, even within a given type of pain [30].
Furthermore, this real-world study including participants from Germany, Brazil, and Japan reported similar responses across all geographies, despite the cultural differences and variability in approaches to assessing and treating headache. This suggests that the relationship between headache intensity and the cognitive parameters is ubiquitous and independent of culture-specific behaviors or influences, indicating scope for generalizability of our results to these three as well as other countries.
Strengths and Limitations
This is the first real-world study to confirm the effect of the most widely available OTC medications on headache intensity and on cognitive and functional parameters in a large sample of headache sufferers. The study design is based on the available guidelines for conducting controlled trials on migraine and tension-type headache [27, 28] due to the lack of specific recommendations for conducting RWE studies in this therapeutic area. The NRS scores clinically validated for the assessment of headache intensity are intuitive for headache sufferers and have well-established cross-cultural utility [38]. In the present study, we aimed to scale the assessment of impacts on cognitive and functional parameters to the established assessment of headache perception by anchoring to the validated pain impact scale, thereby demonstrating the relationships between reduction of headache and impact on these parameters and providing evidence in support of the hypothesis that these are due to a true effect (as opposed to a placebo effect).
For predefined analyses, NRS scores were treated as a continuous variable. This is consistent with the results of major randomized trials that have used NRS pain scores as primary outcome measures [39, 40]; however, we acknowledge that this could be considered interpretation bias. Nevertheless, the findings of the sensitivity analysis, conducted on a categorical basis, as well as the responder/non-responder sensitivity analysis supported the findings of the main analyses. Our responder definitions were based on those typically used in chronic disease; the definitions are therefore conservative when applied to the benefits of treatment for an acute condition, such as headache. However, although the responses were assessed just 2 h post-treatment, meaningful pain relief was observed in ≥ 80% of participants.
As anticipated for this type of digital study conducted in a real-world setting [41] and as outlined in Table 1, the delay between recruitment and active participation affected dropout rates. This highlights the difficulty in recruiting participants who meet the eligibility criteria to form a representative consumer panel, subsequently causing delays in achieving the desired sample size. Furthermore, including only those with > 1 attack per month may have also contributed to the dropouts.
In addition, the included participants may not be representative of the general population in each country, and since the study involved the use of an eDiary app, the inclusion of participants may have been biased in ways that are not apparent from the summarized demographic data, i.e., selection of participants with greater affinity for technology. However, the inherent sampling limitations [42] of the web-based survey were not deemed to significantly affect our conclusions, owing to the enhanced suitability and user-friendliness of digital apps for evaluating pain impact and related lifestyle factors [43]. No attempts were made to corroborate the participant-reported data. This was because only the participants could accurately record their experiences and the impact of OTC treatment on headache intensity and cognitive and functional parameters. Moreover, external verification of reported data was not considered to be appropriate or valid.
Another possible limitation is that the full analysis used only the first headache episode reported during the 15-day evaluation period, which was treated using one of the OTC medications. However, all headache episodes during the 15-day period in the enrolled set were considered for secondary analyses, and the improvement in headache intensity and in the cognitive and functional parameters were reported for those episodes. Another limitation is that the responses were only assessed at one time point post-treatment (1.5–2.5 h), and thus the timing of headache relief was not evaluated. Although this study reports a high level of headache relief at 2 h post-treatment, suggesting that headache relief was initiated prior to this time point, further studies should be performed to identify the initiation point of headache relief.
Moreover, cognitive and functional categories were defined based on prior medical feedback; NRS was used due to the unavailability of any other tool to assess the parameters included in this real-world study. This emphasizes the need for an objective assessment of these parameters, by measuring performance in a test paradigm. Furthermore, treatment benefits could not be confirmed by headache type due to the variability in the index event experienced by the participants. Most participants in Germany and Brazil reported general headache, whereas those in Japan reported both general headache and migraine. Moreover, differences were observed in the percentage of participants diagnosed with headache by healthcare providers from each country (Germany: 40.6%; Brazil: 14.8%; Japan: 26.5%), which could be attributed to various OTC headache treatments or societal and/or healthcare system differences.
The parameters assessed in this study could serve as a self-administered and disease-related outcome tool to measure the severity of symptoms that impact functional and cognitive parameters in individuals experiencing headache; thus, they could be included in future studies to define the QoL of individuals experiencing headache.
Conclusion
This study highlights the significant impact of headache intensity on cognitive and functional aspects and on the overall QoL for headache sufferers. The results emphasize the role of OTC medications in managing headaches, based on data from a large sample of individuals with headache in Germany, Brazil, and Japan, which consequently impact clinical practice by highlighting patient preferences for accessible treatments, revealing risks like medication-overuse headache, and guiding clinicians to tailor treatment strategies. Moreover, the study suggests that headache intensity could be used as a self-administered tool to measure symptom severity, underscoring the need for new parameters in the OTC domain to improve public health outcomes for headache sufferers, which could lead to better treatment strategies and outcomes.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors wish to thank the participants and centers that participated in this study; Sanofi local employees from Germany, Brazil, and Japan; and the Global Communication team for their support.
Authorship
All authors adhere to the guidelines for authorship adapted from ICMJE, Defining the Role of Authors and Contributors, Transparency in authors’ contributions and responsibilities to promote integrity in scientific publication.
Medical Writing, Editorial, and Other Assistance
The preparation of the manuscript (medical writing) was supported by Ian C Grieve, PhD, of Ashfield MedComms, an Inizio company, Macclesfield, UK, and Meena Ravuri, an employee of Opella, A Sanofi Company.
Authors’ Contributions
Peter J. Goadsby, Andrew Stewart, Mamoru Shibata, Mario Fernando Prieto Peres, Caroline Amand, Andreas Straube, and Luminita Constantin were involved in the conception and study design via advisory boards. Chris Colby, Mary Kay Margolis, Valentine Polivka, Caroline Amand, Luminita Constantin, and Andrew Stewart were additionally involved in the acquisition, data analysis, and data interpretation. All authors critically reviewed the manuscript for important intellectual content and are responsible for the decision to submit it for publication. All authors have read and approved the final manuscript.
Funding
This study was funded by Sanofi. The funding body conceptualized and designed the study. Data collection was performed by Evidera and sponsored by Sanofi. Data/statistical analysis was performed by Sanofi and Evidera. The journal’s Rapid Service Fee was funded by Opella, a Sanofi Company.
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
Peter J. Goadsby reports, over the last 36 months, personal fees from Sanofi; grant from Kallyope, and personal fees from Aeon Biopharma, AbbVie, Aurene, CoolTech LLC, Dr Reddy’s, Eli Lilly and Company, Linpharma, Lundbeck, Pfizer, PureTech Health LLC, Satsuma, ShiraTronics, Teva Pharmaceuticals, Tremeau, and Vial; personal fees for advice from Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters; and publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer. Peter J. Goadsby is an Editorial Board member of Pain and Therapy. He was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Andrew Stewart has received honoraria for advisory boards and educational talks from Allergan/AbbVie, AllergoSan, Eli Lilly, Lundbeck, Novartis, Sanofi, and Teva. Mamoru Shibata has no competing interests. Mario Fernando Prieto Peres has received personal fees from Ache, Allergan/AbbVie, Eli Lilly, Eurofarma, Libbs, Lundbeck, Novartis, Pfizer, Sanofi, and Teva, and has received research support from Allergan/AbbVie, Eli Lilly, Eurofarma, Janssen-Cilag, Libbs, Natura, Novartis, and Teva. Mary Kay Margolis is a former employee of PPD, part of Thermo Fisher Scientific, which provides consulting and other research services to pharmaceutical, device, government, and non-government organizations. As a PPD employee, she worked with a variety of companies and organizations and was expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. Chris Colby is an employee of PPD, part of Thermo Fisher Scientific. Valentine Polivka is an employee of the AIXIAL Group, an ALTEN company, which provides statistical consulting and research services to Sanofi, and has no other competing interests. Luminita Constantin, Caroline Amand, and Andrew Stewart are currently employees of Sanofi and may hold shares and/or stock options in the company.
Ethical Approval
The study (21062-01) was submitted and approved by the US Institutional Review Board (IRB): Ethical and Independent (E&I) Review Services, which is now known as Salus IRB. The study was approved by local ethics committees in Germany, Brazil, and Japan. All participants provided informed consent electronically before initiation of data collection.
Footnotes
Prior presentation: The manuscript is based on work that was reported in its preliminary form at the 16th European Headache Congress (Vienna, Austria, 07–10 December 2022).
References
- 1.Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. 10.1177/0333102417738202 [DOI] [PubMed]
- 2.GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–858. 10.1016/s0140-6736(18)32279-7. [DOI] [PMC free article] [PubMed]
- 3.Gil-Gouveia R, Oliveira AG, Martins IP. Cognitive dysfunction during migraine attacks: a study on migraine without aura. Cephalalgia. 2015;35(8):662–74. 10.1177/0333102414553823. [DOI] [PubMed] [Google Scholar]
- 4.Goadsby PJ, Constantin L, Ebel-Bitoun C, et al. Multinational descriptive analysis of the real-world burden of headache using the Migraine Buddy application. Eur J Neurol. 2021;28(12):4184–93. 10.1111/ene.15037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Begasse de Dhaem O, Sakai F. Migraine in the workplace. NeurologicalSci. 2022;27:100408. 10.1016/j.ensci.2022.100408. [DOI] [PMC free article] [PubMed]
- 6.Kothari SF, Jensen RH, Steiner TJ. The relationship between headache-attributed disability and lost productivity: 1. A review of the literature. J Headache Pain. 2021;22(1):73. 10.1186/s10194-021-01264-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Thomas H, Kothari SF, Husøy A, et al. The relationship between headache-attributed disability and lost productivity: 2. Empirical evidence from population-based studies in nine disparate countries. J Headache Pain. 2021;22(1):153. 10.1186/s10194-021-01362-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Saylor D, Steiner TJ. The global burden of headache. Semin Neurol. 2018;38(2):182–90. 10.1055/s-0038-1646946. [DOI] [PubMed] [Google Scholar]
- 9.Bonafede M, Sapra S, Shah N, et al. Direct and indirect healthcare resource utilization and costs among migraine patients in the United States. Headache. 2018;58(5):700–14. 10.1111/head.13275. [DOI] [PubMed] [Google Scholar]
- 10.Linde M, Gustavsson A, Stovner LJ, et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012;19(5):703–11. 10.1111/j.1468-1331.2011.03612.x. [DOI] [PubMed] [Google Scholar]
- 11.Lipton RB, Lee L, Saikali NP, Bell J, Cohen JM. Effect of headache-free days on disability, productivity, quality of life, and costs among individuals with migraine. J Manag Care Spec Pharm. 2020;26(10):1344–52. 10.18553/jmcp.2020.20103. [DOI] [PMC free article] [PubMed]
- 12.Shehnaz SI, Agarwal AK, Khan N. A systematic review of self-medication practices among adolescents. J Adolesc Health. 2014;55(4):467–83. 10.1016/j.jadohealth.2014.07.001. [DOI] [PubMed] [Google Scholar]
- 13.Sobotka JL, Kochanowski BA. Chapter 1: Self-Care and Nonprescription Pharmacotherapy. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care, 20th Edition. Washington, DC: American Pharmacists Association; 2020.
- 14.Lantéri-Minet M, Massiou H, Nachit-Ouinekh F, et al. The GRIM2005 study of migraine consultation in France I. Determinants of consultation for migraine headache in France. Cephalalgia. 2007;27(12):1386–97. 10.1111/j.1468-2982.2007.01426.x. [DOI] [PubMed] [Google Scholar]
- 15.Lipton RB, Serrano D, Holland S, et al. Barriers to the diagnosis and treatment of migraine: effects of sex, income, and headache features. Headache. 2013;53(1):81–92. 10.1111/j.1526-4610.2012.02265.x. [DOI] [PubMed] [Google Scholar]
- 16.Wang SJ, Fuh JL, Young YH, Lu SR, Shia BC. Frequency and predictors of physician consultations for headache. Cephalalgia. 2001;21(1):25–30. 10.1046/j.1468-2982.2001.00138.x. [DOI] [PubMed] [Google Scholar]
- 17.Cerrada CJ, Min JS, Constantin L, et al. A prospective real-world study exploring associations between passively collected tracker data and headache burden among individuals with tension-type headache and migraine. Pain Ther. 2022;11(1):153–70. 10.1007/s40122-021-00336-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Benseñor IM. To use or not to use dipyrone? Or maybe, Central Station versus ER? That is the question. Sao Paulo Med J. 2001;119(6):190–1. 10.1590/s1516-31802001000600001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Stromer W, Palladini M. Metamizole: A comprehensive approach to its benefit-risk profile. Evidence for Self-Medication. 2022;2. 10.52778/efsm.22.0153.
- 20.Peck J, Urits I, Zeien J, et al. A comprehensive review of over-the-counter treatment for chronic migraine headaches. Curr Pain Headache Rep. 2020;24(5):19. 10.1007/s11916-020-00852-0. [DOI] [PubMed] [Google Scholar]
- 21.Lipton RB, Diener HC, Robbins MS, Garas SY, Patel K. Caffeine in the management of patients with headache. J Headache Pain. 2017;18(1):107. 10.1186/s10194-017-0806-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Schramm SH, Moebus S, Özyurt Kugumcu M, et al. Use of aspirin combinations with caffeine and increasing headache frequency: a prospective population-based study. Pain. 2015;156(9):1747–54. 10.1097/j.pain.0000000000000239. [DOI] [PubMed] [Google Scholar]
- 23.Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: The American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3–20. 10.1111/head.12499. [DOI] [PubMed] [Google Scholar]
- 24.Diener H-C, Gold M, Hagen M. Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies. J Headache Pain. 2014;15(1):76. 10.1186/1129-2377-15-76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Marathe PA, Kamat SK, Tripathi RK, Raut SB, Khatri NP. Over-the-counter medicines: Global perspective and Indian scenario. J Postgrad Med. 2020;66(1):28–34. 10.4103/jpgm.JPGM_381_19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol. 2014;5(1): e45. 10.1038/ctg.2013.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bendtsen L, Bigal ME, Cerbo R, et al. Guidelines for controlled trials of drugs in tension-type headache. Cephalalgia. 2010;30(1):1–16. 10.1111/j.1468-2982.2009.01948.x. [DOI] [PubMed] [Google Scholar]
- 28.Diener HC, Tassorelli C, Dodick DW, et al. Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults. Cephalalgia. 2019;39(6):687–710. 10.1177/0333102419828967. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Smith AP. Acute tension-type headaches are associated with impaired cognitive function and more negative mood. Front Neurol. 2016;7:42. 10.3389/fneur.2016.00042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Attridge N, Eccleston C, Noonan D, Wainwright E, Keogh E. Headache impairs attentional performance: a conceptual replication and extension. J Pain. 2017;18(1):29–41. 10.1016/j.jpain.2016.09.007. [DOI] [PubMed] [Google Scholar]
- 31.Farmer K, Cady R, Bleiberg J, Reeves D. A pilot study to measure cognitive efficiency during migraine. Headache. 2000;40(8):657–61. 10.1046/j.1526-4610.2000.040008657.x. [DOI] [PubMed] [Google Scholar]
- 32.Moore DJ, Keogh E, Eccleston C. Headache impairs attentional performance. Pain. 2013;154(9):1840–5. 10.1016/j.pain.2013.06.006. [DOI] [PubMed] [Google Scholar]
- 33.Leonardi M, Raggi A. A narrative review on the burden of migraine: when the burden is the impact on people’s life. J Headache Pain. 2019;20(1):41. 10.1186/s10194-019-0993-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Constantin L, Armand-Bourdon C, Polivka V, et al. A prospective observational real-world evidence (RWE) study to describe the impact of OTC headache treatments on headache intensity and the association of headache intensity on functional and cognitive parameters. J Headache Pain. 2022;23(1):192. 10.1186/s10194-022-01527-4. [Google Scholar]
- 35.Jensen MP, Turner JA, Romano JM, Fisher LD. Comparative reliability and validity of chronic pain intensity measures. Pain. 1999;83(2):157–62. 10.1016/s0304-3959(99)00101-3. [DOI] [PubMed] [Google Scholar]
- 36.Cohen J. Statistical power analysis for the behavioral sciences, 2nd edn. Lawrence Erlbaum Associates; 1988.
- 37.Farmer K, Cady R, Bleiberg J, et al. Sumatriptan nasal spray and cognitive function during migraine: results of an open-label study. Headache. 2001;41(4):377–84. 10.1046/j.1526-4610.2001.111006377.x. [DOI] [PubMed] [Google Scholar]
- 38.Loder E, Burch R. Measuring pain intensity in headache trials: which scale to use? Cephalalgia. 2012;32(3):179–82. 10.1177/0333102411434812. [DOI] [PubMed] [Google Scholar]
- 39.Horne AW, Vincent K, Hewitt CA, et al. Gabapentin for chronic pelvic pain in women (GaPP2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2020;396(10255):909–17. 10.1016/s0140-6736(20)31693-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Tesfaye S, Sloan G, Petrie J, et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. Lancet. 2022;400(10353):680–90. 10.1016/s0140-6736(22)01472-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Walsh EI, Brinker JK. Rapid communication: delay between recruitment and participation impacts on preinclusion attrition. Quart J Exp Psychol. 2015;68(4):635–40. 10.1080/17470218.2015.1008019. [DOI] [PubMed] [Google Scholar]
- 42.Wright KB. Researching internet-based populations: advantages and disadvantages of online survey research, online questionnaire authoring software packages, and web survey services. J Comput-Mediat Commun. 2017;10:3. 10.1111/j.1083-6101.2005.tb00259.x. [Google Scholar]
- 43.Bälter O, Fondell E, Bälter K. Feedback in web-based questionnaires as incentive to increase compliance in studies on lifestyle factors. Public Health Nutr. 2012;15(6):982–8. 10.1017/s1368980011003041. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.