Abstract
Objective
To investigate whether early administration of sumatriptan prevents migraine induced by ATP-sensitive potassium (KATP) channel opener levcromakalim.
Methods
This single-centre, randomised, double-blind, placebo-controlled, two-way crossover study included adults with migraine without aura. Participants received a 20-minute intravenous infusion of levcromakalim on two separate occasions, followed immediately by a 10-minute intravenous infusion of either sumatriptan or placebo (isotonic saline) in a balanced allocation. The primary endpoint was the difference in the incidence of levcromakalim-induced migraine aftersumatriptan versus placebo over 12 hours. A secondary endpoint was the area under the curve (AUC) for headache intensity scores between experimental days.
Results
Twenty of 24 participants completed the study. The incidence of migraine induced by levcromakalim was 75% following sumatriptan and 85% following placebo (p = 0.69). The AUC for headache intensity scores showed no difference between sumatriptan and placebo days (p = 0.12). Post-hoc analyses correcting for intensity at 40 minutes post-levcromakalim revealed a significantly lower AUC for headache intensity following sumatriptan compared with placebo (p = 0.002).
Conclusions
Early sumatriptan treatment does not prevent migraine induced by KATP channel opening, suggesting that KATP-induced migraine occurs downstream of sumatriptan's site of action. However, sumatriptan reduces headache intensity, warranting further exploration of its modulatory effects.
This is a visual representation of the abstract.
Introduction
Migraine is a disabling neurological disorder affecting more than one billion people globally (1) and characterised by recurrent attacks of moderate to severe headache, often accompanied by photophobia, phonophobia, nausea and vomiting (1). Despite recent advances in migraine research, the neurobiologic underpinnings remain incompletely understood, limiting the development of targeted, mechanism-based treatments (1–3).
Sumatriptan, a selective serotonin 5-HT1B/1D receptor agonist, is a cornerstone in the acute treatment of migraine attacks (4–6). Its mechanism of action involves constriction of cranial arteries (6,7) and inhibition of neuropeptide release (6). Pioneering preclinical experiments have also demonstrated that sumatriptan disrupts the nociceptive signalling between first- and second-order trigeminal neurons (6,8), comprising essential components of the ascending cephalic pain pathways (1). Human experimental studies have further shown that early administration of sumatriptan can mitigate headache induced by molecular migraine triggers, such as pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (9,10).
Recent studies have implicated the opening of ATP-sensitive potassium (KATP) channels in migraine pathogenesis (11–14). Levcromakalim, a KATP channel opener and potent dilator of cranial arteries, has been shown to induce migraine in people with migraine and mild or no headache in healthy adults (11–14). Conversely, a recent experimental investigation reported that NN414, a selective non-vascular KATP channel opener acting on neurons, failed to induce migraine attacks in people with migraine (15). These findings suggest that levcromakalim induces migraine attacks by opening of KATP channels on vascular smooth muscle cells (VSMCs) within the walls of cranial arteries.
Here, we conducted a randomised, double-blind, placebo-controlled, two-way crossover study in adults diagnosed with migraine without aura aiming to evaluate whether early administration of sumatriptan could prevent migraine attacks induced by levcromakalim. We hypothesised that sumatriptan would prevent the migraine-inducing effects of KATP channel opening.
Methods
The study protocol was approved by the Regional Health Research Ethics Committee of the Capital Region of Denmark (H-21011542) and registered on ClinicalTrials.gov (NCT05211050). The study was conducted at a single centre in Denmark, in accordance with the Declaration of Helsinki with later revisions. All participants provided written informed consent before any study-related assessments or procedures. This study adheres to the CONSORT reporting guidelines (16).
Design
This study applied a randomised, double-blind, placebo-controlled, two-way crossover design involving adults diagnosed with migraine without aura. Potential participants attended an initial screening visit to determine eligibility. Eligible participants were scheduled for two experimental days where they received an intravenous (IV) infusion of levcromakalim on both study days, followed immediately by a 10-minutes IV infusion of either sumatriptan or placebo (isotonic saline) in a random and balanced manner. On the alternate experimental day, participants received the other intervention, ensuring that each participant received both interventions (Figures 1 and 2). A period of at least one week separated the two experimental days to ensure sufficient washout and avoid carry-over.
CONSORT 2010 Flow Diagram.
Study design.
Participants
The inclusion criteria required participants to be adults (≥18 years of age) diagnosed with migraine without aura in accordance with the International Classification of Headache Disorders, 3rd edition (ICHD-3) (17). Furthermore, eligible participants had to report an average of one to five migraine attacks per month over the past year. The main exclusion criteria were a history of any other primary or secondary headache disorder, except for episodic tension-type headache occurring on five or fewer days per month. Potential participants were also excluded if they reported daily intake of any medication other than oral contraceptives. A complete account of the inclusion and exclusion criteria is available in the supplemental material.
Randomisation and blinding
Participants were randomly allocated to receive IV sumatriptan or placebo of identical appearances on the first experimental day and the alternate intervention on the second day. The randomisation code was generated by independent staff at the study site, using a computer-generated randomisation schedule with a block size of six. Both site investigators and participants were masked to drug allocation. The randomisation code was kept in a lightproof envelope in a locked cabinet until study completion, with separate envelopes prepared for each participant in case of emergency unblinding.
Levcromakalim was synthesised and supplied as a powder by Sigma-Aldrich, then sterilised and packaged at the Hospital Pharmacy of the Capital Region of Denmark. Sumatriptan was procured as 12 mg/ml Imigran injection from GlaxoSmithKline Pharma A/S. The preparation of IV sumatriptan or placebo was performed by independent staff at the study site to maintain blinding.
Procedures
At the screening visit, site investigators conducted a semi-structured interview to collect baseline characteristics and medical history, performed a neurological examination, measured vital signs and obtained a 12-lead electrocardiogram. The participants were informed that levcromakalim might induce headache or migraine in some individuals and that sumatriptan might mitigate these effects. No information on expected timing, headache characteristics, or potential mechanisms of action was discussed.
Participants were instructed to avoid certain activities before the two experimental days. The session was rescheduled if they had taken any medication (except oral contraceptives) within 24 hours or five drug plasma half-lives of infusion start, whichever was longer. It was also rescheduled if they had consumed alcohol, tobacco or caffeine within 12 hours; experienced any headache within 24 hours; or had a migraine attack within 48 hours of infusion start. Females of childbearing potential were required to have a negative pregnancy test.
The experimental days were separated by at least seven days to avoid carry-over effects. Participants arrived at the same scheduled time on both days between 08.00 h and 14.00 h. They were placed in a supine position in a controlled, quiet laboratory environment with dimmed lighting. A venous catheter was inserted into the antecubital vein, and participants rested for 30 minutes before the baseline measurements. These included headache assessment, vital signs, facial skin blood flow and diameter of the left superficial temporal artery (STA). The participants then received a 20-minute continuous IV infusion of levcromakalim (0.05 mg/min), followed immediately by a 10-minute continuous IV infusion of sumatriptan (0.4 mg/min) or placebo (isotonic saline). The in-hospital phase lasted two hours and included regular assessments to collect data on headache characteristics, vital signs, facial skin blood flow and STA diameter. The participants were then discharged and instructed to complete a headache diary with hourly entries until 12 hours post-levcromakalim infusion start (Figure 3). Rescue medication was permitted at any timepoint; however, triptans were only allowed 160 minutes after administration of levcromakalim.
Experimental timeline.
Headache and associated symptoms
A headache diary was used to record detailed information on headache features, associated symptoms, rescue medication use and adverse events at baseline and every 10 minutes until two hours after levcromakalim administration. Upon discharge, participants were instructed to continue hourly home entries until 12 hours post-experiment start. The total 12-hour observation period was chosen for feasibility, aligning with participants’ daily routines to ensure most data were collected before bedtime.
The headache diary included a numerical rating scale (NRS) for headache intensity reporting, with 0 being “no pain”, 1 indicating “changed but not painful sensation” and 10 indicating the “worst headache imaginable”. Headache features such as pain quality and localisation, aggravation by routine physical activity and migraine associated symptoms such as nausea, photophobia and phonophobia (17) were also captured. Participants were asked to report whether their headache mimicked their usual migraine attacks and to log whether they experienced any heat sensations, flushing, heart palpitations or any other symptoms.
Experimental criteria for migraine attacks
Experimentally induced migraine attacks were defined as attacks fulfilling either of the following criteria (3):
Headache fulfilling ICHD-3 criteria C and D for migraine without aura (17), or Headache mimicking the participant's usual migraine and treated with their usual acute migraine medication.
Haemodynamic parameters
During the two-hour in-hospital period, vital signs were monitored every 10 minutes using an auto-inflatable cuff (ProPaq Encore). Mean arterial pressure (MAP) was calculated from systolic and diastolic blood pressures. The diameter of the frontal branch of the left STA and facial skin blood flow was measured at baseline, every 10 minutes from 20 to 40 minutes, and then every 20 minutes until two hour after the start of levcromakalim administration. The STA diameter was measured using a high-resolution ultrasonography unit (Dermascan C; Cortex Technology). For accuracy and reliability, we calculated the mean of four measurements per time point. Facial skin blood flow was assessed using Laser Doppler Flowmetry (moorFLPI; LDI, Moor Instruments). The participants were instructed to lie completely still and relaxed, keeping their eyes closed for at least five seconds before image collection. The images were processed manually to produce scaled and color-coded live flux images, with high perfusion indicated by red and low perfusion by blue.
Statistical analysis
Sample size calculation was performed using a two-sided McNemar's test for paired proportions with the “MESS” package in R, version 3.6.3 (R Foundation). Based on levcromakalim-mediated migraine induction rates from previous studies, efficacy estimates of IV sumatriptan and placebo rates from interventional studies (1,11,12,18), we assumed that 10% of participants would report a migraine attack exclusively after sumatriptan and 60% exclusively after placebo. At 80% power and a significance level of 5%, we estimated that at least 20 participants were needed.
The primary endpoint was the incidence of migraine attacks during the 12-hour observational period following levcromakalim administration. Secondary endpoints included the incidence of headache and adverse events within the same period. We also analysed the area under the curve (AUC) values for headache intensity scores from 0 to 12 hours (AUC0–720 min). In addition, we assessed the STA diameter change from zero to two hours (AUC0–120 min). Exploratory endpoints included the incidence of facial flushing and AUC values for facial skin blood flow changes from zero to two hours (AUC0–120 min).
Descriptive statistics are presented as means ± SD or medians with ranges, as appropriate. We used a two-sided McNemar's test for paired data to analyse the differences in migraine and headache induction, as well as the incidence of facial flushing and adverse events. AUC values were calculated using the trapezium rule (19). Differences in AUC values for headache intensity scores were analysed using a two-sided Wilcoxon signed-rank test. The AUC values for STA diameter changes and alterations in facial skin blood flow were analysed using paired t-tests.
To address the potential confounding effect of sumatriptan-induced transient headache and headache exacerbation (9,20), we conducted post-hoc analyses to better interpret our findings. Sumatriptan is known to cause transient headache exacerbation that typically lasts approximately 10–15 minutes following parenteral administration (9,20). We evaluated the baseline-corrected incidence of migraine and headache, as well as the baseline-corrected AUC for headache intensity scores (AUC40–720 min). We selected T40 min (10 minutes after the end of IV sumatriptan or placebo infusion) as the new baseline. This approach accounts for the transient, immediate exacerbation of headache intensity reported previously (9,20), and allows for a more equitable comparison of the two study days by excluding the potential impact of levcromakalim alone on the outcomes. In addition, we adjusted for headache intensity at T40 min and analysed AUC values for headache intensity changes beyond T40 min (intensity-corrected AUC40–720 min), as a result of observing a slight trend toward a lower headache intensity score following sumatriptan infusion.
We tested for period and carry-over effect on primary outcome using Fisher's exact test for binary outcomes (21).
p < 0.05 was considered statistically significant. All analyses were performed using Prism, version 8.4.2.679 (GraphPad Software Inc.). No adjustments were made for multiple comparisons.
Data availability
Deidentified study data can be made available through the corresponding author upon reasonable request.
Results
Participants
In total, 24 participants were enrolled between March 2022 and November 2023 and underwent randomisation. Of these, 20 completed both experimental days and provided data for the final analysis (Figure 1). Median time between visits was 2.3 weeks (range 1.0–12.9 weeks). Baseline characteristics for all participants and each treatment sequence, including sex, age, body mass index, number of monthly headache days and monthly migraine attacks are shown in Table 1.
Characteristics of the study population.
Baseline characteristics of all who completed both study days (n = 20) and by treatment sequence.
Migraine
During the 12-hour observational period, 15 out of 20 participants (75%) reported a levcromakalim-induced migraine attack after sumatriptan compared to 17 participants (85%) after placebo (p = 0.69) (Table 2; see also supplementary material, Table S1). Of these, 13 (65%) had a migraine attack on both study days, four (20%) on placebo-day only and two (10%) on sumatriptan-day only. One (5%) participant had no migraine on both study days (Table 2). The incidence of levcromakalim-induced migraine between 40 and 720 minutes post-levcromakalim infusion start (baseline-corrected migraine incidence) remained unchanged. The median time to migraine onset was 180 minutes on both experimental days (range 20–420 minutes and 30–720 minutes after sumatriptan and placebo day, respectively). An overview of the clinical characteristics of the provoked headache is provided in the supplementary material (Table S1). No significant period or carry-over effects for migraine induction were observed between the sumatriptan and placebo days (p > 0.99 and p = 0.43, respectively).
Clinical characteristics of spontaneous and provoked (0–12 hour observational period) headache and associated symptoms in participants with migraine without aura.
NA = not applicable.
Localisation/intensity/quality (throb = throbbing; pres = pressing)/aggravation or avoidance of physical activity (by cough during in-hospital phase and by movement during out-hospital phase).
Nausea / photophobia / phonophobia.
Migraine-like attacks are defined according to criteria described in Methods.
Pain freedom or pain relief (≥50% decrease of intensity) within two hours.
Headache
Nineteen of 20 participants (95%) reported levcromakalim-induced headache of any intensity on the sumatriptan day compared to all (100%) participants on the placebo day (p > 0.99) (Table 2; see also supplementary material, Table S1). Baseline-corrected headache incidence remained unchanged on the two days. The AUC0–720 min values for headache intensity scores did not differ between the two experimental days (p = 0.12) (Figure 4(a)), nor did the baseline-corrected AUC40–720 min values (p = 0.10) (Figure 4(b)). However, the post-hoc baseline- and intensity-corrected AUC40–720 min values revealed lower headache intensity scores after sumatriptan compared to placebo (p = 0.002) (Figure 4(c)). The median peak headache intensity was 6 (range 0–8) after sumatriptan and 6 (range 1–9) after placebo (see supplementary material, Table S1).
Headache intensity.
Hemodynamic parameters
The AUC0–120 min values for STA diameter changes were significantly smaller after sumatriptan compared to placebo (p < 0.001), as was the AUC0–120 min for facial skin blood flow changes (p = 0.01) (Figure 5). The incidence of facial flushing did not differ between the sumatriptan and placebo days (85%, n = 17 versus 100%, n = 20) (p = 0.25) (Table 3). Graphs of mean changes in MAP and heart rate can be found in the supplementary material (Figure S1).
Superficial temporal artery and facial skin blood flow.
Adverse events.
Adverse events (AEs) reported by participants within the 12-hour observational study-period on levcromakalim-sumatriptan and levcromakalim-placebo day. Eighteen out of 20 participants (90%) reported AEs on active intervention day compared with all (100%) on placebo day.
*Sensory disturbances: sensations of burning, cramping, tingling, prickling or “pins and needles” feeling.
Adverse events and rescue medication use
Eighteen of 20 participants (90%) reported adverse events on sumatriptan day, compared with all (100%) participants on placebo day (p = 0.50). All adverse events are listed in Table 3; no serious adverse events were reported. Rescue medication use was reported by 15 participants (75%) after sumatriptan and 16 participants (80%) after placebo (Table 2).
Discussion
In this randomised, double-blind, placebo-controlled, two-way crossover study, we have demonstrated that IV sumatriptan did not reduce the incidence of levcromakalim-induced migraine attacks compared to placebo, although it did cause immediate vasoconstriction of the STA. Specifically, migraine attacks occurred in 15 (75%) participants after IV sumatriptan and in 17 (85%) participants after placebo. However, post-hoc analyses revealed that sumatriptan attenuated baseline-and-headache intensity adjusted intensity scores from 40 minutes post-levcromakalim infusion until study day completion. These post-hoc results require cautious interpretation but suggest that, although sumatriptan cannot prevent the onset of levcromakalim-induced migraine attacks, it might modulate headache severity.
Vascular KATP channels in migraine pathogenesis
Mounting evidence from human experimental studies implicates the activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signalling pathways in migraine pathogenesis (1). Recent insights suggest that the opening of certain potassium channels (1), particularly KATP channels, might serve as a downstream unifying mechanism (1). Of these, the Kir6.1/SUR2B channel subtype is of particular interest. This subtype is predominantly expressed in migraine-relevant tissues and represents the major KATP channel subtype in VSMCs within the walls of cranial arteries (22).
Administration of levcromakalim, a Kir6.1/SUR2B-specific KATP channel opener (23), induces migraine attacks in people with migraine and mild, transient headache in healthy adults (11–14). Systemic administration of levcromakalim has also been shown to dilate cranial arteries in humans (11–14). In line with this, a recent study in rodents demonstrated that only systemic administration of levcromakalim could elicit cutaneous hypersensitivity (24), whereas intracerebroventricular or intraplantar administration resulted in anti-nociception or no effect, respectively (24). Similarly, intradermal and intramuscular injections of levcromakalim into trigeminal and non-trigeminal regions in healthy adults did not produce more pain than placebo (25). These findings indicate that direct activation of Kir6.1/SUR2B-specific KATP channels within the meningeal VMSCs might mediate migraine pain. Supporting this notion, NN414, a selective agonist of the Kir6.2/SUR1 KATP channel subtype predominantly found on neurons, failed to induce migraine attacks in people with migraine (15). Furthermore, genetically-modified mice lacking the vascular Kir6.1 subunit did not exhibit tactile hypersensitivity induced by levcromakalim (24).
Additional experimental studies have demonstrated that the actions of well-known molecular migraine triggers and vasodilators, such as nitric oxide (NO), calcitonin gene-related peptide (CGRP) and PACAP, involve subsequent KATP channel activation (26–28). The opening of KATP channels leads to membrane hyperpolarisation and promotes vasodilation, which might constitute mechanical stimuli for perivascular meningeal nociceptor activation and sensitisation (1,22,29). Furthermore, potassium efflux and accumulation of potassium ions in the perivascular space, constituting chemical stimuli, could also contribute to activating and sensitising the perivascular nociceptors (1,22,29).
Sumatriptan–proposed site(s) and mechanism(s) of action
Sumatriptan is a well-established therapeutic agent in migraine management, primarily due to its agonistic activity at 5-HT1B/1D receptors, which are coupled to Gi/o-proteins (6,30,31). Activation of these receptors initiates a cascade of intracellular events, including inhibition of adenylyl cyclase (i.e. downregulation of cAMP), activation of phospholipases, modulation of intracellular calcium concentrations and direct regulation of ion channels (30,31).
Previous studies using sumatriptan interventions have been reported, yet most are not directly comparable to our study because of key design differences. These include variations in timing (pre-treatment and post-migraine treatment versus early-treatment), administration route (oral and subcutaneous versus IV), study population (healthy controls versus individuals with migraine) and trigger protocols (oral administration of cilostazol and two-hour infusion of CGRP versus 20-minute infusion of levcromakalim) (32–35). One study with a design similar to ours demonstrated that early administration of IV sumatriptan can prevent PACAP-induced migraine attacks and STA dilation (9). By contrast, our study revealed that, although IV sumatriptan intervention fully reversed STA dilation caused by the opening of KATP channels, it did not prevent the subsequent migraine attack. This dissociation suggests that cranial vasodilation may not be the sole trigger in migraine pathogenesis.
All known migraine-triggering molecules are potent vasodilators that induce sustained dilation (1,22,36). Our findings support the hypothesis that vasodilation triggers a potassium efflux. We propose that an increase in extracellular potassium at the neurovascular interface may play a crucial role in activating and sensitising perivascular nociceptors, ultimately leading to migraine pain and contributing to the initiation of a migraine attack (1). In this context, cranial vasodilation may serve as an indicator of the extent to which molecular triggers activate potassium channels via cAMP- or cGMP-mediated signalling pathways.
Additional evidence reinforces the importance of potassium channel dynamics in migraine pathophysiology. Substances such as adenosine and vasoactive intestinal peptide (VIP), which exhibit only transient vasodilatory effects when administered as 20-minute infusions, induce migraine attacks in only a few patients (37,38). When VIP is infused over a prolonged period of two hours, the cumulative dose increases along with the likelihood of potassium channel opening. This prolonged exposure results in sustained STA dilation and migraine induction (39). One study further demonstrated that reducing the duration of PACAP-38-mediated vasodilation with sumatriptan effectively prevented PACAP-38-induced migraine in individuals with migraine (9). This effect is likely due to the interruption of PACAP-38-driven activation and sensitisation of perivascular afferents via potassium channels (1,26).
Although sumatriptan does not prevent migraine attacks induced by levcromakalim, our post-hoc analyses suggest it might reduce headache intensity. This observation likely reflects the ability of sumatriptan to modulate nociceptive signalling within the trigeminovascular system. It may achieve this modulation by inhibiting neuropeptide release or interrupting pain transmission pathways (6,8). The delayed effect observed may indicate that sumatriptan requires time to exert its modulatory effects on the CNS.
Limitations
This study has several limitations that should be considered when interpreting the results. First, IV administration of levcromakalim and sumatriptan might not fully replicate the natural course of spontaneous migraine attacks or the typical clinical use of sumatriptan, which is often administered orally or subcutaneously. The controlled laboratory setting also differs from real-world conditions, potentially affecting the generalisability of the findings. Second, the timing of sumatriptan administration was fixed and might not reflect the optimal therapeutic window for preventing or attenuating levcromakalim-induced migraine attacks. It is possible that different dosing regimens or timing relative to the levcromakalim infusion could yield different outcomes. In addition, we did not establish any eligibility criteria based on triptan naivety, response or non-response. We believe that our power calculation adequately accounts for this inherent variability in the study population (1,11,12,18). Lastly, while intriguing, the post-hoc analyses that revealed attenuation of headache intensity by sumatriptan should be interpreted with caution, and warrant confirmation in future studies.
Conclusions
Our results suggest that sumatriptan does not prevent migraine attacks induced by vascular KATP channel opening. This finding suggests that the underlying mechanisms of these attacks occur downstream of the primary site of action of sumatriptan. Post-hoc analyses indicate that sumatriptan might reduce headache intensity scores. This observation points to a potential modulatory effect. However, this should be interpreted with caution and requires confirmation in future studies. These results emphasise the need for novel therapeutic approaches for the acute treatment of migraine attacks. Targeting the Kir6.1/SUR2B subunits of KATP channels may offer a promising approach. Further research is warranted to explore the mechanisms by which vascular KATP channel opening within the meninges might cause migraine attacks.
Early sumatriptan treatment did not prevent migraine triggered by KATP channel opening in individuals with migraine without aura. Migraine was triggered despite immediate constriction of the superficial temporal artery by sumatriptan, suggesting that elevated extracellular potassium levels at the neurovascular interface, rather than vasodilation, play a pivotal role in migraine induction. Post-hoc analysis suggested that sumatriptan might reduce headache intensity.
Supplemental Material
sj-docx-1-cep-10.1177_03331024251341464 - Supplemental material for Effect of sumatriptan on ATP-sensitive potassium channel opening in migraine: A randomised controlled trial
Supplemental material, sj-docx-1-cep-10.1177_03331024251341464 for Effect of sumatriptan on ATP-sensitive potassium channel opening in migraine: A randomised controlled trial by Zixuan Alice Zhuang, Mohammad Al-Mahdi Al-Karagholi, Håkan Ashina, Thien Phu Do and Messoud Ashina in Cephalalgia
Footnotes
Acknowledgements
We thank all of the participants for their contribution in this study, as well as the involved site personnel for their help in conducting the study. Figure 2 was created in BioRender. Zhuang, Z. (2025) https://BioRender.com/v65o066; Figure 3 was created in BioRender. Zhuang, Z. (2025) 
.
Author contributions
ZAZ, MMK, HA, TPD and MA contributed to study design, protocol development, participant enrolment, data acquisition, data processing, analysis, statistics and interpretation, and drafting and revision of the article. The study was conceived, initiated and sponsored by MA
Data availability
Deidentified study data can be made available through the corresponding author upon reasonable request.
Declaration of conflicting interest
ZAZ, MMK and TPD have nothing to disclose. HA has received personal fees from AbbVie, Lundbeck, Pfizer and Teva Pharmaceuticals, outside of the submitted work. MA has received personal fees from AbbVie, Amgen, Astra Zeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals, outside of the submitted work. MA also serves as an Associate editor of Brain and The Journal of Headache and Pain.
Ethical statement
The study protocol was reviewed and approved by the Regional Health Research Ethics Committee of the Capital Region of Denmark (H-21011542). All participants provided their written informed consent prior to enrolment, ensuring that they were fully informed and aware of study-related assessments and procedures, as well as potential risks.
Funding
This study received funding from the Lundbeck Foundation Professor Grant (R310-2018–3711). ZAZ was supported by a research grant from Rigshospitalets Forskningspuljer (E-23327-03).
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References
Supplementary Material
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