Characterizing the patient experience during the prodrome phase of migraine: A qualitative study of symptoms and their timing

Abstract

Objective

This study explores and documents the patient experience during the prodrome phase of migraine.

Background

Migraine attacks can be divided into four stages: the prodrome (or premonitory phase), the aura, the headache phase, and postdrome. Qualitative data on the range of symptoms during the prodrome and their timing relative to headache onset are sparse. Prodromal symptoms may predict the onset of migraine headache pain and provide a clinically useful benchmark for initiation of treatment early in an attack before pain begins.

Design/Methods

Eligible participants with a clinician‐confirmed diagnosis of migraine and at least one prodromal symptom were consented, screened, and then participated in 60‐min interviews. The interview guide included open‐ended questions to elicit spontaneous reports and specific probes about prodromal symptoms based on a clinician‐established list. A theory approach was used to analyze the qualitative data collected in interviews to identify key themes and gather insights; data were analyzed using ATLAS.ti.

Results

Data collection for this study occurred from March 8, 2022, to May 16, 2022. Twenty interviews were conducted, and analyses demonstrated that concept saturation was achieved. Participants reported 36 unique prodromal symptoms, and each participant experienced a mean of 13 symptoms (standard deviation [SD] = 6.6) and a median of 11 symptoms (interquartile range [IQR] = 7.8–17.0) during the prodrome phase. The most commonly reported prodromal symptoms were nausea (n = 17/20, 85%), fatigue/tiredness (n = 16/20, 80%), sensitivity to light (n = 13/20, 65%), neck pain/stiffness (n = 12/20, 60%), and dizziness/vertigo/light‐headedness (n = 10/20, 50%). Of the symptoms reported by at least four participants (n ≥ 4/20, 20%), neck pain/stiffness was rated most bothersome (8.9 out of 10) and sensitivity to light was rated most severe (8.5 out of 10). Almost 40% of all symptoms reported occurred less than 2 h before the start of migraine headache. Of the commonly reported symptoms, nausea (0.8h), sensitivity to light (1.0 h), and dizziness/vertigo/lightheadedness (2.0 h) began closest to headache onset; fatigue/tiredness (4.0 h) and neck pain/stiffness (4.8 h) were the most remote from headache onset.

Conclusion

This study identified frequently reported prodromal symptoms, with participants commonly reporting that a migraine headache would follow their experience of prodrome within a 1‐ to 6‐h window. Characterizing the prodrome experience may improve measurement strategies for the burden of migraine and create opportunities to treat during the prodromal phase to prevent the onset of moderate or severe headaches.

Plain Language Summary

Before the onset of migraine headache, many patients experience prodromal symptoms or warning signals indicating that a migraine headache is coming. This study explored the experiences of patients with migraine during the prodrome phase, revealing 36 unique symptoms, including nausea, fatigue, sensitivity to light, neck pain/stiffness, and dizziness/vertigo/light‐headedness, which typically appeared 1 to 6 h before the migraine headache began; this information provides a possible window for early intervention. Understanding these early signs may help in treating migraine before severe pain starts, potentially reducing the burden of migraine attacks.

Abbreviations

ICHD‐3

International Classification of Headache Disorders Verion 3.0

WIRB

Western institutional review board

INTRODUCTION

Migraine is a complex condition that affects approximately 1.1 billion people around the world. It is a chronic condition characterized by attacks that occur in up to four phases: the prodrome (also known as premonitory phase), the aura, the headache, and the postdrome. ¹

Although the prodrome typically occurs hours (and sometimes for a day or more) before headache onset, typical aura usually precedes the headache pain and can last minutes to an hour. The headache phase typically lasts 4–72 h, and the postdrome can last hours or days following the cessation of headache pain. ² , ³

Prodromes occur in the majority of people living with migraine. ⁴ , ⁵ , ⁶ Prodromes may predict the onset of the headache phase in many people and can be the key to early treatment of migraine for some people. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ The prodrome phase allows some patients to accurately predict migraine headache up to 12h before its onset, ⁸ and this ability to predict a migraine headache may create a window for early treatment.

Many studies have documented prodromal features through clinic‐based surveys, population‐based questionnaires, and daily diary findings. ⁶ , ¹¹ , ¹² Others have established methods for studying prodrome, linking it to headache, ¹³ , ¹⁴ and have examined its potential underlying mechanisms. ¹⁵ However, the variability of symptom onset and the possible conflation between the prodrome and aura phases make these distinctions challenging. Although prior studies have explored various prodrome symptoms, they often considered the symptoms' relation to migraine headache frequency, triggers, and functional brain connectivity. Available literature on the prodrome phase of migraine has rarely explored the timing of individual prodrome symptoms relative to headache onset or whether patients are capable of reliably predicting the onset of their migraine headache pain. Furthermore, qualitative studies based on systematic interviews with individuals who experience migraine are sparse and rarely report symptoms during the prodrome; nor does available literature systematically assess the severity or bothersomeness of prodromal symptoms. ¹¹ , ¹⁶ Last, the resources allocated to prodrome research are limited relative to headache or migraine generally in part due to therapeutic approach of treating symptoms once the headache phase has already begun, which results in a lack of focus in this area; notably, the term “prodrome” is relatively new and was first introduced in migraine literature approximately 20 years ago. ¹⁷

Purpose and research objective

This qualitative interview study primarily sought to better understand the range and timing of prodrome symptoms. When evaluating the efficacy of early treatment interventions, clinical trials require a high probability of headache onset following one's experience of prodromal symptoms; therefore, patient confidence in the likelihood of a headache following each of their prodrome symptoms was examined. This work was also conducted to characterize the humanistic burden of prodrome from a patient perspective, including key symptoms, impacts on health‐related quality of life, and medication usage.

METHODS

Qualitative approach and research design

The present study used a grounded theory approach by using the data collected in interviews to identify common themes and insights via frequency of report in the experiences of the prodrome phase of migraine. ¹⁸ , ¹⁹

Researcher characteristics and reflexivity

Interviews were conducted via Health Insurance Portability and Accountability Act–compliant Zoom or in‐person by trained and experienced interviewers who have completed Protecting Human Research Participants Training as well as internal data protection, comprehensive interview training, and study‐specific interview training. The interviewers for this study had no previous clinical experience with migraine and had no prior contacts or relationships with the interview participants.

Ethical issues pertaining to human subjects

The study protocol and associated study materials were submitted to the Western institutional review board for ethics review before any contact with participants (study number: 1327966).

Sampling strategy

Eligible participants were recruited through two clinical sites: a neurology institute and an internal medicine practice. Key inclusion criteria were (1) the participant was 18–75 years old; (2) had at least a 1‐year history of migraine with or without aura consistent with a diagnosis according to the International Classification of Headache Disorders v3.0 (ICHD‐3); (3) had a history of two to eight migraine attacks per month with moderate to severe headaches in each of the 3 months before screening; (4) commonly experienced prodrome symptom(s) or other sensations before experiencing pain caused by a migraine headache; and (5) reported experiencing qualifying prodrome event three or more to ≤16 times in the previous 4 weeks before screening (i.e., prodrome events). A qualifying prodrome event was defined as an event in which the participant experienced a clinically identifiable prodrome, and the participant was confident (i.e., at least 75.0% of the time) that a headache would follow the experience of the prodrome symptom(s). Participants' assessment of confidence was gathered via open‐ended interview probes asking how confident they were a migraine would occur after the onset of prodrome reported symptoms, as well as what evidence led them to that conclusion.

Participants were excluded if (1) they were unable to distinguish prodrome symptoms from migraine triggers or other symptoms unrelated to migraine; (2) they had confounding pain syndromes, confounding psychiatric conditions, dementia, epilepsy, or other significant neurological disorders other than migraine; or (3) they had a current diagnosis of chronic migraine as defined by the ICHD‐3, or a history of 15 or more headache days per month on average in the 6 months before the study in the clinician's judgment. A headache day was defined as a day in which there was any occurrence of a headache of a minimum duration of 2 h or a headache of any duration for which acute medication was taken.

Eligible participants provided written consent to participate in a 60‐min interview.

Under the saturation principle, it is difficult, a priori, to determine the number of participants needed for qualitative research studies. However, evidence suggests that saturation can be achieved in a sample of 12–25 participants, depending on the homogeneity of the sample and whether various subgroup analyses are desired. ²⁰ , ²¹ , ²² Therefore, 20 participants were targeted for this interview study.

Data collection methods

The interview guide was developed with open‐ended questions designed to encourage spontaneous responses followed by structured questions to elicit potential symptoms that were not reported spontaneously (Supporting Information). The interview guide covered prodrome symptoms included in a symptom checklist created by academic researchers (DWD), which covered the domains identified in surveys, diary studies, and a meta‐analysis. ⁴ , ⁵ , ⁶ , ⁷ Covered domains included general, vestibular, pain, sensory hypersensitivity, visual, autonomic, appetite, emotional, cognitive, and cranial parasympathetic symptoms. The interview guide also included questions regarding impacts of migraine prodrome, experiences related to prodrome, and treatment and management methods from a patient perspective. During interview guide development, feedback was solicited from experienced headache clinicians (R.B.L., D.W.D.), with research interests in the migraine prodrome. Before formal interview conduct, the interviewers and research leads conducted a mock interview to identify interview priorities and potentially challenging aspects of the interview guide. Once formal interviews with participants began, interviews were audio‐recorded with the participant's prior consent and lasted approximately 60 min each. Data collection for this study occurred from March 8, 2022, to May 16, 2022.

Data analysis

Audio‐recordings of the interviews were transcribed verbatim, anonymized, and analyzed using processes guided by established qualitative research methods, including grounded theory and constant comparison methods. ¹⁸ , ¹⁹ , ²³ , ²⁴ A coding scheme was applied and operationalized using ATLAS.ti version 8.0 (Lumivero LLC, Denver, CO, USA). The coding scheme catalogued concepts that were reported by participants spontaneously or following interviewing probing. Coding is an iterative process and therefore the initial code list was updated as necessary to reflect the actual terms participants used to describe concepts as well as to incorporate newly emerging data. Codes were applied to specific text within each transcript and then queried for frequency across transcripts. In the results section below, categorical data are presented for demographic and health information, whereas symptoms and impacts of migraine prodrome are presented as discrete data.

Techniques to improve the quality of the data analysis

Intercoder reliability was initially assessed based on the first interview transcript. We evaluated percent agreement based on coding by two independent coders and the research lead; greater than or equal to 90.0% agreement is considered an acceptable threshold based on benchmarks outlined in the literature. ²⁴ Notably, the coding software used for this project did not allow for the calculation of Cohen's or Fleiss' kappa. As formal coding of the remaining interviews began, the two coders discussed any discrepancies or emerging situations with the research leads to align the coding strategy across all interview transcripts. After coding was completed and quality‐checked, data were also assessed for conceptual saturation (i.e., the point where additional interviews will not lead to additional information) according to guidelines from previous qualitative research in similar types of studies. ¹⁸ Concepts reported spontaneously in the interviews were analyzed in groups based on the order in which the data were collected (i.e., as the interviews were conducted), such that concepts reported in the first five interviews were compared to the next five interviews, both of these cohorts (n = 10) were then compared with the next five interviews, and subsequently these 15 interviews were compared to the last five interviews.

RESULTS

Participant demographic and health information

Of the 22 potential participants screened for this study, all were considered eligible; however, two participants were lost to follow‐up (i.e., not responsive to multiple requests for interview scheduling), resulting in 20 participants completing an interview. Of the 20 participants that completed a concept elicitation interview, 15 were women and five were men. Participants were on average 43.8 years old (standard deviation [SD]: 12.1 years, min–max: 23–72). Eleven participants (n = 11/20, 55%) identified as White, and all participants (n = 20/20, 100%) identified as non‐Hispanic. Participants most commonly rated their health status as “Good,” “Very good,” or “Excellent” (n = 14/20, 70%). Additionally, participants most commonly used triptans (n = 15/20, 75%) and/or over‐the‐counter pain relievers (n = 14/20, 70%) to treat their migraine. See Table 1 for a summary of participant‐reported demographic and health information.

TABLE 1.

Participant‐reported demographic and health information.

Demographic information	n (%)
Sex
Female	15 (75)
Male	5 (25)
Age, years
Mean	43.8
Standard deviation	12.1
Range	23–72
Race (check all that apply)
White	11 (55)
Black or African American	5 (25)
Asian	3 (15)
American Indian or Alaska Native	1 (5)
Health status
Excellent	1 (5)
Very good	7 (35)
Good	6 (30)
Fair	4 (20)
Poor	2 (10)
Current treatment for migraine (check all that apply)
Sumatriptan	9 (45)
Aspirin/paracetamol/caffeine	5 (25)
Ibuprofen	5 (25)
Acetaminophen	3 (15)
Propanolol	3 (15)
Rizatriptan	3 (15)
Topiramate	3 (15)
Eletriptan	2 (10)
Muscle relaxers (unspecified)	2 (10)
Naproxen	2 (10)
Ondansetron	2 (10)
Aspirin	1 (5)
OnabotulinumtoxinA	1 (5)
Butalbital	1 (5)
Diclofenac	1 (5)
Diphenhydramine	1 (5)
Erenumab	1 (5)
Fremanezumab	1 (5)
Indomethacin	1 (5)
Lorazepam	1 (5)
Magnesium supplement	1 (5)
Medical marijuana	1 (5)
Nerve blocks	1 (5)
Rimegepant	1 (5)
Pseudoephedrine	1 (5)
Sumatriptan/naproxen	1 (5)
Eptinezumab	1 (5)

Conceptual saturation

Conceptual saturation was assessed for the 28 unique symptoms and 27 unique impacts that were reported spontaneously by participants. Although a few symptoms and impacts were reported spontaneously in the last 25% of interviews, including difficulty concentrating, olfactory hallucinations, and feeling uncomfortable, the concepts were closely related to symptoms that were reported previously, like difficulty thinking/brain fog, visual disturbances, and multiple sensations that can produce discomfort (e.g., eye pain/pressure, muscle tension, numbness/tingling in face, and heavy feeling in head).

Defining symptoms of the prodrome phase of migraine

The most frequently reported symptoms of the prodrome phase of migraine were nausea (n = 17/20, 85%), fatigue/tiredness (n = 16/20, 80%), sensitivity to light (n = 13/20, 65%), neck pain/stiffness (n = 12/20, 60%), dizziness/vertigo/light‐headedness (n = 10/20, 50%), sensitivity to sound (n = 9/20, 45%), irritability (n = 9/20, 45%), sensitivity to temperature (n = 9/20, 45%), difficulty thinking/brain fog (n = 8/20, 40%), and difficulty concentrating (n = 8/20, 40%). On average, participants experienced approximately 13 symptoms of prodrome each (SD: 6.6; median: 11; IQR: 7.8–17.0; min–max: 3–27).

See Table 2 for a summary of symptoms reported by at least four participants (n ≥ 4/20, 20%). Participants also reported how confident they were that if they experienced a specific symptom, they will get a migraine soon after, considering factors such as the frequency of the symptom and the frequency of a migraine headache following the symptom. Confidence ratings were categorized as “high (3.0),” “moderate (2.0),” and “low (1.0)” confidence. See Table 3 for key symptom concepts, confidence a migraine headache will follow, and associated exemplary quotes.

TABLE 2.

Spontaneously reported and elicited symptoms of the prodrome phrase of migraine reported by n ≥ 4 participants in order of relative frequency.

Symptom	Total (N = 20)
	n (%)
Nausea	17 (85) S = 13 (65), E = 4 (20)
Fatigue/tiredness	16 (80) S = 6 (30), E = 10 (50)
Sensitivity to light	13 (65) S = 11 (55), E = 2 (10)
Difficulty thinking/brain fog/difficulty concentrating	12 (60) S = 3 (15), E = 9 (45)
Sub‐concepts
Difficulty thinking/brain fog	8 (40) S = 3 (15), E = 5 (25)
Difficulty concentrating	8 (40) S = 1 (5), E = 7 (35)
Neck pain/stiffness	12 (60) S = 7 (35), E = 5 (25)
Dizziness/vertigo/light‐headedness	10 (50) S = 5 (25), E = 5 (25)
Sensitivity to sound	9 (45) S = 8 (40), E = 1 (5)
Irritability	9 (45) S = 4 (20), E = 5 (25)
Sensitivity to temperature	9 (45) S = 0 (0), E = 9 (45)
Blurred vision	7 (35) S = 3 (15), E = 4 (20)
Sensitivity to smell	7 (35) S = 3 (15), E = 4 (20)
Eye pain/pressure	6 (30) S = 6 (30), E = 0 (0)
Loss of appetite	5 (25) S = 3 (15), E = 2 (10)
Pale or flushed face	5 (25) S = 1 (5), E = 4 (20)
Muscle tension	4 (20) S = 4 (20), E = 0 (0)
Visual disturbances (e.g., spots, stars, lines, lights) a	4 (20) S = 4 (20), E = 0 (0)
Difficulty speaking	4 (20) S = 2 (10), E = 2 (10.0)
Yawning	4 (20) S = 2 (10), E = 2 (10)
Stuffy nose	4 (20) S = 1 (5), E = 3 (15)
Teary eyes/red eyes	4 (20) S = 0 (0), E = 4 (20)

Note: Symptoms reported by n = 3 participants or less include: numbness/tingling in face (n = 3), moodiness (n = 3), muscle pain or aching (n = 3), thirst (n = 3), changes in bowel movement (n = 2), food craving or hunger (n = 2), heavy feeling in head (n = 2), anxiety (n = 1), difficulty reading or writing (n = 1), feeling uncomfortable (n = 1), olfactory hallucinations (n = 1), pulsating sensation in head (n = 1), sensitive skin (n = 1), weakness (n = 1), and vomiting (n = 1).

Abbreviations: E, elicited; S, spontaneous.

^a Visual disturbances likely represent aura, not prodrome.

TABLE 3.

Key symptom concepts, confidence a migraine headache will follow, and exemplary quotes.

Symptom concept	Confidence a migraine headache will follow a	n (%) b	Exemplary quotes
Nausea 17 (85%)	High c	9 (60)	02–04: So I don't get nausea often…I've only vomited once in 30 years due to a migraine. So that's not a common thing for me, but the nausea—and usually the nausea is almost immediately before. So if I'm getting all these other things and then I hit nausea, I know that the migraine is within minutes and then sometimes it hangs on in the beginning of the migraine, but it doesn't last very long
	Moderate d	2 (13)
	Low e	4 (27)
Fatigue/tiredness 16 (80%)	High	5 (36)	01–01: So I usually have a ton of energy…And so just the feeling of fatigue, it notifies me about—like again, like something's wrong. I would be pretty confident…Because it is out of character for me. And most of the time the fatigue ties in with the nausea. And that's why I'm a little—I'm pretty confident when it comes to that being a prodrome to the migraine
	Moderate	2 (14)
	Low	7 (50)
Sensitivity to light 13 (65%)	High	9 (82)	01–03: And sensitivity to light is a indicator to me that it's not a regular headache versus a migraine. That's the first thing I notice. I don't want to be smart, but after many years of experiencing it, I know, equate what I s—what my senses tell me that I'm about to experience
	Moderate	1 (9)
	Low	1 (9)
Difficulty thinking/brain fog/difficulty concentrating 12 (60%)	High	5 (63)	02–04:…and then I get brain fog, severe…Well, I think like some of the other things that you said about difficulty concentrating, difficulty staying focused, remembering—I can't remember things. I have trouble, cognitively finishing sentences, not just having the words come out of my mouth, but being able to think to the end of a sentence, I have difficulty with…I would say probably 90% of the time when it happens, I know that it's either a pre—a prodrome and it hangs on for the postdrome and through the whole migraine
	Low	3 (38)
Sub‐concepts Difficulty thinking/brain fog 8 (40%)	High	2 (50)	01–07: Sometimes, it starts as if my head—I have like—my head is kind of heavy, and I don't—I can't think straight…I'm very confident [that a migraine headache will follow]…Because once I become that foggy and not thinking, I become—that's the time I would start—it's like the pain is coming gradually once it starts that way. I would start experiencing eye heaviness and all that. So I know the migraine is coming.
	Low	2 (50)
Difficulty concentrating 8 (40%)	High	4 (67)	01–05: That might be hard to concentrate…because you're like it's just experiencing it…when you know you're fixing to get a migraine, you can't think or concentrate to where it's hard, like people trying to talk to you or something like that and it's like your body warning you that you're fixing to get a migraine, so you can't comprehend too well
	Low	2 (33)
Neck pain/stiffness 12 (60%)	High	5 (63)	02–01: I start to get tension in my neck, and I don't know if it's a knot I feel. I start to feel a knot in my—the same spot, right where almost my angel bone is area. And it can be either side, so I always wonder if I'm holding my kids on that side and it tenses up or—but it will be on either side, so I don't know. It always feels like a knot starts. And then it travels up through my neck. And that's always how it starts…I had been working with my neurologist…he had showed me all the nerves connected…and all the nerves in your neck and shoulder and connect all the way up into your head…So that's why I had just linked it. And it always just starts with that. So I think I just noticed that, when that starts, then I immediately, in the next day, get a migraine
	Moderate	1 (13)
	Low	2 (25)
Dizziness/vertigo/light‐headedness 10 (50%)	High	6 (75)	01–12: So it usually starts with feeling a little bit of dizziness…So basically, what it feels like is if you get up too fast. Q: And then how confident are you that if you have that dizziness that you're going to be getting a migraine pretty soon after? A: Like 80% sure…Because it's been consistent. It's—I at least get four or five a year that are really, really, really severe, and it's all the same
	Moderate	1 (13)
	Low	1 (13)
Sensitivity to sound 9 (45%)	High	3 (50)	01–07: I just feel as if my head is exploding when I hear noise. I mean, the—might be less—little noise that I just don't want to hear. Even people talking—I don't want to hear them…I'm definitely going to have a migraine when I feel that way…Very confident [that a migraine headache will follow] …Because I'm definitely going to have a migraine with that type of sensitivity—the noise
	Moderate	2 (33)
	Low	1 (17)
Irritability 9 (45%)	High	5 (56)	02–04: I find that when I'm irritable without a reason—and I specify without a reason because sometimes things in life irritate, and they are irritating, but I found that there were times when I was irritated for no reason…And after a few times of this happening, I was like—and we noticed sequentially. It was like I would be in the—irritable for no reason and then within a few hours, I'd have a migraine. So it just took repetitive pairing that I was like, huh. It's not every time I'm irritable. It's when I'm irritable and there's no obvious reason for it
	Moderate	2 (22)
	Low	2 (22)
Sensitivity to temperature 9 (45%)	High	5 (71)	01–14: That actually happens right beforehand…my face and my body—the temperature just warms up real fast…And then, afterwards, because I sweat so much—literally I can just, oh, gosh, I'm sweating. The chills will come on and then that's where it [migraine] starts from right here I can feel it…I think it just all goes hand‐in‐hand. It's a cycle. This starts happening and then that starts happening, so—yeah, I think it is
	Moderate	1 (14)
	Low	1 (14)

^a Participants were asked, “How confident are you that if you have [symptom], you will get a migraine soon after?”. During analysis, confidence levels were categorized as “high,” “moderate,” and “low” confidence.

^b Confidence percentages are calculated out of those providing confidence data; some confidence data were not collected due to interviewer discretion and time constraints.

^c Confidence was classified as high if participants' responses included at least one of the following: confirmation that [symptom] is followed by a migraine headache at least 75% of the time; rating of 8–10 on a scale of 0–10 in terms of the likelihood of experiencing a migraine headache after [symptom]; or qualitative descriptors such as “very/really confident” that indicate their high confidence that [symptom] will be followed by a migraine headache.

^d Confidence was categorized as moderate if participants' responses included at least one of the following: confirmation that [symptom] is followed by a migraine headache 51.0%–74.0% of the time; rating of 6–7 on a scale of 0–10 in terms of the likelihood of experiencing a migraine headache after [symptom]; or qualitative descriptors like “moderately” or “fairly confident” when describing their confidence that [symptom] will be followed by a migraine headache.

^e Confidence was classified as low if participants' responses included at least one of the following: confirmation that [symptom] is followed by a migraine headache ≤50% of the time; rating of 0–5 on a scale of 0–10 in terms of the likelihood of experiencing a migraine headache after [symptom]; or qualitative descriptors like “not confident” or “very/really low percentage” that indicate low confidence that [symptom] will be followed by a migraine headache.

Bothersome and severity ratings for symptoms of the prodrome phase of migraine

Participants provided bothersome and severity ratings for symptoms of prodrome on a scale of 0 (not bothersome at all/no [symptom]) to 10 (extremely bothersome/[symptom] as bad as you can imagine); however, not all symptoms reported received enough (i.e., n ≥ 4/20, 20%) bothersome/severity ratings due to interviewer discretion or time constraints. Of the symptoms with bothersome/severity data reported from at least four participants overall, neck pain/stiffness received the highest bothersome rating on average (8.9) and sensitivity to light received the highest severity rating on average (8.5). See Table 4 for a summary of bothersome and severity ratings for symptoms of the prodrome phase of migraine provided by at least four participants overall (n ≥ 4/20, 20%).

TABLE 4.

Bothersome and severity ratings for prodrome symptoms reported by n ≥ 4 participants in order of relative frequency.

Symptom	n Rating	Mean (SD)	Median (IQR)	Minimum–maximum
Bothersome ratings a
Nausea	16	7.3 (2.3)	8.0 (9.5–5.3)	3–10
Fatigue/tiredness	15	6.8 (2.5)	7.0 (8.0–6.0)	2–10
Sensitivity to light	11	7.8 (2.0)	8.0 (10.0–7.0)	4–10
Difficulty thinking/brain fog/difficulty concentrating	10	7.5 (2.0)	7.5 (10.0–5.8)	4–10
Sub‐concepts
Difficulty concentrating	5	7.8 (1.3)	8.0 (9.0–6.5)	6–10
Difficulty thinking/brain fog	5	7.2 (2.5)	7.0 (10.0–4.5)	4–10
Neck pain/stiffness	9	8.9 (1.1)	9.0 (10.0–8.0)	7–10
Dizziness/vertigo/light‐headedness	10	7.1 (2.1)	7.0 (9.3–5.8)	3–10
Sensitivity to sound	6	8.3 (1.9)	9.0 (10.0–6.5)	5–10
Irritability	9	7.1 (2.2)	7.0 (9.0–6.0)	2–10
Sensitivity to temperature	6	6.5 (1.6)	7.0 (8.0–4.8)	4–8
Sensitivity to smell	6	8.5 (1.3)	8.5 (10.0–7.0)	7–10
Blurred vision	6	8.0 (2.8)	9.0 (10.0–6.5)	2–10
Teary eyes or red eyes	4	5.3 (2.9)	4.0 (8.8–3.0)	3–10
Severity ratings b
Nausea	15	7.3 (1.5)	7.0 (8.0–6.0)	4–10
Fatigue/tiredness	14	7.3 (2.5)	7.5 (9.3–5.8)	2–10
Sensitivity to light	12	8.5 (1.8)	9.0 (10.0–6.5)	5–10
Difficulty thinking/brain fog/difficulty concentrating	12	7.3 (2.4)	7.5 (10.0–5.0)	4–10
Sub‐concepts
Difficulty concentrating	7	7.9 (1.9)	7.5 (10.0–6.0)	5–10
Difficulty thinking/brain fog	5	6.4 (2.6)	5.0 (9.5–4.0)	4–10
Neck pain/stiffness	9	7.7 (1.5)	8.0 (9.0–6.0)	6–10
Dizziness/vertigo/light‐headedness	10	7.8 (2.0)	8.0 (10.0–6.5)	4–10
Sensitivity to sound	6	7.3 (1.8)	7.5 (8.5–6.3)	4–10
Irritability	9	7.6 (1.4)	8.0 (8.5–6.5)	5–10
Sensitivity to temperature	6	6.0 (1.9)	6.0 (7.5–4.5)	3–9
Sensitivity to smell	6	7.0 (1.2)	6.5 (8.3–6.0)	6–9
Blurred vision	5	7.8 (2.5)	9.0 (9.5–5.5)	3–10
Eye pain/pressure	4	7.5 (1.5)	7.0 (9.3–6.3)	6–10
Teary eyes or red eyes	4	5.0 (1.9)	4.5 (7.3–3.3)	3–8

Abbreviations: IQR, interquartile range; SD, standard deviation.

^a Participants were asked to indicate how much each of their pre‐headache symptoms bother them on a scale of 0–10, where 0 means not bothersome at all and 10 is extremely bothersome.

^b Participants were asked to indicate how severe each of their pre‐headache symptoms is on a scale of 0–10, where 0 means not severe at all and 10 is extremely severe.

Timing of migraine prodrome symptoms

Of the 36 unique symptoms reported by participants, most occurred at least an hour before the onset of migraine headache pain (n = 29/36, 81%), with many symptoms (n = 26/36, 72%) occurring specifically between 1 to 6 h before the onset of headache pain. Symptoms that were reported to occur within 1 h of the migraine attack aligned closely with what would be expected with the aura phase of migraine (i.e., visual disturbances and difficulty speaking). Blurred vision also occurred close in time to headache onset. Symptoms followed by the greatest delay in headache onset included sensitivity to smell, changes in bowel movements, and loss of appetite that on average occurred more than 6 h before the start of the migraine attack. See Figure 1 for participant‐reported timing of prodrome symptoms.

FIGURE 1.

Participant‐reported timing of prodrome symptoms. [Colour figure can be viewed at wileyonlinelibrary.com]

Defining impacts of the prodrome phase of migraine

The most frequently reported impacts of the prodrome phase of migraine were associated with emotional, social, and work domains; these included a negative impact on the ability to work (n = 15/20, 75%), increased anxiety (n = 15/20, 75%), increased stress (n = 11/20, 55%), and a negative impact on family life (n = 8/20, 40%). See Table 5 for a summary of impacts reported by at least four participants and Table 6 for key impact concepts and exemplary quotes.

TABLE 5.

Spontaneously reported and elicited impacts of the prodrome phase of migraine reported by n ≥ 4 participants.

Impact	Total (N = 20)
	n (%)
Activities of daily living
Stay (close to) home/cancel plans	7 (35) S = 7 (35), E = 0 (0)
Difficulty driving	4 (20) S = 4 (20), E = 0 (0)
Emotional
Anxiety	15 (75) S = 3 (15), E = 12 (60)
Stress	11 (55) S = 1 (5), E = 10 (50)
Annoyance/frustration	6 (30) S = 6 (30), E = 0 (0)
Physical
Need to lie down/rest	6 (30) S = 6 (30), E = 0 (0)
Difficulty engaging in physical activity	4 (20) S = 4 (20), E = 0 (0)
Sleep
Difficulty sleeping	7 (35) S = 1 (5), E = 6 (30)
Social
Negative impact on family life	8 (40) S = 8 (40), E = 0 (0)
Negative impact on ability to socialize	6 (30) S = 4 (20), E = 2 (10)
Work
Negative impact on ability to work	15 (75) S = 13 (65), E = 2 (10)
Negative impact on work attendance	4 (20) S = 4 (20), E = 0 (0)

Abbreviations: E, elicited; S, spontaneous.

TABLE 6.

Key impact concepts and exemplary quotes.

Impact concept	Exemplary quotes
Anxiety 15 (75%)	02–01:…I start to get very anxious that now I know that a migraine's coming. And so it's also a physical and then an emotional thing for me, because it's coming. And I get very nervous…it becomes an emotional thing for me too, not just a physical thing…when I feel the knot and the tension in my neck, I know those are sy—those are the symptoms of a migraine, so those start to give me—I start to feel anxious
Negative impact on ability to work 15 (75%)	01–11: When I'm at work and nausea, or nausea sets in and my—it starts here, around my—right above my eyebrows, and I can't focus because it makes light very sensitive, sounds very sensitive, and it makes it hard to focus.
Stress 11 (55%)	01–10: Yes, at times I do, especially if I'm working on a project for work, like I was yesterday. I was stressed out, just knowing that if I'm about to have this migraine, it's going to take me now. I was supposed to finish up some work yesterday. And I got home, but I literally ate, and I fell asleep on the couch. And my son woke me up…So it's just like I was just kind of mad at myself, because I had stuff to do, but it's just like the migraines and the symptoms are just—it's overwhelming.
Negative impact on family life 8 (40%)	02–08: We used to go out to dinner a lot. I don't feel like doing that anymore. I don't feel like going out and doing anything anymore as a couple or as a family. When my kids ask me over for pic—cookouts and stuff and it's just—if I'm not feeling well, I can't do these things I don't want to do them.
Difficulty sleeping 7 (35%)	01–12: From the very beginning, pre‐migraine symptoms to full‐blown migraine, I cannot sleep.
Stay (close to) home/cancel plans 7 (35%)	01–14: There's times where I'm supposed to be going somewhere and I can't go because I know it's coming. And so not showing up to things because of it. So I don't go far so that I know that I can make it back home so that things are going to be OK…stay close to home…I can feel that some of this stuff is coming on. Sometimes I feel like it's coming on. Sometimes I just wake up with it. But I try to stay as close as possible to the house.
Annoyance/frustration 6 (30%)	02–04: It's frustration and all these things about having to d—how it changes my life. It's just—sometimes—OK, prodrome can be useful, but it sucks.
Need to lie down/rest 6 (30%)	01–07: Oh, a bad day is that I don't want to get out of bed. I just want to lie down and sleep…everywhere is spinning around. I just want to lie down…I will need to rest.
Negative impact on ability to socialize 6 (30%)	01–09: I'm not running out to—if I get a onset of migraine, if I have anything scheduled with friends or family, I'm canceling it because I'm not going to participate until I feel better…Well, the fatigue and the nausea…of course, the smell, because if I'm around people, for example, my father‐in‐law's house, I know that they smoke. And if I'm having pre‐symptoms of migraines, smell is a big thing for me.

Bothersome ratings for impacts of the prodrome phase of migraine

Participants provided bothersome ratings for impacts on a scale of 0 (not bothersome at all) to 10 (extremely bothersome); bothersome ratings were not obtained from all participants due to time constraints. Of the impacts with bothersome data from at least four participants (n ≥ 4/20, 20%), stress was reported as the most bothersome impact of migraine prodrome, on average (8.8). Stress was also reported as the most bothersome impact when considering median scores, at 10 (extremely bothersome). Sufficient severity data (i.e., n ≥ 4/20, 20%) were not provided for any impact. See Table 7 for a summary of bothersome ratings for impacts of the prodrome phase of migraine provided by at least four participants overall (n ≥ 4/20, 20%).

TABLE 7.

Bothersome ratings for impacts reported by n ≥ 4 participants. ^a

Impact	n Rating	Mean (SD)	Median (IQR)	Minimum–maximum
Negative impact on ability to work	13	8.1 (2.1)	9.0 (9.5–7.5)	2–10
Anxiety	13	7.2 (2.9)	8.0 (10.0–4.5)	2–10
Stay (close to) home/cancel plans	8	8.0 (1.4)	7.5 (9.8–7.0)	6–10
Stress	6	8.8 (1.7)	10.0 (10.0–6.8)	6–10
Difficulty sleeping	5	8.4 (1.6)	9.0 (10.0–6.5)	6–10
Difficulty driving	5	7.0 (1.4)	7.0 (8.5–5.5)	5–9
Negative impact on ability to socialize	4	8.0 (1.2)	8.5 (9.0–6.5)	6–9
Negative impact on family life	4	2.3 (2.2)	1.0 (4.8–1.0)	1–6

Abbreviations: IQR, interquartile range; SD, standard deviation.

^a Participants were asked to indicate how much each of their impacts of migraine prodrome bother them on a scale of 0–10, where 0 means not bothersome at all and 10 is extremely bothersome.

Treatment experience and management

Most participants (n = 16/20, 80%) reported taking medication (e.g., triptans, NSAIDs, etc.) during the prodrome phase of migraine. Of these participants, over half (n = 11/16, 69%) reported that they take medication at least 50.0% of the times they experience migraine prodrome symptoms. Additionally, over half of participants who take medication during the prodrome phase (n = 10/16, 63%) reported that taking medication during the prodrome phase helps prevent migraine headache pain or reduce its severity at least 50% of the time. Of the remaining six participants, four (n = 4/16, 25%) reported that the medication helps reduce/prevent migraine headache pain less than 50% of the time (e.g., 20%–40% of the time or “not often”) and two participants (n = 2/16, 13%) noted that the frequency of the medication's effectiveness in reducing/preventing migraine headache pain varies. Although participants were asked about treatments that they take for migraine and the timing of medication administration, they were not asked about specific treatments taken during the prodrome because migraine treatment administration guidelines recommend treating after headache pain begins.

The four participants who indicated that they do not take medication during the prodrome phase were asked if they would be willing to if it reduced or prevented a migraine attack. Most of these participants (n = 3/4, 75%) indicated that they would be willing to take medication during the prodrome phase. Participants were also asked if they ever felt unsure of whether or when to take medication during the prodrome phase. Of those with evaluable data, just over half (n = 11/19, 58%) reported that they felt sure and the remaining participants (n = 8/19, 42%) felt unsure.

DISCUSSION

The primary objective of this research was to characterize the prodrome phase of migraine through qualitative interviews. Concept elicitation interviews were conducted with 20 participants to understand the cardinal symptoms and impacts they experience. Participants also provided information on the timing, severity, and bothersomeness of prodromal features, as well as the treatment and management of these features during the prodrome phase.

Interviews revealed that nausea, fatigue/tiredness, sensitivity to light, neck pain/stiffness, dizziness/vertigo/light‐headedness, irritability, sensitivity to sound, sensitivity to temperature, difficulty concentrating, and difficulty thinking/brain fog were the most common prodrome symptoms. Conceptually, difficulty concentrating and difficulty thinking/brain fog were identified and analyzed as distinct constructs based on participant descriptions that concentration was a more advanced cognitive function than thinking more generally; however, it is worth noting that these are conceptually similar from a measurement standpoint as related examples of cognitive functioning. On a domain level, autonomic symptoms (e.g., nausea, pale or flushed face) were often experienced by participants, followed by general symptoms (e.g., fatigue/tiredness, yawning), pain or pressure, sensory hypersensitivity, and cognitive symptoms.

Participants were asked how confident they were that a migraine would follow each prodrome symptom, the amount of time between symptom onset and headache onset, and the average duration of each symptom. During their interview, nearly all participants (n = 19/20, 95.0%) reported being highly confident that migraine headache pain would occur after experiencing at least one of their prodromal symptoms. Specifically, among the top 10 most frequently reported symptoms, sensitivity to light, dizziness/vertigo/light‐headedness, and sensitivity to temperature received high confidence ratings related to subsequent headache onset from the majority of participants (n ≥ 5/7, 71%) who provided confidence data. Additionally, at least half of the participants (n ≥ 3/6, 50%) who provided confidence data reported high confidence that a headache would follow nausea, neck pain/stiffness, sensitivity to sound, irritability, difficulty thinking/brain fog, and difficulty concentrating. Five of the participants who provided confidence data for fatigue/tiredness (n = 5/14, 36%) reported having high confidence that a headache would follow this prodrome symptom. Although confidence associated with individual symptoms varied, participants reported that the occurrence of multiple prodrome symptoms, simultaneously or sequentially, increased their confidence that a subsequent headache would occur. Therefore, a singular symptom in isolation may not be a highly reliable indicator of a subsequent headache but experiencing more than one symptom may more reliably suggest the impending onset of a migraine headache.

Many prodromal symptoms (26/36, 72%) occurred from 1 to 6 h before the onset of headache pain. This finding suggests that there is a feasible timeframe for the administration of treatment during the prodrome phase. If the interval was too short, there may not be sufficient time for the absorption and onset of treatment effect for oral medications. If the interval was too long, a drug could be metabolized before the headache began. Migraine prodrome is normally characterized as occurring a few hours to days before the onset of headache pain, whereas the aura phase typically begins from 5 to 60 min before a migraine attack. ¹⁷ Based on the average time reported from symptom onset to migraine headache, 22 of 36 symptoms (61%) occurred more than an hour from the start of the migraine on average. Those warning symptoms that occurred within an hour of migraine headache onset were often typical of the aura phase (i.e., visual disturbances, difficulty speaking). Blurred vision is not commonly considered as a symptom of the aura phase; however, clinical details are required for accurate classification. Symptoms with long intervals from prodrome to headache onset include loss of appetite (9.1 h), sensitivity to smell (8.5 h), changes in bowel movement (6.5 h), sensitive to temperature changes (5.2 h), and muscle tension (5.0 h). A comprehensive pathophysiology of migraine would need to account for the variation in the interval from prodrome symptom onset to migraine headache onset.

The most common impacts of the prodrome phase included decreased ability to work, anxiety, stress, negative impact on family life, and having to stay (close to) home/cancel plans. These data suggest that the burden of disease also occurs during the prodrome and is not confined to the headache phase. Of the total number of impacts reported (28), a quarter of impacts (7/28, 25%) were related to the emotional and activities of daily living domains. These findings align with previous studies that observed functional impairment and burden of disease occurring during the prodrome. ⁵ , ²⁵

Although conceptual saturation was not met as a few symptoms and impacts were spontaneously reported in the last 25% of interviews, the concepts were conceptually similar to symptoms that were reported in earlier interviews, suggesting that no new themes would emerge from additional interviews. Therefore, the N = 20 sample size can be considered adequate for this study and is consistent with other sample sizes used in qualitative research of this nature. ²²

When comparing the symptoms reported in this study to those found in key articles on migraine prodrome symptom experience, there was at least 63% agreement in symptoms across the four articles ⁴ , ⁶ , ⁷ , ²⁶ that were used for comparison and notably 100% agreement with Eigenbrodt et al.⁴ It should be noted that Eigenbrodt et al.⁴ treated depressive symptoms as an impact, and not as a symptom of prodrome, in contrast with the present report. Symptoms that were not reported in this qualitative study that were included in the previous literature included: tingling in extremities, ear symptoms, taste distortions, chest symptoms, clumsiness, back/shoulder tightness, neck cracking, jaw tightness, difficulty breathing, restlessness/excess energy, swelling, and depression. Novel symptoms reported in the current study and not included in prior articles included: loss of appetite, sensitivity to smell, pale or flushed face, anxiety, feeling uncomfortable, sensitive skin, and vomiting. Differences may be attributable to the samples of patients across studies, the variable nature of the prodrome experience, and the fact that the four stages of migraine do not fit neatly into four distinct categories. Overall, most symptoms reported in this study are supported by the existing literature in this indication.

Given the multitude of symptoms and impacts reported during the prodrome, this migraine phase has a substantial impact on an individual's life. Most participants (80%) reported taking medication during the prodrome phase, and over half of these participants (63%) reported that medication helped to reduce/prevent migraine headache pain at least half of the time. At the time this qualitative research was conducted, treatment administration during the prodrome had not yet been proven effective in randomized controlled trials; however, recent evidence for this strategy has since emerged. ⁹ However, 42% of participants indicated that they felt unsure about the choice to administer and/or timing of medication during the prodrome. Overall, recent evidence will aid in educating patients on treating symptoms during the prodrome phase to prevent the onset of migraine headaches.

Given the prevalence and burden of prodromal symptoms, they should be viewed as a potential independent target for treatment. Although treating these symptoms during the prodrome is often discussed as a strategy to prevent the headache phase, addressing them directly may also be beneficial. Available evidence suggests that ubrogepant during the prodrome not only significantly reduces the probability of a headache, it also reduces the duration of symptoms that begin during the prodrome phase. ⁹ Recent evidence also indicates that ubrogepant administered during the prodrome phase significantly reduced or prevented functional disability associated with headache pain. ⁹

This study has several limitations. First, our classification of prodrome symptoms is imperfect. For example, we separately assessed difficulty thinking/brain fog and difficulty concentrating; of the 12 participants (60%) who had one of these features, four (33%) had both. From our perspective, difficulty thinking/brain fog is a passive cognitive construct, whereas difficulty concentrating involves an active process of mental focus. Furthermore, the Patient‐Reported Outcomes Measurement Information (PROMIS)‐Cognitive Function (a validated measure) asks about both concepts separately, providing precedence for treating these two concepts as distinct. Similarly, dizziness, vertigo, and light‐headedness were grouped together during analysis; though these symptoms overlap in patient descriptions, clinicians view them as mechanistically and symptomatically distinct; this area requires further investigation in the prodrome phase. ²⁷ Additionally, we did not fully distinguish between the symptoms of prodrome and the symptoms of aura. Specifically, symptoms such visual disturbances, difficulty speaking, numbness/tingling in face, difficulty reading or writing, and dizziness/vertigo may be manifestations of the aura phase of migraine. Because many of these symptoms (i.e., difficulty speaking, visual disturbances) occur within an hour of migraine headache onset, the timing is compatible with aura. Despite this limitation, most symptoms were followed by a headache by more than 1 h but are not characteristic of the aura phase. Therefore, future work will be needed to disentangle aura and prodrome from each other. Furthermore, the concept of “confidence” used by researchers and participants to theorize the probability of migraine onset after certain prodromal symptoms have occurred could be susceptible to recall bias or overestimation. Specifically, more recent episodes of prodrome symptoms may be more salient and easier to remember by participants than symptoms experienced further in the past or less often. Therefore, patients may feel more confident that more salient symptoms are characteristic of the prodrome compared to symptoms experienced less frequently or in the distant past.

Other limitations of this work arise from the eligibility criteria and recruitment sites used for this study. These criteria impose limitations on the generalizability of our findings. Because one of the clinical sites was a neurological institute, participants from that site may have been advised specifically to take medication during the prodrome phase; however, until recently, this was not supported by an evidence‐based treatment approach. ⁹ Finally, because this was a qualitative study, not every question was asked of every patient; therefore, the occurrence of missing data for bothersomeness and severity of prodrome symptoms and impacts reveals some limitations on the interpretation of our findings.

This study is one of the first to assess the humanistic burden of migraine prodrome from the patient perspective. Findings related to symptom timing contribute to the distinction between migraine phases as well as the progression of prodromal symptoms. Specifically, people with migraine are often uncertain about when to take medication; currently, we instruct patients to treat early, while pain is mild, but not too often. This study sets the stage for assessing the benefits of treating in the prodrome phase, when initial symptoms that signal impending headache develop. Identifying prodrome symptoms that reliably predict headache provides a foundation for treating during prodrome, a strategy tested previously in a recent randomized trial. ⁹ Prodrome symptom identification could encourage early treatment intervention, possibly resulting in improved efficacy and better patient outcomes. The findings herein can be used to inform future studies exploring this potential benefit. Specifically, more research is needed to explore the incidence of migraine prodrome across a larger patient population, including whether early intervention with acute migraine medication leads to the reduction of migraine headache pain, or prevents its onset altogether. This future research will aid the effort to mitigate the incidence and humanistic burden of migraine attacks.

CONCLUSION

This qualitative research study is among the first studies specifically exploring the experience of the migraine prodrome phase from the perspective of patients. Overall, these findings help characterize the humanistic burden of migraine prodrome, including the most common prodrome symptoms, their variable nature, their timing, and the use and effectiveness of acute medications taken during prodrome.

AUTHOR CONTRIBUTIONS

Richard B. Lipton: Conceptualization; writing – original draft. Jonathan Stokes: Conceptualization; formal analysis; writing – original draft. Christopher J. Evans: Conceptualization; data curation; formal analysis; writing – original draft. Elizabeth Hribal: Conceptualization; data curation; formal analysis; writing – original draft. Kailee White: Conceptualization; data curation; formal analysis; writing – original draft. Katelyn Keyloun: Conceptualization; writing – original draft. Krutika Parikh: Formal analysis; writing – original draft. Pranav Gandhi: Conceptualization; data curation; formal analysis; writing – original draft. David W. Dodick: Formal analysis; writing – original draft.

FUNDING INFORMATION

The research associated with this manuscript was funded by AbbVie. AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Endpoint Outcomes, a Lumanity company, received consulting fees by AbbVie to conduct this research.

CONFLICT OF INTEREST STATEMENT

Richard B. Lipton has had research support paid to his institution from the Czap Foundation, the National Institutes of Health, the S&L Marx Foundation, and the US Food and Drug Administration; and personal fees from AbbVie/Allergan, Amgen, Axsome, Biohaven, BioVision, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Merck, Pernix, Pfizer, Teva, Vector, and Vedanta Research; and he holds stock/options in Axon, Biohaven, CoolTech, and Manistee. Jonathan Stokes, Katelyn Keyloun, Krutika Parikh, and Pranav Gandhi are employees of AbbVie and may hold AbbVie stock. Christopher J. Evans, Elizabeth Hribal, and Kailee White are employees of companies that received consultancy fees for the current and other studies. David W. Dodick has the following disclosures: Consulting: Amgen, Atria, CapiThera Ltd., Cerecin, Ceruvia Lifesciences LLC, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, Pfizer. Honoraria: American Academy of Neurology, Headache Cooperative of the Pacific, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company (Clinical Education Alliance LLC), Teva (speaking), Amgen (speaking), Eli Lilly (speaking), Lundbeck (speaking), Pfizer (speaking), Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, Medica Communications LLC, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Non‐profit board membership: American Brain Foundation, American Migraine Foundation, ONE Neurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, Domestic Violence HOPE Foundation/Panfila. Research support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Henry Jackson Foundation, and Patient Centered Outcomes Research Institute (PCORI). Stock options/shareholder/patents/board of directors: Ctrl M (options), Aural analytics (options), Axon Therapeutics, ExSano (options), Palion (options), Man and Science, Healint (options), Theranica (options), Second Opinion/Mobile Health (options), Epien (options/board), Nocira (options), Matterhorn (shares/board), Ontologics (shares/board), King‐Devick Technologies (options/board), Precon Health (options/board), AYYA Biosciences (options), Axon Therapeutics (options/board), Cephalgia Group (options/board), and Atria Health (options/employee). Patent 17189376.1‐1466:vTitle: Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (Non‐royalty bearing). Patent application submitted: Synaquell® (Precon Health).

Supporting information

Data S1.

Lipton RB, Stokes J, Evans CJ, et al. Characterizing the patient experience during the prodrome phase of migraine: A qualitative study of symptoms and their timing. Headache. 2025;65:1355‐1368. doi: 10.1111/head.15024