Clinical characteristics and patient-reported outcomes of chronic and episodic migraine patients at a US tertiary headache center: A retrospective observational study

Abstract

Objective

To describe differences in clinical and demographic characteristics between patients with episodic migraine (EM) or chronic migraine (CM) and determine the effect of migraine subtype on patient-reported outcome measures (PROM).

Background

Prior studies have characterized migraine in the general population. While this provides a basis for our understanding of migraine, we have less insight into the characteristics, comorbidities, and outcomes of migraine patients who present to subspecialty headache clinics. These patients represent a subset of the population that bears the greatest burden of migraine disability and are more representative of migraine patients who seek medical care. Valuable insights can be gained from a better understanding of CM and EM in this population.

Methods

We conducted a retrospective observational cohort study of patients with CM or EM seen in the Cleveland Clinic Headache Center between January 2012 and June 2017. Demographics, clinical characteristics, and patient-reported outcome measures (3-Level European Quality of Life 5-Dimension [EQ-5D-3L], Headache Impact Test-6 [HIT-6], Patient Health Questionnaire-9 [PHQ-9]) were compared between groups.

Results

Eleven thousand thirty-seven patients who had 29,032 visits were included. More CM patients reported being on disability 517/3652 (14.2%) than EM patients 249/4881 (5.1%) and had significantly worse mean HIT-6 (67.3 ± 7.4 vs. 63.1 ± 7.4, p < 0.001) and median [interquartile range] EQ-5D-3L (0.77 [0.44–0.82] vs. 0.83 [0.77–1.00], p < 0.001), and PHQ-9 (10 [6–16] vs. 5 [2–10], p < 0.001).

Conclusions

There are multiple differences in demographic characteristics and comorbid conditions between patients with CM and EM. After adjustment for these factors, CM patients had higher PHQ-9 scores, lower quality of life scores, greater disability, and greater work restrictions/unemployment.

Abbreviations

CaMEO

Chronic Migraine Epidemiology and Outcomes

CM

chronic migraine

EHR

electronic health record

EM

episodic migraine

EQ-5D-3L

3-Level European Quality of Life 5-Dimension

HIT-6

Headache Impact Test-6

HRQOL

health-related quality of life

IBMS

International Burden of Migraine Study

ICD-9

International Classification of Diseases, Ninth Revision

ICD-10

International Classification of Diseases, Tenth Revision

ICHD-3

International Classification of Headache Disorders, 3rd edition

IQR

interquartile range

KP

Knowledge Program

MIDAS

Migraine Disability Assessment

PHQ-4

Patient Health Questionnaire-4

PHQ-9

Patient Health Questionnaire-9

PROM

patient-reported outcome measures

PROMIS

Patient-Reported Outcomes Measurement Information System

SD

standard deviation

UCNS

United Council for Neurologic Subspecialties

INTRODUCTION

Of the nearly 68.5 million Americans living with migraine, approximately 5% have chronic migraine (CM), and an additional 3% of patients with episodic migraine (EM) may transition to CM every year.^{1, 2} Approximately 33% to 65% of patients with CM transition back to EM in the general population.^3-5 CM is defined as headache occurring at least 15 days per month for >3 months, with ≥8 of those days meeting the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria for migraine.⁶ EM is defined as having fewer migraine/headache days than the ICHD-3 definition of CM. Prior studies have provided a well-formed, longitudinal understanding of the prevalence and characterization of migraine, along with its associated comorbidities and disability, in the general population.^7-12 While this provides a basis for our understanding of EM and CM, we have less insight into the characteristics, comorbidities, and outcomes of patients with migraine who present to subspecialty headache clinics. Few studies have characterized patients referred to specialized headache clinics, and many of these studies are small and limited in scope.^{13, 14} These patients represent a subset of the general population that bears the greatest burden of migraine disability and, as a result, are more representative of migraine patients who seek medical care. Thus, valuable insights can be gained by a more detailed characterization of patients presenting to specialized headache clinics. The objectives of this study were to describe differences in clinical and demographic characteristics of patients with EM and CM who seek care from headache specialists and to identify the independent association of migraine type with patient-reported outcomes measures (PROMs). We hypothesized that patients with CM would have significantly higher headache-related disability and worse quality of life based on PROMs compared to patients with EM.

METHODS

Study design and data source

The present study is a retrospective, observational, cohort study of patients with EM or CM seen at the Cleveland Clinic Headache Clinic. This is the primary analysis of these data. The Headache Clinic operates at nine health facilities in the Cleveland, Ohio, area and conducted approximately 15,000 visits per year during the time the data were collected. The headache sections consist of ten physicians and six advanced practice providers who only see patients for headache or facial pain. The primary data source for the study was the Cleveland Clinic Electronic Health Record (EHR; Epic Systems) and the Cleveland Clinic Knowledge Program (KP) database.¹⁵ Patients completed tailored questionnaires either using electronic tablets at their visit or through Epic's web-based patient portal, MyChart, prior to their appointment. Responses were immediately available for the provider to review and were verified within the Epic encounter. Data are stored discretely in the KP database. Patient-entered questions are deployed at appointments at pre-set intervals and are not administered if patients have a visit within that time interval.

Clinical data, including patient questionnaires, were collected as part of routine care. This study was approved by Cleveland Clinic's Institutional Review Board (#18-1161). Because the study consisted of analyses of pre-existing data, the requirement for patients’ written informed consent was waived.

Patients

Patients (≥18 years of age) with a primary or secondary encounter diagnosis of CM or EM for at least one visit to the Cleveland Clinic Headache Clinic between January 2012 and June 2017 were included in the cohort. The International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes used to identify EM or CM are presented in Table 1. Diagnosis was determined by United Council for Neurologic Subspecialties (UCNS)–certified headache specialists. Corresponding ICD-9 and ICD-10 codes were extracted and independently verified in a random sample of 50 patient charts. All ICD codes in this sample accurately reflected the patient's group status. Individuals were classified as either EM or CM patients if they were diagnosed with only that category of migraine during the study period.

TABLE 1. ICD codes for chronic versus episodic migraine classification.

Diagnosis	ICD-9 code	ICD-10 code
Episodic migraine	346.0x	G43.0x
	346.1x	G43.1x
	346.4x	G43.80x, G43.81x, G43.82x, G43.83x
	346.9x	G43.90x, G43.91x
Chronic migraine	346.7x	G43.7, G43.70x, G43.71x

• Abbreviations: ICD-9, International Classification of Diseases, Ninth Revision (ICD-9); ICD-10, International Classification of Diseases, Tenth Revision (ICD-10).

Demographics and clinical characteristics

Patient demographics included age, race, sex, marital status, and household income, estimated from 2010 census data by ZIP code. Clinical characteristics included indicators of nine comorbid conditions recorded in the EHR: anxiety, depression, fibromyalgia, obesity, head injury, coronary artery disease, diabetes, hypertension, and stroke.

Patient-reported outcome measures

In this study, the following PROMs were assessed:

1. Global health-related quality of life (HRQOL) was assessed at the Cleveland Clinic Headache Clinic using the 3-Level European Quality of Life 5-Dimension (EQ-5D-3L) questionnaire from January 2012 to October 2015.^{16, 17} Starting in October 2015, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.0 was collected.¹⁸ An algorithmic mapping method was used to equate PROMIS scores to an EQ-5D-3L index score.¹⁹
2. Headache Impact Test (HIT-6) is a measure of the impact of headache on daily life in patients with migraine.²⁰ It has been validated in both EM and CM patients and can help differentiate between the two populations.²¹
3. Patient Health Questionnaire-9 (PHQ-9) is a commonly used screening tool for depressive symptoms.²²
4. Patient-reported headache characteristics were measured by individual items examining the current level of migraine pain, as well as typical location, character, duration, and frequency of pain. Patients also reported current work status, whether they had seen a specialist in the past, and whether they had been hospitalized or had an emergency department visit due to migraine pain.

Statistical analysis

The data presented in this study have not been previously published. All analyses were determined a priori. Descriptive statistics were used to summarize sample demographics, clinical characteristics, and PROMs. Frequency count with percentage was used to describe categorical data, and mean with standard deviation or median with interquartile range (IQR) was used to describe continuous data. Chi-square tests were used to compare categorical variables, and independent-samples t-tests (parametric) or Mann–Whitney U tests (nonparametric) were used to compare continuous variables across patient types.

Multivariable regression models were constructed to determine whether migraine type was an independent predictor of HIT-6, HRQOL, PHQ-9, and patient work status. For the first three measures, linear regression models were fit to examine the effect of migraine status, controlling for demographic variables (age, sex, race, marital status, median income by ZIP code) and comorbidities (history of anxiety, history of depression, fibromyalgia, obesity, head trauma, coronary artery disease, diabetes, hypertension, stroke) determined a priori. We hypothesized that these demographic and comorbidity variables would be related to the outcomes and thus included them as important confounders. For work status, a logistic regression model was constructed based on a dichotomous outcome calculated as working with restriction or not working versus working without restriction. Retired patients and patients who were unable to work and received full disability compensation were excluded from the model sample. For patients with multiple PROMs, the first score for each PROM was used as the outcome in multivariable models. As a sensitivity analysis, identical models were fit using mean values across all patient visits for continuous PROMs, and for the work status model, we also fit a model using the patient's last visit. No statistical power calculation was conducted. The sample size was based on the available data. Missing data were handled using complete case analysis. The only covariates with missing data were race, marital status, and median household income by ZIP code. Each of these variables were missing in <5% of patients. About 10% of patients did not complete any PROM data during the study period. All analyses were completed in R, version 3.6.0 (R Core Team). All tests were two-tailed, and statistical significance was established at p < 0.05.

RESULTS

Demographic and clinical characteristics

The final study sample consisted of 11,037 patients who had 29,032 visits in our headache clinic during the study period. Figure 1 shows a flow diagram for our patient sample. Key characteristics of the cohort are presented in Table 2. Overall, the cohort was largely female (79.8%) and White (80.9%), with an average age at first visit of 42.4 years (standard deviation [SD] 14.3 years). Chronic and episodic migraine patients in the cohort differed in marital status, with EM patients being more likely to be married (56.1% vs. 51.5% for EM and CM patients, respectively). EM patients had a higher estimated median household income ($51,960 vs. $48,210 for EM and CM patients, respectively). CM patients were more likely to have all the measured comorbidities, with statistical significance reached for all except obesity.

FIGURE 1

Study population. ICD, International Classification of Diseases.

TABLE 2. Demographic and clinical characteristics of unique patients seen in the headache center with a diagnosis of chronic or episodic headache between January 2012 and June 2017.

Characteristics	Patients with chronic migraine (N = 4761)	Patients with episodic migraine (N = 6276)	p values^a
Demographic characteristics
Female sex, n (%)	3795 (79.7%)	5012 (79.9%)	0.865
Race, n (%)
White	3864 (81.2%)	5064 (80.7%)	0.056
Black	548 (11.5%)	750 (12.0%)
Asian	29 (0.6%)	70 (1.1%)
Other	109 (2.3%)	135 (2.2%)
Unknown	211 (4.4%)	257 (4.1%)
Marital status, n (%)
Married	2451 (51.5%)	3519 (56.1%)	<0.001
Non-married	2228 (46.8%)	2673 (42.6%)
Unknown	82 (1.7%)	84 (1.3%)
Age at first headache visit, years, mean (SD)	43.0 (14.3)	41.8 (14.2)	<0.001
Median household income [IQR]^b^,^c	48.2 [40.5–62.3]	52.0 [41.9–64.8]	<0.001
Comorbid conditions, n (%)
Anxiety	1853 (38.9%)	1971 (31.4%)	<0.001
Depression	2276 (47.8%)	1970 (31.4%)	<0.001
Fibromyalgia	1243 (26.1%)	1104 (17.6%)	<0.001
Obesity	1007 (21.2%)	1255 (20.0%)	0.143
Head injury	645 (13.5%)	754 (12.0%)	0.018
Coronary artery disease	268 (5.6%)	258 (4.1%)	<0.001
Diabetes	463 (9.7%)	416 (6.6%)	<0.001
Hypertension	1394 (29.3%)	1461 (23.3%)	<0.001
Stroke	426 (8.9%)	439 (7.0%)	<0.001

• Abbreviations: IQR, interquartile range; SD, standard deviation.
• ^a p values reflect a comparison of chronic and episodic migraine patients.
• ^b In thousands of dollars. Estimated from ZIP code based on 2010 Census data. ZIP code taken from first headache center visit. Non-parametric test used.
• ^c Based on first available value.

Patient-reported headache characteristics

Headache characteristics and work status are presented in Table 3. There were notable differences between the groups. CM patients were more likely to endorse higher pain levels than EM patients, as well as to endorse all headache locations on a “select all that apply” scale. CM patients were more likely to select all categories of headache character, except the “other” category. The majority of patients chose the pressure, aching, and throbbing categories. CM patients also reported a higher frequency of days in a month with headache (mean [SD], 20.8 [9.1] days; median, 22 days) compared to EM patients (mean [SD], 12.1 [9.0] days; median, 9 days).

TABLE 3. Patient-reported headache characteristics for patients completing patient questionnaires: First visit with available data.

Characteristics, n (%)	All patients with chronic migraine	All patients with episodic migraine	p values
Headache characteristics
Headache/face pain level^a	N = 3751	N = 4741
	Median = 6, IQR = (3, 7)	Median = 2, IQR = (0, 5)	<0.001
Headache location^b	N = 3521	N = 3670
Right side	1754 (49.8%)	1527 (41.6%)	<0.001
Left side	1659 (47.1%)	1442 (39.3%)	<0.001
Top side	1444 (41.0%)	1084 (29.5%)	<0.001
Face	799 (22.7%)	665 (18.1%)	<0.001
Behind the eyes	1685 (47.9%)	1557 (42.4%)	<0.001
Forehead	1679 (47.7%)	1377 (37.5%)	<0.001
Back of head	1762 (50.0%)	1338 (36.5%)	<0.001
Neck	1662 (47.2%)	1305 (35.6%)	<0.001
Headache character	N = 3545	N = 3700
Shooting	638 (18.0%)	430 (11.6%)	<0.001
Burning	332 (9.4%)	288 (7.8%)	<0.001
Throbbing	1818 (51.3%)	1603 (43.3%)	<0.001
Aching	1880 (53.0%)	1900 (51.4%)	<0.001
Sharp	922 (26.0%)	731 (19.8%)	<0.001
Dull	948 (26.7%)	1468 (39.7%)	<0.001
Pressure	2128 (60.0%)	2158 (58.3%)	<0.001
Electrical	219 (6.2%)	180 (4.9%)	<0.001
Band-like	425 (12.0%)	323 (8.7%)	<0.001
Exploding	487 (13.7%)	304 (8.2%)	<0.001
Squeezing	893 (25.2%)	704 (19.0%)	<0.001
Other	163 (4.6%)	208 (5.6%)	0.596
Headache frequency/month (in days)	N = 1835	N = 2317
	Mean (SD) = 20.8 (9.1); median = 22	Mean (SD) = 12.1 (9.0); median = 9	<0.001
Work status	N = 3652	N = 4881
Full-time work, school, or homemaker (no restrictions)	1587 (43.5%)	3215 (65.9%)	<0.001
Full-time work, school, or homemaker (with restricted duty)	210 (5.8%)	202 (4.1%)
Part-time work, school, homemaker (no restrictions)	310 (8.5%)	445 (9.1%)
Part-time work, school, homemaker (with restricted duty)	135 (3.7%)	77 (1.6%)
Neither studying nor working for medical reasons (without compensation of SSDI, SSI, or BWC)	324 (8.9%)	208 (4.3%)
Neither studying nor working for non-medical reasons, including looking for work	76 (2.1%)	108 (2.2%)
Not working and applying for compensation (SSDI, SSI, or BWC)	268 (7.3%)	124 (2.5%)
Unable to work and receive full disability compensation	517 (14.2%)	249 (5.1%)
Retired	225 (6.2%)	253 (5.2%)
Seen by specialist prior to going to CC headache center	N = 3614	N = 4024
	2788 (77.1%)	2494 (62.0%)	<0.001

• Abbreviations: BWC, Bureau of Workers’ Compensation; CC, Cleveland Clinic; IQR, interquartile range; SD, standard deviation; SSDI, Social Security Disability Insurance; SSI, Supplemental Security Income.
• ^a Unique N's are provided for each measure, as they varied.
• ^b For location and character, patients picked all responses that applied; hence, percentages do not sum to 100%.

A larger proportion of CM patients reported being on disability (14.2%) compared to EM patients (5.1%). In addition, more CM patients reported having previously seen a headache specialist (77.1%) compared to EM patients (62.0%).

Patient-reported outcome measures

PROMs were collected in 22,454 (77.3%) patient visits among 9939 patients. This included PROMs completed by 4336 CM patients at 11,321 visits and by 5603 EM patients at 11,133 visits. Compared to the 9939 patients who completed PROMs, patients who did not complete any PROMs during the study period (n = 1098) were less likely to be female (76.9% vs. 80.1%, p = 0.012); less likely to be White (73.5% vs. 81.7%, p < 0.001); less likely to be married (48.5% vs. 54.7%, p < 0.001); had lower median household income (median = $49,486 vs. $51,765, p = 0.013); were less likely to have history of depression (35.2% vs. 38.8%, p = 0.023); and were more likely to have diabetes (10.1% vs. 7.7%, p = 0.007), hypertension (29.4% vs. 25.5%, p = 0.005), and stroke (10.1% vs. 7.6%, p = 0.004). Although there were fewer CM patients, CM patients were seen more frequently than EM patients (mean [SD], 3.2 [4.4] CM visits vs. 2.2 [2.2] EM visits; median [IQR] = 1 [1, 3] visits for both groups); as a result, CM patients completed a higher number of visits with corresponding PROMs (mean [SD], 2.6 [3.3] CM visits vs. 2.0 [1.8] EM visits; median [IQR] = 1 [1, 3] visits for CM vs. 1 [1, 2] visits for EM). Overall, CM patients had a median interval of 91 days between visits, while EM patients had a median interval of 150 days between visits. Patients with CM had worse scores on all PROMS compared to patients with EM (Table 4).

TABLE 4. Patient-reported outcomes for patients completing questionnaires.^a

Characteristics	Patients with chronic migraine	Patients with episodic migraine	p values
HRQOL: EQ-5D-3L,^b median [IQR]	0.77 [0.44, 0.82] N = 3238	0.83 [0.77, 1.00] N = 4295	<0.001
Headache Impact Test-6,^c mean (SD)	67.3 (6.0) N = 4140	63.1 (7.4) N = 5176	<0.001
Patient Health Questionnaire-9,^c median [IQR]	10 [6, 16] N = 3969	5 [2, 10] N = 5183	<0.001

• Abbreviations: EQ-5D-3L, 3-Level European Quality of Life 5-Dimension; HRQOL, health-related quality of life; IQR, interquartile range; SD, standard deviation.
• ^a Includes first visit data available from patients with primary or secondary diagnosis of chronic or episodic migraine at any time during the study period.
• ^b Patients were given the EQ-5D-3L from January 2012 through October 11, 2015 and Patient-Reported Outcomes Measurement Information System Global Health scale from October 2015 through June 2017.
• ^c Higher scores reflect worse symptoms.

Multivariable models were constructed to further determine whether migraine type is an independent predictor of PHQ-9, HRQOL, HIT-6, and unrestricted/non-work status (Table 5). After controlling for demographic variables and comorbidities, results for all four models affirmed that CM patients reported worse depressive symptoms (higher PHQ-9), lower HRQOL, and worse headache impact, and were more likely to be working with restriction or not working compared to EM patients (Table 5). Patterns of results were similar when using the mean values (or last values in the case of work status) across completion (data not shown).

TABLE 5. Multivariable models of PHQ-9 (N = 8603), HRQOL (N = 7074), HIT-6 (N = 8804), and unrestricted work status (N = 7632).

Name	PHQ-9^a estimate (95% CI)	p values	HRQOL (EQ-5D-3L) estimate (95% CI)	p values	HIT-6^a estimate (95% CI)	p values	Restricted work/non-work status odds ratio (95% CI)	p values
Chronic migraine patients (vs. episodic)	3.8 (3.5, 4.0)	<0.001	−0.125 (−0.134, −0.116)	<0.001	3.9 (3.6, 4.2)	<0.001	2.7 (2.4, 3.1)	<0.001
Age at start of study (per decades)	0.0 (−0.1, 0.1)	0.913	−0.002 (−0.006, 0.002)	0.249	−0.7 (−0.8, −0.6)	<0.001	1.2 (1.2, 1.3)	<0.001
Female (vs. male)	−0.7 (−1.0, −0.4)	<0.001	0.011 (−0.001, 0.023)	0.068	1.1 (0.8, 1.5)	<0.001	0.7 (0.6, 0.8)	<0.001
White (vs. non-White)	0.1 (−0.3, 0.5)	0.621	0.018 (0.004, 0.032)	0.011	−1.1 (−1.6, −0.7)	<0.001	1.2 (1.0, 1.4)	0.085
Married	−0.7 (−0.9, −0.4)	<0.001	0.031 (0.021, 0.041)	<0.001	−0.3 (−0.6, 0.0)	0.092	0.6 (0. 6, 0.7)	<0.001
Household income (per $10,000)^b	−0.3 (−0.4, −0.3)	<0.001	0.012 (0.009, 0.014)	<0.001	−0.4 (−0.5, −0.3)	<0.001	0.9 (0.9, 0.9)	<0.001
History of anxiety	0.8 (0. 5, 1.0)	<0.001	−0.025 (−0.035, −0.014)	<0.001	0.1 (−0.2, 0.5)	0.392	0.9 (0. 8, 1.0)	0.095
History of depression	3.3 (3.0, 3.6)	<0.001	−0.066 (−0.077, −0.056)	<0.001	1.6 (1.3, 1.9)	<0.001	2.2 (2.0, 2.5)	<0.001
Fibromyalgia	0.8 (0.5, 1.1)	<0.001	−0.064 (−0.075, −0.052)	<0.001	0.5 (0.1, 0.8)	0.008	2.1 (1.8, 2.4)	<0.001
Obesity	0.1 (−0.2, 0.4)	0.549	−0.003 (−0.015, 0.009)	0.607	−0.3 (−0.6, 0.1)	0.157	0.9 (0.8, 1.0)	0.433
Head trauma	0.2 (−0.2, 0.5)	0.390	−0.019 (−0.033, −0.005)	0.007	0.2 (−0.2, 0.6)	0.369	1.1 (0.9, 1.3)	0.397
CAD	−0.4 (−1.0, 0.2)	0.212	−0.002 (−0.025, 0.021)	0.861	−0.0 (−0.7, 0.7)	0.99	1.0 (0.7, 1.4)	0.978
Diabetes	0.9 (0.4, 1.3)	<0.001	−0.047 (−0.065, −0.029)	<0.001	0.7 (0.1, 1.2)	0.022	1.9 (1.5, 2.4)	<0.001
HTN	0.0 (−0.3, 0.3)	0.908	−0.005 (−0.017, 0.007)	0.45	−0.3 (−0.6, 0.1)	0.161	1.2 (1.0, 1.4)	0.033
Stroke	0.4 (−0.1, 0.8)	0.129	−0.031 (−0.049, −0.013)	0.001	0.5 (0.0, 1.1)	0.059	2.3 (1.8, 2.8)	<0.001

• Note: Estimates with 95% confidence intervals presented from linear regression models; odds ratios with 95% confidence intervals presented from multivariable regression model.
• Abbreviations: CAD, coronary heart disease; CI, confidence interval; EQ-5D-3L, 3-Level European Quality of Life 5-Dimension; HIT-6, Headache Impact Test-6; HRQOL, health-related quality of life; HTN, hypertension; PHQ-9, Patient Health Questionnaire-9.
• ^a Higher scores reflect worse symptoms.
• ^b Estimated median household income based on ZIP code.

DISCUSSION

Our study found numerous differences in demographic and clinical characteristics between patients with CM and EM who presented to a large tertiary headache clinic. Patients with CM were older, were less likely to be married, and had lower estimated household income than patients with EM. Demographic characteristics, including age and race, of our cohort are comparable to those reported in prior studies evaluating migraine in the general population.¹⁰

While many institutions use the Migraine Disability Assessment (MIDAS) to document headache-related disability, our headache center opted to use HIT-6. First, all questions refer to headache pain within the last month. HIT-6 similarly asks patients about the impact of headache on daily life in the prior month. It was deemed important to maintain the recall consistency between questionnaires for patient ease and accuracy of collected data. This also may help reduce recall bias because MIDAS requires recalling headache frequency in the last 3 months. In addition, HIT-6 was thought to be easier for patients to complete than MIDAS because there are fewer questions and less calculation required for answering the questions.²³

In our study, approximately 74% of patients with CM reported moderate to severe pain (scores ranging from 4–10, on a scale of 1–10, with 10 being most severe). Only 38% of patients with EM reported moderate to severe pain during a headache. Results of the International Burden of Migraine Study (IBMS), a large international study that surveyed patients from nine countries with self-reported migraine, showed that 99.2% of patients with CM and 96.3% of patients with EM reported moderate to severe pain using the same 1 to 10 pain scale.⁸ This difference between those results and ours is likely attributed to patient selection methods and the different population of patients studied in the respective studies. Our population of patients consisted of new and follow-up patients with diagnoses by headache specialists of EM or CM. Patients in the IBMS study were selected based on responses to a headache screening tool on which patients with greater severity of headache were more likely to respond. In addition, the smaller percentage of patients with moderate to severe pain in our study compared to the IBMS study may reflect their ongoing migraine treatment. Many of the patients included in the IBMS were not under the care of a headache specialist and, as a result, may represent patients with untreated migraine.

The Chronic Migraine Epidemiology and Outcomes (CaMEO) study was a cross-sectional and longitudinal study that recruited patients over the internet.⁷ Patients who met screening criteria were asked to complete web-based questions every 3 months for 12 months. The study compared patients with EM to patients with CM with respect to differences in demographics, headache characteristics, and migraine-related disability as assessed with the MIDAS questionnaire. The CaMEO study found that patients with EM reported a moderate degree of headache-related disability (mean MIDAS score = 13.1) and patients with CM had severe headache-related disability (mean MIDAS score = 60.5).⁷ The IBMS study reported that 78% of patients with CM had MIDAS scores within the severe range, while only 23% of patients with EM had MIDAS scores in the severe range (score ≥ 21).⁵ In our study, both CM and EM patients had mean HIT-6 scores in the severe impact range (67.3 vs. 63.1). Although HIT-6 and MIDAS scores tend to correlate with each other, studies have shown that HIT-6 is weighted more toward headache severity, whereas the MIDAS is weighted more toward headache frequency.²³ This may explain, to some degree, why headache-related disability for patients with EM versus CM showed greater similarity using HIT-6 in our cohort compared with using MIDAS in the CaMEO study. The combination of findings suggests that although EM patients in the general population have lower headache-related disability compared to CM patients, the degree of headache-related disability of EM patients visiting a tertiary headache center approaches that of patients with CM. Patients receiving work-related disability are not necessarily receiving it because of headache but rather due to comorbid conditions. This highlights that CM is comorbid with conditions that are associated with work-related disability.

Despite the differences in headache pain and headache-reported disability between our study and the IBMS and CaMEO studies, the percentages of patients who indicated they were on disability were similar: in our study, 14% and 5.2% of CM and EM patients, respectively, reported being on at least partial work-related disability, whereas in the IBMS study, 13.6% and 5.1% of CM and EM patients, respectively, reported being on disability.^{7, 8} These data indicate that patients with EM seen in headache clinics, despite having headache-related disability within the severe range, are less likely to be receiving benefits. This finding may be because having fewer headaches correlates with less time missed from work and, perhaps, less need for disability-related benefits.

Almost half of the patients with CM in our study cohort have a clinical diagnosis of depression (47.8%), a higher proportion than in patients with EM (31.4%). These rates were similar to what was seen in the IBMS study, which used the Patient Health Questionnaire-4 (PHQ-4) anxiety and depression screen and reported moderate to severe anxiety and depression (PHQ-4 > 5) in 47% of CM and 25% of EM patients. These rates were also similar to those in the CaMEO study, which found rates of self-reported depression of 56% and 30% in their CM and EM patients, respectively.

Apart from obesity, the other comorbid conditions evaluated in this study were also significantly more frequent in patients with CM compared to EM. As expected, many of these were associated with worse patient-reported health and disability from work; however, after adjusting for these and demographic variables, the CM subtype remained associated with worse patient-reported outcomes for all measures assessed in this study. After adjusting for multiple clinical and demographic variables, patients with CM had, on average, a PHQ-9 depression score 3.8 points worse and a HIT-6 score 3.9 points worse than patients with EM. CM patients had 2.7 greater adjusted odds of restricted work compared to EM patients.

Strengths and limitations

Much of our current understanding of CM comes from cross-sectional surveys or claims-based data sets, which often rely on patient self-diagnosis of migraine or diagnosis by non-headache specialists.^{7, 8, 10, 11} In addition, surveys may be affected by a non-response bias. High completion rates helped to reduce non-response bias in our study.

A strength of this study is that the diagnosis of EM and CM was made by UCNS-certified headache specialists. Migraine diagnosis corresponded to patient-reported characterization, including the severity of headache (higher in patients with CM than in those with EM), frequency of headache (median 22 days/month in CM compared to 9 days/month in EM), and description of pain (throbbing; more common in patients with CM than those with EM). An additional strength is the availability of multiple PROMs in the study cohort, which assess different domains of health.

A limitation of our study is that it was performed in a single academic institution and results may not be generalizable to other specialty clinics or the general migraine population. In this study, 60% to 70% of patients had already seen a specialist prior to their visit to our headache center. In addition, we did not evaluate outcomes of CM and EM patients over time, which was beyond the scope of this study.

CONCLUSION

In summary, this large cohort study of patients with physician-diagnosed migraine seen in a tertiary headache clinic demonstrated differences in multiple clinical and demographic characteristics between patients with CM and EM. CM was associated with worse patient-reported health and disability than EM, even after adjustments for these factors.

AUTHOR CONTRIBUTIONS

Study concept and design: Irene L. Katzan, Zubair Ahmed. Acquisition of data: Andrew Schuster, Ryan Honomichl, Nicolas R. Thompson, Brittany Lapin. Analysis and interpretation of data: Irene L. Katzan, Zubair Ahmed, Andrew Schuster, Ryan Honomichl, Nicolas R. Thompson. Drafting of the manuscript: Zubair Ahmed, Ryan Honomichl, Stephen F. Thompson, Joshua M. Cohen, Andrew Schuster, Nicolas R. Thompson, Brittany Lapin, Belinda L. Udeh, Verena Ramirez Campos, Lynda J. Krasenbaum, Irene L. Katzan. Revising it for intellectual content: Zubair Ahmed, Ryan Honomichl, Stephen F. Thompson, Joshua M. Cohen, Andrew Schuster, Nicolas R. Thompson, Brittany Lapin, Belinda L. Udeh, Verena Ramirez Campos, Lynda J. Krasenbaum, Irene L. Katzan. Final approval of the completed manuscript: Zubair Ahmed, Ryan Honomichl, Stephen F. Thompson, Joshua M. Cohen, Andrew Schuster, Nicolas R. Thompson, Brittany Lapin, Belinda L. Udeh, Verena Ramirez Campos, Lynda J. Krasenbaum, Irene L. Katzan.

ACKNOWLEDGMENTS

Editorial support for formatting of this manuscript was provided by Alanna Kahhan of Cello/MedErgy Scientific, in accordance with Good Publication Practice (GPP3) guidelines and funded by Teva Pharmaceuticals.

FUNDING INFORMATION

This study was funded by Teva Pharmaceuticals.

CONFLICT OF INTEREST STATEMENT

Zubair Ahmed, Belinda L. Udeh, Ryan Honomichl, Andrew Schuster, Nicolas R. Thompson, Brittany Lapin, and Irene L. Katzan are employees of the Cleveland Clinic. Stephen F. Thompson, Verena Ramirez Campos, and Lynda J. Krasenbaum are employees of Teva Pharmaceuticals. Joshua M. Cohen is a former employee of Teva Pharmaceuticals.

Open Research

DATA AVAILABILITY STATEMENT

De-identified data will be made available upon reasonable request to the corresponding author.