Headache 2009 the Authors Journal compilation 2009 American Headache Society

ISSN 0017-8748 doi: 10.1111/j.1526-4610.2009.01369.x Published by Wiley Periodicals, Inc.

Research Submissions
Economic Burden of Transformed Migraine: Results From the American Migraine Prevalence and Prevention (AMPP) Study
Julie Munakata, MS; Elisabeth Hazard, PhD; Daniel Serrano, MS; David Klingman, PhD; Marcia F.T. Rupnow, PhD; Jonothan Tierce, CPhil; Michael Reed, PhD; Richard B. Lipton, MD

Objective.To evaluate the impact of incident transformed migraine on health care resource utilization, medication use, and productivity loss. In addition, the study estimates the total direct and indirect costs associated with transformed migraine. Background.Emerging evidence indicates that migraine may be a chronic progressive disorder characterized by escalating frequency of headache attacks, often termed transformed migraine. Little is known about the economic impact of transformed migraine. Methods.AMPP is a 5-year, national, longitudinal survey study of headache in the US. The study utilized data from the 2006 follow-up survey based on an initial sample of 14,544 adults identied as having migraine in either the 2004 screening or 2005 baseline survey. A diagnosis of migraine was assigned based on criteria proposed by the International Classication of Headache Disorders, 2nd Edition. Participants completed self-administered, validated questionnaires on headache features, frequency, impairment, resource use, medication use, and productivity loss. Direct and indirect headache-related costs were estimated using unit cost assumptions from the PharMetrics Patient-Centric database, wholesale acquisition costs (Red Book), and wage data from the US Bureau of Labor Statistics. Those who developed transformed migraine were compared with those who did not develop transformed migraine in the 1-2 year interval between screening/baseline and follow-up. Results.A total of 7796 (54%) identied migraine cases completed the 2006 follow-up survey. Of those cases, 359 (4.6%) developed transformed migraine. Participants who developed transformed migraine reported signicantly more primary care visits, neurologist or headache specialist visits, pain clinic visits, and emergency room visits compared with participants whose migraine remained episodic. Hospital nights and urgent care visits did not reach statistical signicance. Transformed migraine participants reported signicantly more time missed at work or school because of headaches and more time where work or school productivity was reduced by >50% in the previous 3 months because of headaches. Average per-person annual total costs, including direct and indirect costs, were 4.4-fold greater for those who developed transformed migraine ($7750) compared with those who remained episodic ($1757). Conclusion.Transformed migraine exacts a signicantly higher economic toll on patients and health care systems compared with other forms of migraine. Our ndings support the need to prevent migraine progression and to provide appropriate management and treatment of transformed migraine. Key words: migraine, transformed migraine, economic, productivity loss, resource utilization

From IMS Consulting, Falls Church, VA, USA (J. Munakata, E. Hazard, D. Klingman, and J. Tierce); Vedanta Research, Chapel Hill, NC, USA (D. Serrano and M. Reed); Ethicon, Inc., Somerville, NJ, USA (M.F.T. Rupnow); Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); The Monteore Headache Center, Bronx, NY, USA (R.B. Lipton); Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton). Address all correspondence to J. Munakata, IMS Consulting, 300 N. Washington Street, Suite 303, Falls Church, VA 22046, USA. Financial Support: This research was sponsored by the National Headache Foundation through a grant from Ortho-McNeil Janssen Scientic Affairs, LLC. Accepted for publication February 7, 2009. Conict of Interest: IMS (J.M., D.K., E.H., J.T.) and Vedanta (D.S., M.R.) received payment for research services. R.B.L. has received grants and honoraria from Ortho-McNeil. M.F.T.R. is a former employee of Ortho-McNeil Janssen Scientic Affairs, LLC.

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Abbreviations: AMPP American Migraine Prevalence and Prevention Study, TNS Taylor Nelson Sofres, MIDAS Migraine Disability Assessment Questionnaire, ICHD-2 International Classication of Headache Disorders, 2nd Edition (Headache 2009;49:498-508)

Emerging evidence indicates that migraine may be a chronic progressive disorder characterized by escalating frequency of headache attacks.1 Population-based studies have shown that approximately 3-5% of individuals with episodic headache progress to chronic daily headache, a nding that is corroborated by several clinic-based observational studies and a case-control study.1,2 In addition, neuroimaging studies have provided compelling evidence that suggests progressive brain changes in persons with migraine. Kruit and colleagues3 recently demonstrated that migraine frequency is associated with increases in posterior circulation infarcts and diffuse white-matter lesions, and Welch et al4 showed that impairments in iron homeostasis in the periaqueductal grey were associated with migraine duration and chronic daily headache. Transformed migraine is the most common and challenging subtype of the chronic daily headache disorders.5 Patients with transformed migraine often report an evolutionary process that occurs over months or years in which headaches increase in frequency, change characteristics and ultimately result in patterns of daily or near-daily headaches resembling a mixture of tension-type headache and migraine. Although transformed migraine has been the subject of numerous clinical and population-based studies over the past decade, the disorder is not yet addressed in the International Classication of Headache Disorders.6-8 The prevalence of transformed migraine is incompletely understood, but estimates have varied from approximately 50% to 80% of individuals with chronic daily headache and approximately 1% to 2% of the general population.2,9 Most patients with transformed migraine are women with a past history of episodic migraine that began in their teens or 20s.10 Medication overuse is a factor in 80% of transformed migraine cases, but transformation may occur without overuse.10 Additional risk factors associated with transformed migraine include frequency of migraine attacks, caffeine overuse, obesity, and stressful life events.11,12

While transformed migraine is clinically equated with an unfavorable evolution of migraine with loss of symptom-free intervals, the disorder is associated with additional adverse effects on health and healthrelated quality of life (HRQoL). Two independent studies found that transformed migraine patients have signicantly reduced pain thresholds to mechanical stimuli in various regions of the body compared with episodic migraine patients and individuals without headaches.13,14 Based on detailed sleep interviews with 147 patients with transformed migraine, Calhoun et al15 found a very high prevalence of nonrestorative sleep. Furthermore, Meletiche and colleagues16 showed that transformed migraine patients had statistically and clinically signicantly lower mean scores on 7 of the 8 domains and mental and physical summary scores on the 36-item Medical Outcomes Study Short Form questionnaire (SF-36) compared with episodic migraine patients. While the clinical and humanistic burden of transformed migraine is increasingly recognized, no research has been conducted to date on the economic impact of transformed migraine. Indeed the economic impact of migraine in general is well documented, with annual direct cost estimates ranging from $127 to $7089 and annual indirect cost estimates of absenteeism ranging from $709 to $4453 per migraineur.17-20 Given the chronicity of transformed migraine and its detrimental effects on HRQoL, it is hypothesized that migraine-related direct and indirect costs will be further amplied in transformed migraine relative to other types of migraine. This study utilizes data from the American Migraine Prevalence and Prevention (AMPP) Study, a 5-year, longitudinal study of headache in the US, to evaluate the impact of transformed migraine on health care resource utilization, medication use, and productivity loss. In addition, the study estimates the total direct and indirect costs associated with transformed migraine.

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April 2009 Since this research involved direct participation by human subjects, the study was approved by the institutional review board (IRB) at Albert Einstein Medical College, Bronx, NY. The requirement for written informed consent from all participating human subjects was waived by the IRB. Sample and Outcome Measures.The current study utilized data collected in the 2006 follow-up phase of the AMPP study from 14,544 participants (age 18 years) who were identied as having episodic migraine in either the screening survey or the baseline survey. A diagnosis of episodic migraine (<15 headache days per month) was assigned based on the criteria proposed by the International Classication of Headache Disorders, 2nd Edition (ICHD-2).6 For all identied migraine cases, the following headacherelated, self-reported outcomes were evaluated: Headache Frequency.Participants were asked to report the number of headache days experienced in the past month and in the past 12 months. Health Care Resource Use.Participants were asked to report the number of visits to a primary care doctors ofce, hospital emergency room, urgent care center, neurologist or headache specialists ofce, or pain clinic in the past 12 months. Participants were also asked to report the number of nights spent in the hospital in the past 12 months. Medication Use.Participants were provided with a checklist of 29 potential migraine preventives (consisting of anti-seizure, anti-depressant, blood pressure, vitamin, mineral, and herbal products) and were asked to identify any medications ever used and currently used to prevent headaches and to report the number of months of use of each. Similarly, participants were asked to identify any medications currently used to treat acute headache attacks from a checklist of 31 non-prescription and prescription products and to report the number of days taken per month for each. For the purposes of this study, analysis of medication use was restricted to the most commonly used acute medications and to group 1 preventive medications for migraine, as identied by the U.S. Headache Consortium.24 Group 1 preventive medications were selected because they are associated with medium to high efcacy, strong supporting evidence, and mild to moderate side effects.24

METHODS Population Survey.AMPP is a 5-year, longitudinal, national study of headache in the US. Detailed study methods have been described previously.21,22 AMPP consists of 3 phases: (1) an initial screening phase to identify individuals in the general population with self-reported severe headache; (2) a baseline phase to survey identied cases about headache symptoms and impact; and (3) a follow-up phase, consisting of 3 additional annual questionnaires, to survey changes in symptoms, impairment, and resource utilization. In the rst phase of the study, a screening survey was developed by a panel of headache and health care experts. In June 2004, the screening survey was mailed to a stratied random sample of 120,000 US households included in the Taylor Nelson Sofres (TNS; formerly National Family Opinion) Consumer Survey Panel. The TNS panel consists of more than 600,000 households throughout the US and is intended to be representative of the US population in terms of geographic residence, age of head of household, household size, and income. The validated, self-administered questionnaire consisted of 21 questions assessing headache features. In addition, the survey included the Migraine Disability Assessment (MIDAS) questionnaire.23 The screening survey was completed by the head of household, who answered for up to 3 household members. In the second phase of the study, the baseline survey was mailed in June 2005 to a random but representative sample of individuals who were selfidentied in the screening survey as having severe headache (n = 24,000). The baseline survey consisted of 60 detailed questions on headache features, frequency, impairment, medication use, resource utilization, and productivity loss. In the third phase of the study, the rst follow-up survey was mailed in June 2006 to a random sample of baseline respondents (n = 20,639) who were selfidentied as having severe headache in the screening survey. The follow-up survey consisted of 71 detailed questions on headache features, frequency, impairment, medication use, resource utilization, and productivity loss.

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Table 1.Unit Costs for Migraine in the US

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Resource

Unit cost (2006 USD)

Reimbursement

Source

Primary care visit Urgent care visit Neurologist visit Pain clinic visit Emergency room visit Hospital stay Medications Hourly wage

70.00 70.00 115.00 70.00 528.00 1655.00 Variable 15.78

Allowed amount Allowed amount Allowed amount Allowed amount Allowed amount Allowed amount 80% NA

PharMetrics analysis PharMetrics analysis PharMetrics analysis PharMetrics analysis PharMetrics analysis PharMetrics analysis Red Book28 US Bureau of Labor Statistics29

Productivity Loss.Absenteeism and reduced productivity were addressed by the MIDAS questionnaire, in which participants were asked to report the number of days over the previous 3 months that they missed work or school because of a headache, and how many days their productivity was reduced by half or more.23 These estimates were summed, multiplied by 4 and weighted by the national average number of hours worked by women to obtain an annual average estimate of productivity loss.25 Survey Data Analyses.To assess the impact of transformed migraine on economic outcomes, the population of identied individuals with episodic migraine was divided into 2 groups: those who developed transformed migraine (transformed migraine) and those who did not develop transformed migraine (migraine) in the interval between the 2004 screening/2005 baseline surveys and the 2006 follow-up survey. Transformed migraine was dened as migraine plus 15 or more headache days per month, based on the Silberstein-Lipton criteria.26 Since many individuals are unable to record their evolutive history, we assumed the evolutive history in transformed migraine cases, as the study did not require its report, as suggested by the SilbersteinLipton criteria for transformed migraine.26 Linear, Poisson and negative binomial regression models were applied to compare headache frequency, health care resource use, medication use, and productivity loss outcomes reported in the 2006 follow-up survey among those with transformed migraine and those with migraine. Item phrasing and examination of item distributions were used to determine the proper

statistical models for each variable of interest. Productivity-loss variables showed an approximate Gaussian distribution, while headache frequency appeared approximately Poisson distributed, and most health care resource use and medication use variables appeared approximately negative binomial distributed. However, emergency room visits and number of days per month taking non-steroidal antiinammatory drugs and eletriptan appeared approximately Poisson distributed. All models controlled for participant age, gender, income, geographic region, population density, insurance, and insurance with drug coverage status. Contrast ratios from these models comparing headache frequency, health care resource use, medication use, and productivity loss between the migraine and transformed migraine groups are reported as a rate ratio (RR) with 95% condence limits. Cost Calculations.By applying unit cost assumptions to the pattern of health care and medication resource use and productivity loss reported by survey participants in the 2006 follow-up survey, direct and indirect migraine-related costs were assessed for each comparator group. The unit costs used in this study are presented in Table 1. All unit costs are calculated and presented in 2006 US dollars. All unit costs estimated prior to 2006 were converted to 2006 US dollars using the medical care component of the Consumer Price Index.27 Primary care visit, neurologist visit, emergency room visit, and hospitalization costs were based on a separate analysis of the PharMetrics Patient-Centric database, including 866,060 patients with at least one

502 inpatient or outpatient service claim for which migraine or headache was the primary diagnosis, from June 2005 to June 2006. PharMetrics captures charged amounts, allowed amounts and actual paid amounts; in our model, we used the allowed amounts for unit cost assumptions. In total, there were 1,729,555 physician ofce visits, 186,603 advanced imaging procedures (eg, computerized tomography, magnetic resonance imaging), 59,589 other diagnostic procedures (eg, blood test, lumbar puncture), 150,227 emergency room visits, and 22,168 hospitalization days with a primary diagnosis of migraine or headache.The average cost derived from these claims was, therefore, representative of a large pool of service claims generated by health plans across the US. It was conservatively assumed that the cost of an urgent care visit and a pain clinic visit were equivalent to the cost of a primary care visit. The costs of migraine prevention and acute pharmacologic treatment were estimated using wholesale acquisition costs, which were assumed to be equal to published average wholesale drug prices discounted by 20%.28 Lost labor costs were estimated by multiplying hours of productivity loss by the national hourly wage for women aged 25 and older.29 This wage estimate is consistent with other published economic analyses in migraine.30

April 2009 4.38-5.55) and in the past 12 months (RR = 7.00, 95% CI: 6.03-8.13) compared with participants whose migraine remained episodic (P < .01) (Fig. 1). Participants who developed transformed migraine reported signicantly more primary care visits (RR = 3.01, 95% CI: 2.36-3.84), neurologists or headache specialist visits (RR = 4.52, 95% CI: 2.667.69), pain clinic visits (RR = 4.52, 95% CI: 1.3714.91), and emergency room visits (RR = 3.27, 95% CI: 2.78-3.84) (P < .01) compared with participants whose migraine remained episodic (P < .01) (Fig. 2). Hospital nights (RR = 3.05, 95% CI: 0.77-12.16) and urgent care visits (RR = 1.35, 95% CI: 0.53-3.43) did not reach statistical signicance (P > .05) (Fig. 2). Topiramate was the most commonly cited preventive medication used in both participants who developed transformed migraine (6.1%) and those whose migraine remained episodic (2.8%). The most commonly cited medications used for headache relief in both groups were non-prescription analgesics and non-steroidal anti-inammatory drugs. The most commonly cited prescription medications used for headache relief were oral narcotics (14.8%) and butalbital + caffeine + acetaminophen (13.1%) in participants who developed transformed migraine and sumatriptan tablets (8.5%) and oral narcotics (8.4%) in participants whose migraine remained episodic. Among those participants who reported taking medications for headache relief, those who developed transformed migraine were more likely to report a signicantly higher average frequency of use (days/ month) than those whose migraine remained episodic for 11 out of the 14 most commonly used medications (P < .05).A detailed breakdown by drug and by group is shown in the Appendix (Appendix I and II). The mean numbers of hours lost to absenteeism and reduced productivity are presented in Figure 3. Participants who developed transformed migraine reported signicantly more time missed at work or school because of headaches (RR = 6.56, 95% CI: 4.60-9.35) and more time where work or school productivity was reduced by >50% in the previous 3 months because of headaches (RR = 5.23, 95% CI: 4.10-6.67) (P < .01). Average annual total costs, including direct and indirect costs, were 4.4-fold greater for those who

RESULTS Of the original 14,544 identied migraine cases, 7796 completed the 2006 follow-up survey and were included in this analysis. Of these cases, 359 (4.6%) developed transformed migraine and 7437 (95.4%) did not develop transformed migraine and thus remained classied as migraine. The demographic features of the 7796 participants overall and by migraine status are shown in Table 2. Statistical differences in region and household income were observed in participants who developed transformed migraine compared with those whose migraine remained episodic (P < .01). No other signicant differences in demographic features were observed between the 2 groups. Participants who developed transformed migraine reported a signicantly higher frequency of headache days in the past month (RR = 4.93, 95% CI:

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Table 2.Demographic Features of 7796 Participants Overall and by Migraine Status in 2006

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Overall sample (n = 7796) N

Migraine (n = 7437) N

Transformed migraine (n = 359) N

Migraine vs transformed migraine P value

Age (years) 18-24 25-34 35-44 45-54 55-64 65-74 75+ Sex Male Female Region New England Middle Atlantic South Atlantic East North Central West North Central East South Central West South Central Pacic Mountain Population density <100,000 100,000-499,999 500,000-1,999,999 2,000,000+ Household income <$30,000 $30,000-$49,999 $50,000-$74,999 $75,000+ Insurance status Have Do not have

212 998 1761 2489 1588 549 199

(3%) (13%) (23%) (32%) (20%) (7%) (3%)

204 959 1687 2369 1497 528 193

(3%) (13%) (23%) (32%) (20%) (7%) (3%)

8 39 74 120 91 21 6

(2%) (11%) (21%) (33%) (25%) (6%) (2%)

.18

1396 (18%) 6400 (82%) 337 1043 1534 1289 593 626 875 962 537 1386 1447 1824 3139 2534 1650 1492 2120 (4%) (13%) (20%) (17%) (8%) (8%) (11%) (12%) (7%) (18%) (19%) (23%) (40%) (33%) (21%) (19%) (27%)

1321 (18%) 6116 (82%) 326 1008 1461 1208 564 604 844 922 500 1325 1365 1747 3000 2386 1587 1416 2048 (4%) (14%) (20%) (16%) (8%) (8%) (11%) (12%) (7%) (18%) (18%) (24%) (40%) (32%) (21%) (19%) (28%)

75 (21%) 284 (79%) 11 35 73 81 29 22 31 40 37 61 82 77 139 148 63 76 72 (3%) (10%) (20%) (23%) (8%) (6%) (9%) (11%) (10%) (17%) (23%) (21%) (39%) (41%) (18%) (21%) (20%)

.13 <.01

.20

<.01

6419 (82%) 1377 (18%)

6136 (83%) 1301 (18%)

283 (79%) 76 (21%)

.07

developed transformed migraine ($7750) compared with those whose migraine remained episodic ($1757) (Table 3). Costs attributable to lost productive time accounted for the majority of the total cost for those with migraine (55.7%) and to an even greater extent for those who developed transformed migraine (69.6%).

DISCUSSION The AMPP survey is the largest study of migraine sufferers ever conducted, providing longitudinal data on headache-related symptoms, treatment patterns, and disability in the US. The current study utilized

data collected in the rst 2 years of the survey in order to estimate the economic impact of transformed migraine. Our primary objective was to quantify and compare migraine frequency, resource utilization, and productivity loss in migraineurs who subsequently developed or did not develop transformed migraine. The results of our analysis indicate that incident transformed migraine exacts a much higher economic toll on patients and health care systems compared with other forms of migraine. In this study, the incidence of transformed migraine among those previously diagnosed with migraine in the preceding 1-2 years was 4.6%, consis-

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160 Mean No. Headache Days / Person 140 120 100 Migraine 80 60 40 20 3 0 Past month Past 12 months 15 19 Transformed migraine 135

Fig 1.Reported headache frequency by migraine status in 2006.

tent with previous population studies showing that the rate of transformation from episodic migraine to transformed migraine is 2.5-3% per year.31,32 Participants who developed transformed migraine reported having 15 headache days in the past month and 135 headache days in the past 12 months, representing a 5to 7-fold difference in headache frequency over participants whose migraine remained episodic. Consistent with earlier studies of migraine frequency, participants with migraine who did not develop transformed migraine reported an average of approxi-

mately 3 headache days per month.21 Participants who developed transformed migraine reported substantially higher primary care, neurologist, and emergency room visits, and hospitalizations compared with participants with migraine. In addition, participants who developed transformed migraine reported signicantly more lost productive time due to absenteeism and reduced productivity. Our analysis showed that participants with transformed migraine incurred $7750 per patient per year, representing a $5994 or 341% difference in headache-

Primary care visit Neurologist visit 0.22

0.72 2.42

1.06 0.07 0.32 0.05 0.07 0.17 0.60 0.07 0.26 0.50 1.00 1.50 2.00 2.50 3.00

Pain clinic visit

Migraine Transformed migraine

Urgent care visit Emergency room visit Hospital night

0.00

Mean No. / Person / Year

Fig 2.Health care resource use by migraine status in 2006.

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505

300.0 Mean No. of Hours Lost / Person / Year 256.0 250.0

200.0 Migraine Transformed migraine 85.7 48.3 50.0 13.7 0.0 Absenteeism Reduced productivity

150.0

100.0

Fig 3.Absenteeism and reduced productivity by migraine status in 2006.

related direct and indirect costs over those with other forms of migraine. These data provide new evidence of the substantial economic burden associated with the disorder. Coupled with the known clinical and humanistic burden of transformed migraine, our ndings further support the need to prevent migraine progression and, at the very least, provide appropri-

ate management and treatment of transformed migraine. Of note, our analysis showed that approximately one quarter of participants with transformed migraine reported taking a group 1 preventive medication. Although there are no formal recommendations from the American Academy of Neurology or the American Headache Society for the prevention

Table 3.Annual Direct and Indirect Costs by Migraine Status in 2006

Migraine (n = 7437) Sample size Cost (2006 USD) Sample size

Transformed migraine (n = 359) Cost (2006 USD)

Unit cost

Mean (SD)

Mean (SD)

Primary care visit Neurologist visit Pain clinic visit Urgent care visit Emergency room visit Hospital night Prevention medications Acute non-prescription medications Acute prescription medications Lost productive time Total mean cost/person/year

70.00 115.00 70.00 70.00 528.00 1655.00 Variable Variable Variable 15.78

6755 6213 6066 6081 6219 6465 Variable Variable Variable 6081

0.720 (2.126) 0.221 (1.147) 0.072 (0.691) 0.048 (0.496) 0.167 (1.048) 0.075 (0.857) Variable Variable Variable 61.97

50.37 25.39 5.05 3.39 88.39 123.46 111.14 47.62 323.83 977.89 1756.53

329 282 269 274 288 306 Variable Variable Variable 274

2.416 (8.213) 1.064 (6.134) 0.316 (1.798) 0.073 (0.376) 0.060 (2.462) 0.261 (2.192) Variable Variable Variable 341.70

169.15 122.34 22.12 5.11 315.32 432.62 257.90 108.12 925.32 5392.03 7750.03

Allowed amounts, PharMetrics analysis. Wholesale acquisition costs, Redbook. Hourly wage, US Bureau of Labor Statistics.

506 or management of transformed migraine, a recent review of antiepileptic preventive medications showed encouraging data from controlled clinical trials to support the use of topiramate in the treatment of chronic headache forms.33,34 Alternative management strategies include lifestyle modications such as avoiding medication overuse, encouraging weight loss, and utilizing appropriate behavioral therapies and other available preventive drugs. However, the efcacy of these strategies requires further investigation since most available studies are open-label, small-sample trials.5,33 It is possible that our analysis was limited by response bias associated with the TNS study population. Household panels tend to under-represent the very wealthy and poor segments of the population and do not include military or institutionalized individuals. However, reported migraine frequencies and estimates of direct and indirect costs for participants with migraine in this study were commensurate with those obtained from previous studies of patients with migraine.18,21 Comorbid health conditions may inuence migraineurs resource utilization, medication use, and workplace productivity. The current study did not quantify the potential effects of other conditions. To the extent that transformed migraine patients have a greater severity and spectrum of illness, our results may actually underestimate the total incremental economic burden of transformed migraine. Lastly, this analysis included a limited population size of participants with transformed migraine. Although the percentage of participants with transformed migraine appears to reect population-based estimates from previous studies, further research may be needed to conrm these economic ndings. In summary, this study found that headacherelated resource utilization, medication use, productivity loss, and total costs were signicantly higher in those with transformed migraine relative to those with migraine. These data underscore the need not only to address the traditional goals of migraine treatment of relieving pain and restoring patient function, but also to prevent migraine progression. In this respect, denition and implementation of diagnostic criteria and evidence-based treatment guidelines for

April 2009 transformed migraine could have far-reaching clinical and economic benets. Acknowledgments: Part of this research was presented in abstract form at the 60th Annual Meeting of the American Academy of Neurology, May 2008, Chicago, IL. Appreciation is expressed to Mohamed Hussein for reviewing drafts of this manuscript.

REFERENCES
1. Lipton RB, Pan J. Is migraine a progressive brain disease? JAMA. 2004;291:493-494. 2. Kavuk I, Yavuz A, Cetindere U, Agelink MW, Diener HC. Epidemiology of chronic daily headache. Eur J Med Res. 2003;8:236-240. 3. Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as a risk factor for subclinical brain lesions. JAMA. 2004;291:427-434. 4. Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: Cause or the burden of illness? Headache. 2001; 41:629-637. 5. Dodick DW. Clinical practice. Chronic daily headache. N Engl J Med. 2006;354:158-165. 6. Headache Classication Subcommittee of the International Headache Society. The International Classication of Headache Disorders, 2nd edn. Cephalalgia. 2004;24(Suppl. 1):9-160. 7. Manzoni GC, Lambru G, Torelli P. Chronically evolving headaches: Classication and terminology. Neurol Sci. 2006;27(Suppl. 2):S164-S167. 8. Mathew NT, Reuveni U, Perez F. Transformed or evolutive migraine. Headache. 1987;27:102-106. 9. Bigal ME, Lipton RB, Tepper SJ, Rapoport AM, Sheftell FD. Primary chronic daily headache and its subtypes in adolescents and adults. Neurology. 2004;63:843-847. 10. Silberstein SD. Chronic daily headache. J Am Osteopath Assoc. 2005;105:23S-29S. 11. Bigal ME, Lipton RB. Modiable risk factors for migraine progression. Headache. 2006;46:13341343. 12. Bigal ME, Lipton RB. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology. 2006;67:252-257. 13. Cooke L, Eliasziw M, Becker WJ. Cutaneous allodynia in transformed migraine patients. Headache. 2007;47:531-539.

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14. Kitaj MB, Klink M. Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache. 2005;45:992-998. 15. Calhoun AH, Ford S, Finkel AG, Kahn KA, Mann JD. The prevalence and spectrum of sleep problems in women with transformed migraine. Headache. 2006;46:604-610. 16. Meletiche DM, Loand JH, Young WB. Quality-oflife differences between patients with episodic and transformed migraine. Headache. 2001;41:573-578. 17. Pesa J, Lage MJ. The medical costs of migraine and comorbid anxiety and depression. Headache. 2004; 44:562-570. 18. Pradalier A, Auray JP, El HA, et al. Economic impact of migraine and other episodic headaches in France: Data from the GRIM2000 study. Pharmacoeconomics. 2004;22:985-999. 19. Edmeads J, Mackell JA. The economic impact of migraine: An analysis of direct and indirect costs. Headache. 2002;42:501-509. 20. Hawkins K, Wang S, Rupnow MF. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007;49:368-374. 21. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349. 22. Silberstein S, Loder E, Diamond S, Reed M, Bigal M, Lipton R. Probable migraine in the United States: Results of the American Migraine Prevalence and Prevention (AMPP) Study. Cephalalgia. 2007;27:220-234. 23. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56:S20S28. 24. Kaniecki R, Lucas S. Treatment of primary headache: Preventive treatment of migraine. Standards of

507
Care for Headache Diagnosis and Treatment. Chicago, IL: National Headache Foundation; 2004:40-52. Bureau of Labor Statistics, U.S. Department of Labor. Workers are on the job more hours over the course of the year. February 1997. Silberstein SD, Lipton RB, Sliwinski M. Classication of daily and near-daily headaches: Field trial of revised IHS criteria. Neurology. 1996;47:871-875. Bureau of Labor Statistics, U.S. Department of Labor. Consumer Price Index. Available at http:// data.bls.gov/cgi-bin/surveymost?cu. Red Book. Montvale: Thomson Healthcare Inc.; 2006. Bureau of Labor Statistics, U.S. Department of Labor. Highlight of womens earnings in 2005. Report 995. Brown JS, Papadopoulos G, Neumann PJ, Friedman M, Miller JD, Menzin J. Cost-effectiveness of topiramate in migraine prevention: Results from a pharmacoeconomic model of topiramate treatment. Headache. 2005;45:1012-1022. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: A longitudinal population-based study. Headache. 2008;48: 1157-1168. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain. 2003;106:81-89. DAmico D. Antiepileptic drugs in the prophylaxis of migraine, chronic headache forms and cluster headache: A review of their efcacy and tolerability. Neurol Sci. 2007;28(Suppl. 2):S188-S197. Mathew NT. The prophylactic treatment of chronic daily headache. Headache. 2006;46:1552-1564.

25.

26.

27.

28. 29.

30.

31.

32.

33.

34.

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Appendix I Number and Percentage of Participants Reporting Preventive and Acute Medication Use by Migraine Status in 2006
Migraine status Migraine Medication N % Transformed migraine N %

Prevention medication Topiramate Divalproex sodium Amitriptyline Propranolol Timolol Acute medication Acetaminophen Naproxen Aspirin Acetaminophen+aspirin+caffeine Ibuprofen Sumatriptan tablets Sumatriptan nasal spray Sumatriptan injection Rizatriptan tablets or oral wafer Eletriptan tablets Zolmitriptan tablets or oral wafer Meperidine oral or injected Oral narcotics Butalbital+caffeine+acetaminophen

205 85 189 134 6 2736 1279 831 2109 2045 634 81 100 222 130 159 98 621 362

2.76 1.14 2.54 1.80 0.08 36.79 17.20 11.17 28.36 27.50 8.52 1.09 1.34 2.99 1.75 2.14 1.32 8.35 4.87

22 12 21 13 2 132 55 37 116 88 38 6 9 9 12 14 8 53 47

6.13 3.34 5.85 3.62 0.56 36.77 15.32 10.31 32.31 24.51 10.58 1.67 2.51 2.51 3.34 3.90 2.23 14.76 13.09

Appendix II Frequency (days/month) of Acute Medication Use Among Participants Who Reported Taking Each Medication by Migraine Status in 2006
Migraine status Migraine Acute medication Mean SD Transformed migraine Mean SD RR (95% CI) P value <.01 <.01 <.01 <.01 <.01 .01 .05 .18 <.01 <.01 <.01 .31 <.01 <.01

Acetaminophen Naproxen Aspirin Acetaminophen+aspirin+caffeine Ibuprofen Sumatriptan tablets Sumatriptan spray Sumatriptan injection Rizatriptan tablets or oral wafer Eletriptan tablets Zolmitriptan tablets or melt Meperidine oral or injected Oral narcotics Butalbital+caffeine+acetaminophen

6.85 6.56 10.87 6.31 6.69 6.29 4.11 8.09 5.47 4.82 4.61 6.09 9.85 7.34

9.83 9.31 12.99 10.58 9.85 16.61 11.13 23.12 15.70 12.09 11.21 14.77 16.05 14.28

16.93 13.47 15.70 15.72 14.22 14.58 8.67 13.00 10.56 2.33 14.21 10.88 19.00 15.28

12.19 10.52 12.21 9.71 9.77 25.91 11.00 31.90 7.96 1.07 25.32 8.97 22.14 9.57

2.45 2.09 1.45 2.40 2.10 1.73 2.84 0.50 4.68 0.48 3.94 1.62 1.99 2.42

(2.09-2.88) (1.61-2.71) (1.33-1.58) (2.28-2.52) (1.99-2.23) (1.13-2.65) (1.01-7.95) (0.18-1.38) (1.92-11.40) (0.32-0.70) (1.81-8.60) (0.64-4.08) (1.43-2.76) (1.77-3.31)