Headache ISSN 0017-8748 C 2007 the Authors doi: 10.1111/j.1526-4610.2007.00760.x Journal compilation C 2007 American Headache Society Published by Blackwell Publishing Views and Perspectives Pharmacological Approaches to Managing Migraine and Associated Comorbidities���Clinical Considerations for Monotherapy Versus Polytherapy Stephen D. Silberstein, MD David Dodick, MD Fred Freitag, DO Starr H. Pearlman, PhD Steven R. Hahn, MD Ann I. Scher, PhD Richard B. Lipton, MD Comorbidity is defined as an illness that occurs more frequently in association with a specific disorder than would be found as a coincidental association in the general population. Conditions that are frequently comorbid with migraine include depression, anxiety, stroke, epilepsy, sleep disorders, and other pain disorders. In addition, many common illnesses occur concomitantly (at the same time) with migraine and influence the treatment choice. Migraine management, and especially migraine prevention, can be challenging when patients have comorbid or concomitant illnesses. The objectives of this initiative are to review the literature on managing patients who have migraine and common comorbidities, present additional clinical approaches for care of these difficult patients, and evaluate the areas in which research is needed to establish evidence-based guidelines for the management of migraine with associated comorbid conditions. Key words: migraine, polytherapy, monotherapy, comorbidity (Headache 2007 47:585-599) Migraine is a disorder that is present in approxi- mately 13% of the general population and is associated with both comorbid and concomitant illnesses that in- fluence treatment strategy.1,2 Comorbidity is defined as an illness that occurs more frequently in association with a specific disorder than that would be found as From the Thomas Jefferson University, Philadelphia, PA, USA (Dr. Silberstein) Mayo Clinic, Scottsdale, AZ, USA (Dr. Dodick) Diamond Headache Center, Chicago, IL, USA (Dr. Freitag) Savannah, GA, USA (Dr. Pearlman) Albert Ein- stein School of Medicine, Bronx, NY, USA (Drs. Hahn and Lip- ton) and Uniformed Services University, Bethesda, MD, USA (Dr. Scher). Address all correspondence to Dr. Stephen D. Silberstein, Jef- ferson Headache Center, 111 South 11th Street, Suite 8130, Philadelphia, PA 19107. Accepted for publication December 18, 2006. a coincidental association in the general population.3 Concomitant (coexistent) illnesses occur at the same time in the same person at the rate that would be ex- pected by chance. The common illnesses that are associated with mi- graine and influence its management include comor- bid conditions such as depression, anxiety disorders, epilepsy, sleep disorders, and stroke and concomitant illnesses such as hypertension and obesity (Table 1). Both comorbid and concomitant medical conditions impact migraine treatment. Understanding how to de- sign treatment plans that address migraine in patients with other medical conditions is the focus of this re- view. The biological mechanisms that underlie comor- bid conditions and migraine are not understood, and therelationshipmaybeunidirectionalorbidirectional, depending on the associated illness.4 One example of a 585

586 April 2007 Table 1.���Comorbid and Concomitant Conditions Associated with Migraine in Clinical Care or Population Studies Cardiovascular ��� Heart attack/angina ��� Hypertension or hypotension ��� Stroke ��� Raynaud���s syndrome ��� Patent foramen ovale CNS ��� Epilepsy ��� Essential tremor Mood disorders ��� Depression ��� Mania ��� Anxiety ��� Panic GI disorders ��� Ulcer disease ��� Colitis ��� IBS Other ��� Snoring/sleep apnea/sleep disorder ��� Other chronic pain disorders Allergy/asthma bidirectional relationship is that between migraine and blood pressure. Headache-specific medications may lower blood pressure, and elevated blood pressure mighttheoreticallyaggravateheadache.Selectedmed- ical conditions may be comorbid because they share a genetic factor that increases the risk of both conditions (for example, the MTHFR C677T variant associated both with migraine and with ischemic stroke).5 Diag- nosing and treating migraine with associated comor- bidities require follow-up and monitoring of all the disorders, and extra time may be necessary to achieve control of both illnesses. For the last 10 years, recommendations have fo- cused on using one drug to treat migraine and asso- ciated comorbid conditions whenever possible.6,7 For example, when a patient has both migraine and depres- sion, past practice has been to use a single medication, such as a tricyclic antidepressant (TCA) or a serotonin reuptake inhibitor (SSRI), to treat both illnesses. This approach appears to offer the prospect of simplifying management, reducing costs, minimizing potential side effects, and eliminating potential drug interactions. However, the scientific rationale for us- ing a ���two-for-one��� approach in migraine has not been prospectively tested in controlled trials. Recent stud- ies suggest that using multiple medications (polyphar- macy) may confer therapeutic advantages for patients with migraine and other conditions, such as depression or anxiety.8 This review systematically evaluates benefits and limitations of pharmacological monotherapy versus polytherapy for migraine prevention and common as- sociated comorbidities. Individual authors each ad- dressed a specific area of interest, which have been combined into this single comprehensive review. Con- tributing authors participated in the following areas: Background, introduction, epidemiology, and discus- sion (S. Silberstein, R. Lipton, and S. Pearlman), de- pression (S. Hahn), obesity (R. Lipton), stroke and hypertension (D. Dodick), women���s issues (F. Freitag eg, pregnancy, menses, menopause, etc), and epilepsy (A. Scher). This review also identifies specific areas in which research is needed to establish evidence- based treatment recommendations for patients with migraine and comorbid illnesses (all participants). EPIDEMIOLOGY OF COMORBIDITIES ASSOCIATED WITH MIGRAINE An illness is comorbid with migraine if it occurs at a higher incidence in migraine patients compared with the general population. For example, patients with de- pression had a significantly higher chance of devel- oping migraine (9.3%) within 2 years compared with subjects without depression (2.8% Fig. 1).9 Similarly, subjects with migraine had a significantly higher risk of developing depression (10.5% Fig. 1) compared with nonmigraine subjects (2.0% Fig. 1) or those with headaches of the nonmigraine type.9 The prevalence of disorders that are comorbid with migraine varies across studies. The heterogene- ity of the patient populations studied may account for the differences among epidemiological rates. Ad- ditionally, variability in definitions and diagnostic cri- teria for selected illnesses differs across studies. For example, definitions for depression can vary based on meeting diagnostic criteria versus those with selected symptoms of depression. The associated comorbidities can be life threaten- ing or severely disabling if not treated appropriately (eg, exacerbation of depression or stroke). Therefore,

Headache 587 2.0% 2.9% 1.1% 0.0% 9.3% 0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% No Headache at Baseline Headache at 2 Years Percent New Migraine. New Migraine New Severe HA New Severe HA D e p r e s s e d Depressed No tD e p r e s s e d Odds ratio 3.4, 95% CI 1.4-8.7 Odds ratio 1.0 Odds ratio 1.0 Odds ratio 0.6, 95% CI 0.1, 4.6 2.0% 0.0% 5.1% 10.5% 0% 2% 4% 6% 8% 10% 12% No Depression at Baseline Depression at 2 Years Percent New Depression New Depression New Depression M i g r a i n e N oH e a d a c he S e v e r e H e a d a c h e Odds ratio 5.8 95% CI 2.7-12.3 Adapted from Breslau et al., Neurology 20039 Odds ratio 2.7 CI 0.9, 8.1 Odds ratio 1.0 Fig 1.���(a) Presence of major depression at baseline was a risk factor for developing migraine (b) Presence of migraine at baseline was a risk factor for developing depression by the 2-year follow-up period. improving awareness, diagnosis, and treatment of mi- graine and its associated comorbidities is critical to improve patient care and reduce the burden of illness on health systems, families, and work forces. LIMITATIONS OF MONOTHERAPY FOR PATIENTS WITH MIGRAINE AND COMORBIDITIES Migraine treatment includes the use of acute and preventive medications, along with nonpharmacolog- ical/behavioral approaches. Several preventive med- ications have proven helpful in migraine patients (Table 2). Previous migraine treatment guidelines re- view the established clinical efficacy of these medica- tions for migraine prevention.6,7 Recommendations to use a ���two-for-one��� treatment approach for migraine suggested that one medication may meet the therapeu- tic need of patients with migraine and an associated comorbid condition.6 However, this approach has not been prospectively studied and there are potential lim- itations to using a single medication to treat 2 separate illnesses such as: ��� Risk of treating only one condition: Giving a single medication may not treat 2 different con- ditions optimally. Although one of the 2 condi- tions may be adequately treated with a specific medication, the second illness may require a dif- ferent medication or a different dose or dosing regimen. Therefore, the patient is at risk of the second illness not being adequately treated. ��� Risk of choosing suboptimal medication: In an effort to use a single medication to treat 2 con- ditions, the physician may select a second- or