REVIEW PREVENTIVE THERAPY FOR MIGRAINE HEADACHE. Carla Rubingh, PharmD * ABSTRACT

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1 PREVENTIVE THERAPY FOR MIGRAINE HEADACHE Carla Rubingh, PharmD ABSTRACT Headache is one of the most common medical complaints. It is estimated that the prevalence of migraine is approximately 13% (18% of women and 6% 7% of men). Most patients with migraine require pharmacologic treatment. Preventive treatments for patients with migraine headache reduce the frequency, severity, and duration of headaches. Many medications are used for migraine prevention, including β blockers, calcium channel blockers, antiseizure medications, and antidepressants. Most agents reduce migraine frequency by approximately 40% to 50%. The selection of a preventive strategy is usually based on the patient s comorbid conditions and ability to tolerate specific side effects. Several vitamins, minerals, and herbal remedies also are used for migraine prevention. Although some of these may reduce migraine headache frequency, they are not regulated by the US Food and Drug Administration and may vary considerably in potency from lot to lot. Nonpharmacologic therapies are also effective for some patients. Migraine prevention may help to reduce lost workplace productivity caused by absenteeism or impaired job performance. In addition, preventive therapy may help to reduce the need for costly acute migraine headache treatments. (Adv Stud Pharm. 2007;4(1):15-20) Assistant Professor, Department of Pharmacy Practice, University of Nebraska Medical Center, Clinical Pharmacist- Ambulatory Care, Veterans Affairs Medical Center, Omaha, Nebraska. Address correspondence to: Carla Rubingh, PharmD, Assistant Professor, Department of Pharmacy Practice, University of Nebraska Medical Center, Clinical Pharmacist- Ambulatory Care, Veterans Affairs Medical Center, Nebraska Medical Center, Omaha, NE crubingh@unmc.edu. Headache is one of the most common medical complaints. It is estimated that the prevalence of migraine is approximately 13% (18% of women and 6% 7% of men). 1 Most patients with migraine require pharmacologic treatment. 1 Migraine headaches cause significant pain and disability, in addition to substantial loss of time spent with family members, at work, or engaged in leisure activities. Preventive treatments are intended to reduce the frequency, severity, and duration of headaches; to increase the response to acute migraine medications; and to maintain the patient s ability to function. 2 Preventive medications should be considered if a patient suffers from 2 or more headaches per month. Other factors that may influence the decision to use preventive medication include migraines that significantly interfere with daily routine despite acute treatment, contraindication to or failure or overuse of acute therapies, inability to tolerate acute therapies, and patient preference. 3 Only 4 medications timolol, propranolol, divalproex sodium, and topiramate are approved by the US Food and Drug Administration (FDA) for the prevention of migraine headache. Many other agents have been used off-label for migraine headache prevention, including β blockers, tricyclic antidepressants (TCA), antiseizure medications, calcium channel antagonists, and selective serotonin reuptake inhibitors (SSRI). 3,4 All of the commonly used preventive agents reduce headache frequency by approximately 40% to 50%, and all have the potential for adverse effects. 2 Therefore, the selection of a preventive therapy is usually made on the basis of comorbid conditions, side effects, cost, patient preference, or other considerations. For example, a patient with migraine headache who also has difficulty sleeping may benefit from a preventive therapy that causes drowsiness, whereas a patient with comorbid depression may do well with an antidepressant. Preventive medications often are selected on the basis of the patient s willingness to tolerate the side effects of a par- University of Tennessee Advanced Studies in Pharmacy 15

2 ticular agent. SSRIs effectively reduce migraine frequency for many patients, but produce sexual side effects that are difficult for many to tolerate. Some agents (eg, certain β blockers, TCAs, and divalproex sodium) cause weight gain that may be undesirable to patients. 4 In addition, it is also important to establish that a preventive treatment is not contraindicated for the patient s comorbid conditions and that treatments being administered for other conditions do not exacerbate migraine. 3 There is often an element of trial-and-error in identifying an appropriate preventive therapy, and it is usually not possible to know in advance how well a particular therapy will work for a particular patient. A common mistake made by patients and providers is not giving an adequate trial to the selected agent being tried for prevention. It should be noted that patients may need to use preventive therapy for at least 4 to 6 weeks before headache frequency improves. 2 When time for dose titration is added, preventive therapy may take up to 6 months to improve migraine symptoms. 5 Medications that are used for migraine prevention are summarized in the Table. 4 β blockers have long been considered a preferred treatment for migraine prevention, especially in patients with comorbid hypertension or angina. 2 Common TCAs used in the United States include amitriptyline and doxepin (both of which produce sedation) and nortriptyline (which is less sedating). 2 Several nonsteroidal anti-inflammatory drugs have been shown to reduce migraine frequency, of which naproxen has been most extensively evaluated. These agents may be especially useful to prevent headaches that occur predictably, such as migraine headaches associated with the menstrual cycle. 2 Calcium channel antagonists and SSRIs also may be effective, but have not been evaluated as extensively. 2 Recent developments in migraine prevention include the anticonvulsant topiramate and botulinum toxin type A. Antiseizure medications have been used for many years to prevent migraine headaches. Divalproex sodium, which was approved in 2000 for this indication, has been shown to significantly reduce the frequency of migraine headaches in randomized, double-blind, placebo-controlled clinical trials. 6 Other anticonvulsants have been used off-label for migraine prevention, including gabapentin and oxcarbazepine. 4 Topiramate was approved for migraine prevention in 2004 and was evaluated in 2 large, randomized, double-blind clinical trials of identical design. 7,8 In both of these studies, patients with 3 to 12 migraine headaches during a 28-day baseline period were randomized to receive placebo or 1 of 3 topiramate doses (ie, 50 mg, 100 mg, or 200 mg/day) for up to 6 months, with headache frequency evaluated monthly. A total of 483 patients were randomized to treatment in one study, 8 and 487 were randomized in the other. 7 In both studies, topiramate doses of 100 and 200 mg per day produced significantly greater reduction in headache frequency than placebo across the 6-month study period (Figure 1). 7 The 50-mg dose did not significantly reduce migraine frequency at most time points. Increasing the dose to 200 mg did not significantly improve treatment efficacy compared with the 100-mg dose. More recently, Wenzel et al reviewed the medical literature regarding the use of topiramate in migraine prevention. 9 The investigators also found that an optimal topiramate dose appears to be 100 mg per day for most patients. This dose of topiramate reduced migraine frequency by an average of approximately 2 headaches per month and also significantly reduced the number of days per month with migraine headache and the use of acute migraine medications. Antiseizure medications may be particularly useful for patients with comorbid bipolar disorder or seizure disorders. 10 Patients should be aware that topiramate may produce mild cognitive impairment or fatigue, which are usually transitory. 11 Other adverse effects reported in more than 10% of patients with migraine headache in placebo-controlled clinical trials include paresthesia, dizziness, diarrhea, anorexia, and upper respiratory tract infection. 12 Although somewhat controversial, and not US FDA approved for this purpose, botulinum toxin type A is used by some specialists to treat migraine. Botulinum toxin injections are typically administered once every 3 months, eliminating issues of medication adherence. 13 Some clinical studies have demonstrated reductions in migraine headache frequency with botulinum toxin injections (Figure 2), 14,15 although one recent randomized, double-blind multicenter trial found that botulinum toxin injections were no more effective than placebo. 16 Vitamins, herbal preparations, and other natural products are also sometimes used for migraine headache prevention. Riboflavin and magnesium have both been shown to significantly reduce the frequency of migraine episodes in placebo-controlled clinical trials. 14 Some evidence also supports the use of feverfew 16 Vol. 4, No. 1 January 2007

3 and butterbur. 17 Although many individuals prefer natural remedies, and these agents have improved migraine symptoms in some studies, herbal products must be used with caution. Herbal remedies may contain many different ingredients with significant biologic activity, are not regulated by the US FDA, may Table. Medications Used for Prevention of Migraine Headaches Daily Dosage Drug Range Major Side Effects Comorbid Considerations β Blockers Propranolol mg Fatigue, depression, weight gain, edema, Hypertension, anxiety disorders, Nadolol mg dizziness, decreased exercise tolerance, status-post MI, and tachycardia Atenolol mg and sexual dysfunction Metoprolol mg TCAs Amitriptyline mg Dry mouth, dry eyes, constipation, Sleep disorders, depression, and Nortriptyline mg weight gain, fatigue, and urinary retention neuropathic pain Imipramine mg Desipramine mg Doxepin mg Calcium Channel Blockers Amlodipine mg Constipation, hypotension, and dizziness Hypertension, connective tissue disorders, Verapamil mg autoimmune disorders, and Raynaud s disease Examples of NSAIDs Indomethacin mg Stomach irritation, ulcer, edema, and Musculoskeletal aches and pains, Naproxen mg renal problems inflammatory disorders, and menstrual migraine Celecoxib mg SSRIs Citalopram mg GI complaints, tremor, dizziness, Depression, obsessive-compulsive disorder, Escitalopram mg insomnia, and sexual dysfunction anxiety disorder, panic disorder, and social Fluoxetine mg phobia Fluvoxamine mg Paroxetine mg Sertraline mg Anticonvulsants Divalproex sodium mg GI disturbances, sedation, tremor, Bipolar disorder, epilepsy, and PTSD hepatotoxicity, transient hair loss, and weight gain Gabapentin mg Sedation and dizziness Neuropathic pain and epilepsy Oxcarbazepine mg Sedation and dizziness Trigeminal neuralgia, neuropathic pain, and epilepsy Topiramate mg Sedation, cognitive/memory problems, Epilepsy, obesity, and mood disorders and weight loss MAO Inhibitor Phenelzine mg Dietary precautions, hypotension, nausea, Severe depression weight gain, edema, and liver function H 1 Blocker/Serotonin Antagonist Cyproheptadine 8 16 mg Weight gain, sedation, and urinary retention First-line agent in children and allergic rhinitis Carbonic Anhydrous Inhibitor Acetazolamide mg Lightheadedness, frequent urination, and Pseudotumor cerebri and altitude sickness taste disturbances with carbonated beverages GI = gastrointestinal; MAO = monoamine oxidase; MI = myocardial infarction; NSAID = nonsteroidal anti-inflammatory drug; PTSD = post-traumatic stress disorder; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant. Reprinted with permission from Rubingh and Baggaley. Headache: Diagnosis and approaches to treatment. In: Lipman, ed. Pain Management for Primary Care Clinicians. Bethesda, Md: American Society of Health System Pharmacists; University of Tennessee Advanced Studies in Pharmacy 17

4 produce significant interactions with other medications, and may vary considerably in the amount of active ingredient contained. 18 Nonpharmacologic methods also may help to reduce the impact of migraine headache. Headaches are often induced by specific triggers, such as certain foods, odors, behaviors, chemicals, or other environmental factors. 19 One way to help reduce the impact of migraine triggers is to use a headache diary or calendar. 19 The diary may be used to record all headache episodes, headache intensity, any trigger factors, foods and beverages consumed, and medications used. Keeping a headache diary may help the patient and the physician to identify triggers, suggest lifestyle modifications to reduce headache impact, and select an appropriate pharmacotherapy strategy. Lifestyle modifications that may help to reduce the frequency of migraine include limiting caffeine consumption, maintaining a regular sleep schedule, eating regularly and avoiding fasting, minimizing stress, and avoiding bright or flashing lights. 19 These lifestyle changes along with the headache diary should be encouraged in all patients with headache. Other nonpharmacologic options include relaxation training, biofeedback, cognitive-behavioral psychotherapy, cervical manipulation, and massage therapy. 3,20 Migraine headaches are often linked to menstrual cycles, 21 and some experts have suggested that reducing the number of menstrual cycles (eg, with an extended contraceptive agent that reduces the number of menstrual cycles to 4 cycles/year) may reduce the number of headaches. At present, this strategy has not been evaluated in controlled clinical trials. 22 acute and preventive therapies, 26,27 the specific effects of migraine prevention on workplace performance have not been evaluated in controlled studies. Direct medical costs associated with migraine headache are incurred because of the use of medications, physician office or clinic visits, emergency Figure 1. Mean (Least Squares Value) Change from Baseline in Monthly Migraine Frequency Mean change from baseline in monthly migraine frequency Treatment month Figure 2. Mean (Least Squares Value) Change from Baseline in Monthly Migraine Frequency Placebo Topiramate, 50 mg/d, Topiramate, 100 mg/d Topiramate, 200 mg/d P <.02 vs placebo; P =.03 for topiramate, 50 mg/d, vs placebo. Reprinted with permission from Silberstein et al. Arch Neurol. 2004;61: WORKPLACE PRODUCTIVITY AND ECONOMIC EFFECTS OF MIGRAINE PREVENTION Onset of migraine headaches is typically between the ages of 5 and However, frequency of migraine often increases between the ages of 30 and 45, a time when many individuals are raising young children and reaching their peak level of workplace productivity. 1 Headache causes significant loss of workplace productivity due to missed work days and, even more importantly, to impaired performance while on the job. 24,25 Migraine headaches also produce significant disruption of childcare and other family responsibilities. Although workplace and non-workplace productivity have been shown to benefit from acute treatments (eg, triptans) or from migraine management programs that incorporate 70% 60% 50% 40% 30% 20% 10% 0% 1 Month 2 Months 3 Months Placebo BTX 25 Percentage of subjects with at least a decrease of 2 headaches in the frequency of their migraines/month, after treatment with botulinum toxin injections. P <.05 at 3 months. BTX = botulinum toxin. Reprinted with permission from Bigal and Lipton. Neurologist. 2006;12: Vol. 4, No. 1 January 2007

5 department visits, laboratory and diagnostic services, and other services. 28 Acute migraine medications are one of the most significant costs of migraine care. 28 Preventive therapy for migraine has been shown to reduce the use of medical services, and therefore, may result in lower total treatment cost. For example, preventive therapy for migraine headaches has been shown to reduce the need for acute triptan medications by more than 20% over a 12-month period, with an even larger decrease for patients with the most frequent triptan use at baseline. 29 It has been suggested that these reductions in medical resource use may lower overall treatment costs associated with migraine headache. 13 An economic analysis of antiseizure medications for migraine prevention found that the cost effectiveness was greatest for patients who had the most severe migraines at baseline. 30 A recent study of migraine prevention with topiramate found that savings associated with reduced need for acute medications and reduced loss of work offset approximately 70% of the cost of treatment. 31 COMBINED THERAPY FOR MIGRAINE HEADACHE PREVENTION Preventive therapies reduce the frequency of migraine headache by approximately 50%, but they do not eliminate headaches. Therefore, patients should also receive abortive medications to treat acute attacks that occur despite their preventive regimens. 20 The goal of combining acute and preventive agents should be to use preventive therapies so that the patient rarely needs acute medications. 32 Detailed clinical guidelines to combine acute and preventive therapies have been developed by several expert consensus s in the United States and Europe. 20 In some cases, it may be necessary to combine 2 or more preventive medications. Adding a second preventive agent may be considered for a patient who still has frequent headaches despite the use of a preventive agent. The second preventive agent is usually selected from a different drug category. 33 Patients who receive combination preventive therapy usually have very frequent headaches before preventive treatment. Although this approach has not been extensively evaluated in controlled trials, some studies have demonstrated additional effectiveness of combining preventive medications. In one study, the combination of sodium valproate and a β blocker in patients with treatment-resistant migraine headaches demonstrated improvement of at least 50% in headache frequency from baseline in 56% of patients. 34 In a second study, adding topiramate to existing preventive therapies (ie, propranolol, flunarizine [not available in the United States], or both for most patients) significantly reduced headache frequency from 17 per month to 3 per month and also reduced the average headache duration and intensity (P <.001). 35 Although this approach may help to control migraine headaches for some patients who have very frequent headaches, it also increases the risk for adverse effects and the potential for drug interactions. 33 CONCLUSIONS Only 4 agents are approved by the US FDA for migraine prophylaxis, although several β blockers, antiseizure medications, calcium channel blockers, antidepressants, and other drugs are used to prevent migraine headaches. Treatment often is selected on the basis of the patient s comorbid conditions and desire to avoid specific side effects. By reducing pain, disability, and the need for acute medications, migraine prevention is cost effective. Some patients continue to exhibit significant disability on a monotherapy preventive regimen, and the use of combinations of preventive agents are sometimes required to reduce migraine headache frequency to tolerable levels. REFERENCES 1. Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41: Diamond S, Wenzel R. Practical approaches to migraine management. CNS Drugs. 2002;16: Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55: Rubingh C, Baggaley SK. Headache: Diagnosis and approaches to treatment. In: Lipman AG, ed. Pain Management for Primary Care Clinicians. Bethesda, Md: American Society of Health System Pharmacists; Dodick DW, Lipsy RJ. Advances in migraine management: implications for managed care organizations. Manag Care. 2004;13: Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58: Silberstein SD, Neto W, Schmitt J, et al. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004;61: Brandes JL, Saper JR, Diamond M, et al. Topiramate for University of Tennessee Advanced Studies in Pharmacy 19

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