Heads Up: The Integrative Approach to Migraine Prophylaxis

By Susan T. Marcolina, MD, FACP. Dr. Marcolina is an internist and geriatrician in Issaquah, WA; she reports no financial relationship to this field of study.

Migraine headaches affect 11% of the world's population.1 Since 90% of migraineurs experience moderate to severe pain and 35% are bedridden with headache episodes, the World Health Organization has listed migraine among the top 20 disability-causing diseases.2

In the United States, 17% of women, 6% of men, and 11% of children 5-15 years of age are affected. Although 25% of migraine patients meet criteria for prophylaxis with two or more monthly episodes of headache and 1) incomplete relief or intolerance/contraindication to acute pharmacologic treatment, 2) absence from school or work, and 3) diminished quality of life, only 3-5% receive preventive therapy.3-5

Since the public often perceives complementary and alternative medicine supplements to be as or more helpful than conventional care for the treatment of headache, neck and back conditions, they frequently purchase over-the-counter (OTC) supplements based on internet searches and positive anecdotal experiences of friends and family.6 Primary care physicians can more specifically advise patients regarding evidence-based preventive treatment strategies for chronic headaches. Such prophylaxis when effective reduces medication overuse and migraine progression; specific OTC supplements can be one aspect of such treatments.7

Clinical Characteristics of Migraine

Migraine headaches typically begin prior to age 40, most often in childhood or teenage years. There is typically an associated family history. Table 1 summarizes the International Headache Society's (IHS) diagnostic criteria for migraine.

Table 1. International Headache Society Diagnostic Criteria for Migraine Headaches8

1. Recurrent (at least 5 episodes fulfilling criteria 2-5)

2. Attacks last 4-72 hours

3. Possess at least two of the following characteristics:

  • Unilateral location (typically)
  • Pulsatile quality
  • Moderate to severe pain intensity
  • Aggravation with routine physical activity

4. Possess at least one of the following during headache:

  • Nausea or vomiting
  • Photophobia and phonophobia

5. Not attributable to another disorder

Application of these criteria improves the accuracy of the headache diagnosis and reserves neuroimaging for patients presenting with headache plus any of the following clinical findings, which may indicate a more serious secondary headache disorder, requiring medical and/or surgical intervention:8

  • onset of headaches after age 40 or before age 5
  • first, worst headache
  • abrupt onset (thunderclap)
  • progressive, changing pattern of headache
  • abnormal physical examination/neurologic symptoms
  • new onset of headaches with immunosuppression, cancer, trauma, pregnancy
  • exacerbation of headache with valsalva, exertion, sexual activity
  • syncope/seizures

A personal headache diary is often recommended because it provides information about a patient's headache history and allows patients and their doctors to understand possible environmental, dietary, and lifestyle precipitants, and to implement appropriate interventions.9

Pathophysiology of Migraine

Migraine headache symptoms occur as a wave of neuronal depolarization spreads across the cerebral cortex. This cortical spreading depolarization activates one or more subdivisions of trigeminal nerve afferents resulting in inflammatory changes in the pain-sensitive meninges and altered blood-brain barrier permeability. Common triggers (see Table 2) destabilize the nervous system and result in headaches for certain individuals.10

Table 2. Common Dietary/Environmental Triggers for Migraineurs10

  • Stress
  • Menses
  • Excessive sensory stimuli (bright lights, loud noises, strong odors)
  • Chronobiologic changes (irregularity in sleep, meals, exercise)
  • Alcohol overindulgence
  • Caffeine withdrawal
  • Aspartame (diet soda)
  • Tyramine (cheese, wine, sauerkraut)
  • Nitrites (hot dogs, cured meats)
  • Monosodium glutamate (MSG; frozen, canned, and processed foods; certain condiments)
  • Chocolate

Migraines and Comorbidities

Since overuse of short-acting analgesics and other acute drugs may interfere with the efficacy of preventive drugs, patients should be educated about how to manage their headache episodes. Patients with recurrent migraine headaches often have other chronic medical conditions such as hypertension or psychiatric comorbidities (i.e., anxiety and depressive disorders) that need to be considered and comanaged as part of the chronic treatment regimen.11

Since migraine headaches have no cure, treatment goals are to manage and reduce the burden of pain and disability. Current FDA-approved drugs for prevention of episodic migraine include propranolol, timolol, valproate, tricyclic antidepressants, and topiramate.11

Different classes of antihypertensives have been studied for migraine prophylaxis. Beta-blockers, especially timolol and propanolol, may be good choices for chronic migraneurs with coexistant hypertension, though they should be avoided in patients with asthma, peripheral vascular disease, a smoking history, and Raynaud's disease, and used judiciously in patients with depression and diabetes.12 Although the calcium channel blockers amlodipine and verapamil may be efficacious for migraine prophylaxis in hypertensive migraineurs, pedal edema is a limiting side effect.13 Lisinipril and candesartan have been found to reduce headache frequency and severity in randomized controlled trials but cost and side effects, such as cough and angioedema, are problematic.14,15

For migraneurs with coexistant depression, tricyclic antidepressants such as amitriptyline have been shown in randomized controlled trials to be effective preventive headache treatment.16 The dose of amitriptyline for migraine prophylaxis is lower than that recommended to treat depression, and its benefits for migraine headaches are independent of improvements in mood. However, dry mouth, constipation, and weight gain are significant, and for some patients, prohibitive side effects. Although SSRIs have been effective in depression treatment, they are not effective for migraine prophylaxis. However, one randomized controlled trial found venlafaxine (a serotonin/norepinephrine reuptake inhibitor) to be effective in the prevention of migraine.17

Anticonvulsants, primarily valproate and topiramate, are effective for migraine prophylaxis due to their potentiation of the neurotransmitter gamma amino butyric acid, reduction of neuronal firing in the trigeminocervical complex, and inhibition of neuronal sodium and calcium channels.18 Valproate can also stabilize mood disorders in patients who have concomitant bipolar depression. Mulleners, in a Cochrane review, concluded that anticonvulsants double the chance of reducing chronic migraine headache by more than 50% compared to placebo.19 However, side effects of osteomalacia, memory and language disturbances, fatigue and liver dysfunction (valproate), and dizziness, drowsiness, and nausea (topiramate) limit the use of this class of drugs, particularly in children and adolescents.

Therapeutic Lifestyle Management of Chronic Migraines

Chronic stress, excessive caffeine, alcohol, frequent and regular analgesic medication intake, and disturbances in chronobiologic rhythms such as sleep deprivation can all be barriers to successful palliation of migraine headaches and other types of chronic headaches.

Overnight headaches or headaches upon awakening reflect a sleep disturbance in 55% of patients with these complaints. It is particularly important to rule out obstructive sleep apnea syndrome with a sleep study in patients with a history of snoring, daytime somnolence, and early morning headaches because treatment results in improvement of both headaches and general medical health.20 The Somogyi effect (rebounding high blood sugar as an exaggerated response to low blood sugar in the early morning, generally secondary to excessive exogenous long-acting evening insulin) may cause chronic morning headaches in patients with diabetes, particularly if coupled with fasting hyperglycemia.

Dietary Triggers. For certain patients, especially children and adolescents, food and food additives can be significant precipitants of migraine headaches. Such triggers are outlined in Table 2. Skipped meals and fasting were reported as migraine triggers in 40-56% of migraineurs from subspecialty headache centers. Postulated mechanisms by which skipped meals can precipitate headache include alterations in serotonin and norepinephrine in the brainstem pathways or in release of stress hormones such as cortisol.21

Low-fat Diet. Bic et al conducted a prospective cohort trial of 54 migraine patients and found that decreasing dietary fat from 66 to 28 grams/day resulted in a significant decrease in headache frequency, intensity, duration, and medication use (P < 0.001 for all measures).22

Exercise. Regular exercise increases plasma beta endorphin levels.23 Koseoglu et al studied 36 migraineurs who engaged in regular home aerobic exercise three times weekly for 30 minutes over 6 weeks. The exercise significantly raised beta endorphin levels after the home exercise program (P < 0.0001) and had beneficial effects on all migraine parameters (P < 0.0001).24 Additionally, persons who exercise regularly increase their cardiovascular and cerebrovascular health with resultant improvements in psychological states, including depression, anxiety, and stress.

Over-the-counter Supplements for the Treatment of Migraine

Consumers may prefer nutraceuticals and OTC supplements for treatment of medical conditions for any number of reasons, including avoidance of possible medication-induced adverse effects. However, per the Dietary Health and Supplements Act of 1994, no standardization is required for over-the-counter supplements that do not claim to treat specific medical conditions. Patient resources for helping to identify safe vitamins and supplements include the United States Pharmacopeia (www.usp.org/USPVerified/dietarySupplements/), the NIH Office of Dietary Supplements (http://ods.od.nih.gov/), and Consumer Lab (www.consumerlab.com), an independent, subscription-based database and laboratory that provides reliable information regarding the labeling accuracy of OTC product content, the presence of contaminants such as lead, and the absorption of the product from the gastrointestinal (GI) tract.

Magnesium. Magnesium is an essential cofactor in more than 300 enzymatic reactions in the central nervous system. For example, magnesium is involved in all reactions resulting in the formation and utilization of adenosine-5'-triphosphate in energy metabolism. Such reactions are critically important to neuronal ion pump functioning, which controls membrane depolarization and neurotransmitter release, processes involved in migraine genesis. Additionally, magnesium concentration influences serotonin receptors, nitric oxide (NO) synthesis, and release of inflammatory mediators.25

In a small randomized, double-blind, multicenter, placebo-controlled trial, Peikert et al found that 600 mg/day of orally supplemented magnesium citrate for 12 weeks significantly decreased migraine frequency by 41.6% compared to a decrement of 15.8% with placebo (P < 0.05). The improvement occurred during the 9- to 12-week treatment interval.26

In another small, randomized, placebo-controlled trial of patients with menstrual migraines (women predisposed to migraine headaches 1-2 days before and during the initial three days of menstrual periods), Facchinetti et al found that oral supplementation with 360 mg/day of magnesium for the last 2 weeks of the menstrual cycle significantly reduced the Pain Total Index compared to subjects receiving placebo after 2 months of treatment.27

In a randomized, placebo-controlled, double-blind study in 86 migranous children 3-17 years of age, Wang et al found a statistically significant decrease in headache frequency for the magnesium oxide-supplemented group over placebo group (P = 0.0037) during a 16-week treatment period. Additionally, the magnesium treated group had significantly lower headache severity compared to the placebo group (P = 0.0029).28

Intravenous magnesium sulfate, in a 1 g dose, administered over 15 minutes in a small, single-blind, placebo-controlled study was significantly more effective (100% response rate) than placebo treatment with an intravenous normal saline infusion (6.6% response rate) for relieving moderate to severe acute migraine headaches.29

Magnesium is the only preventive agent with a Category A rating for pregnancy. Therefore, it is an appropriate choice for prophylaxis for women who are pregnant or trying to conceive.30,31

Riboflavin. Riboflavin is a critical cofactor in oxidative metabolism and energy generation within mitochondria.

Schoenen et al demonstrated in a small, randomized, placebo-controlled study of 55 patients with chronic migraines that supplementation with 400 mg/day of riboflavin (vitamin B2) resulted in a significantly greater proportion of patients with > 50% improvement in headache frequency (54% vs 19% improvement with placebo), headache days (57 vs 15), and migraine index (headache days plus mean severity; 39% vs 8%). These benefits were evident after 3 months of treatment. Riboflavin was well tolerated at this dosage.32

Coenzyme Q10. Coenzyme Q10 plays an essential role in electron transport and energy metabolism in the mitochondria of all cells in the body. It is also a potent free radical scavenger, and plays a role in stimulation of NO release by the vascular endothelium. Due to these vascular effects and its role in mitochondrial oxidative metabolism, coenzyme Q10 has been investigated as a treatment for migraine headache.33

In a randomized, controlled trial of 42 migraine patients, Sandor et al found that treatment with 100 mg three times daily of coenzyme Q10 resulted in > 50% reduction in headache frequency after 3 months of treatment compared to placebo (47.6% vs 14.4%), although it did not decrease severity nor use of acute headache (rescue) drugs.34

Hershey et al demonstrated that, as part of a multidisciplinary treatment program, supplementation of coenzyme Q10-deficient pediatric and adolescent migraine patients significantly decreased their headache frequency (P < 0.0001) and improved quality of life as assessed by their pre- and post-supplementation Pediatric Migraine Disability Questionnaire scores (P < 0.001).35

Botanical Preventive Therapy: Petasites hybridus (Butterbur). Butterbur is a perennial shrub in the Asteraceae or daisy family that can be found along rivers and marshy areas of Europe, Asia, and North America. Two active ingredients of the extract, petasin and isopetasin, have both calcium channel blocking and potent anti-inflammatory effects via inhibition of leukotriene synthesis.

The plant contains hepatotoxic and carcinogenic pyrrolizidine alkaloids (PA), but a proprietary PA-free root extract, Petadolex, (Weber and Weber GmbH & Co. KG, Germany) is approved by the German Commission E for the treatment of migraine headaches. Petadolex is licensed as a pharmaceutical medication under the German Health Authority regulation. It is a food supplement in the United States and therefore not under FDA scrutiny.36

In a double-blind, randomized, parallel group, placebo-controlled study of 229 patients aged 18-65 meeting criteria for chronic migraine headaches, Lipton et al compared Petadolex in doses of 50 mg and 75 mg twice daily to placebo. Patients were treated for 4 months preceded by a 1-month baseline evaluation. Compared to baseline, after 4 months the groups treated with 75 mg and 50 mg twice daily experienced an average 45% and 32% respective reduction in monthly headaches, both significantly different from the 28% reduction seen in the placebo group (P = 0.005). The higher Petadolax dosage was more effective. Long-term safety data for the use of this preparation, however, are lacking.37

Botanical Preventive Therapy: Tenacetum parthenium (Feverfew). A Cochrane review by Pittler concluded there was no evidence of efficacy for feverfew for the prophylaxis of migraine headache.38 A critical consideration with these studies, however, is the fact that the commercial feverfew products varied considerably with respect to stability and concentration of the presumed active constituent, parthenolide. Parthenolide has anti-inflammatory action via inhibition of prostaglandin synthesis; it also has effects on serotonin secretion and cranial vessel contractility.39

A double-blind, multicenter, placebo-controlled study by Diener et al using a standardized, stable feverfew extract (MIG 99) in 85 migraneurs showed a significant reduction in migraine episode frequency after 4 months of treatment compared to placebo.40

Table 3 summarizes dosing and the guidelines for supplements used in migraine prophylaxis.

Table 3. Dosages for Supplements Used in Migraine Prophylaxis

Supplement: Dosage: Commentary

Magnesium: 360-600 mg/day: Not for use in patients with renal insufficiency Diarrhea may be a limiting adverse effect May take up to 3 months to accrue prophylaxis benefit

Coenzyme: Q10 Kids: 1-3 mg/kg/day: Significant reduction in risk of preeclampsia noted in pregnant Adult: 300 mg/day migraineurs taking 100 mg orally twice daily after week 20 Soft gel formulations improve absorption Takes 3 months to accrue prophylaxis benefit May decrease the effect of warfarin

Riboflavin: (vitamin B2) 400 mg/day: Dose is teratogenic; therefore contraindicated in pregnancy and lactation Diarrhea and polyuria possible adverse reactions Takes 3 months to accrue prophylaxis benefit

Petadolex (butterbur): 75 mg twice daily: Not for use in children, or pregnant or lactating patients

MIG-99 (Feverfew): 6.25 mg three times daily: Not for use in children, or pregnant or lactating patients Can potentiate effects of anticoagulants

Adapted from References 25, 26, 28, 31, 32, 35, 36, 37, 40, 41, 46.

Adverse Events

Magnesium supplements can frequently cause diarrhea, but taking them with food can mitigate this side effect. Certain forms of magnesium (such as magnesium citrate, lactate, and gluconate) are more easily absorbed and less likely to cause diarrhea.42 Individuals with renal impairment should not be given supplemental magnesium as toxic levels can accumulate. Appropriate supplementation with magnesium in pregnancy is unlikely to be associated with adverse effects and may effectively prevent premature labor and sudden infant death syndrome.43

Riboflavin is extremely safe, but in high doses may cause diarrhea and polyuria.32 Feverfew, butterbur, and the high doses of vitamin B2 recommended for migraine prophylaxis should be avoided in pregnancy and lactation because they may be teratogenic. They also should not be used in children.44-46

One randomized, placebo-controlled, double-blind study found that a coenzyme Q10 product (Q- Absorb, Jarrow Formulas, Los Angeles, CA) was well tolerated in pregnancy after 20 weeks' gestation without adverse maternal or fetal outcomes, and was associated with a lower incidence of preeclampsia in women at risk for this condition. Mild gastrointestinal symptoms were the most common side effects of coenzyme Q10, but they occurred with similar frequency and severity in the placebo group.41 There have been several case reports, however, in which coenzyme Q10 supplementation has decreased the anticoagulant effects of warfarin.47

Formulations with enhanced solubility are more expensive. Coenzyme Q10 is best absorbed when fat or oil is present in the GI tract as during a meal. Softgels (containing oil) improve absorption.48

The proprietary butterbur product, PA-free Petadolex, was well tolerated by study migraineurs at a maximal dose of 75 mg twice daily for 4 months without associated abnormalities in liver function. The most common adverse effect compared to placebo was eructation.37,49

A randomized, double-blind, controlled trial of a standardized feverfew preparation, MIG-99, showed that it had a side effect profile no different from placebo.40 Since feverfew extract interferes with platelet aggregation, however, it can potentiate the effects of anticoagulant therapy.50

Mouth ulceration, ageusia, and lip swelling may occur as side effects of feverfew use. Although allergic reactions to feverfew have rarely been reported, theoretically persons with allergies to chamomile, ragweed, or yarrow should avoid the use of feverfew-containing products due to cross reactivity.50

Conclusion

As with any chronic illness, a multifactorial approach, in this case guided by information from a headache diary, may help to mitigate pain, lessen disability, and avoid triggers. Identification and treatment of comorbidities such as affective disorders, alcohol and caffeine overuse, sleep disturbances, and analgesic overuse can decrease headache frequency and severity. The National Headache Foundation and the American Academy of Neurology have both identified magnesium and riboflavin as preventive therapies for migraine headaches.51,52

Standardized preparations of certain botanicals, such as butterbur and feverfew, may be useful in certain non-pregnant, non-lactating adult migraineurs, but larger, long-term studies are necessary to substantiate initial promising findings. Coenzyme Q10 as a softgel in a dose of 300 mg/day for adults and 1-3 mg/kg/day in children shows promise for the prophylaxis of migraine headaches. Feverfew and coenzyme Q10 should be used cautiously in persons on chronic warfarin anticoagulation.

Recommendations

Primary care physicians can utilize IHS criteria to diagnose migraine headaches; initiate therapeutic lifestyle interventions such as regular aerobic exercise, a low-fat diet, and avoidance of migraine triggers; and evaluate the need for preventive nutraceuticals such as riboflavin, magnesium, and coenzyme Q10. Comorbidities should be identified and treated. A trial of a standardized preparation of butterbur (Petadolex) or feverfew (MIG-99) may be considered in certain patients who do not respond to therapeutic lifestyle interventions, chronobiologic regulation, and first-line pharmacologic treatment; however, there is a dearth of data for long-term use of these botanical products as preventive therapy. Since feverfew and coenzyme Q10 can interfere with the effects of anticoagulant medication such as warfarin, the risk/benefit ratio for using them in patients receiving such therapy must be carefully considered.

References

1. Stovner L, et al. The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193-210.

2. Leonardi M, et al. The global burden of migraine: Measuring disability in headache disorders with World Health Organization's classification of functioning, disability and health. J Headache Pain 2005;6:429-440.

3. Lipton RB, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343-349.

4. Abu-Arafeh I, Russell G. Prevalence of headache and migraine in schoolchildren. Br Med J 1994;309:765-769.

5. Evers S, et al. European Federation of Neurological Societies (EFNS) guideline on the drug treatment of migraine-revised report of the EFNS task force. Eur J Neurol 2009;6:968-981.

6. Eisenberg DM, et al. Perceptions about complementary therapies relative to conventional therapies among adults who use both. Results from a national survey. Ann Int Med 2001;135:344-351.

7. Schmitz N, et al. Attack frequency and disease duration as indicators for brain damage in migraine. Headache 2008;48:1044-1055.

8. Headache Classification Subcommittee of International Headache Society. The international classification of headache disorders. Cephalalgia 2004;24(Suppl 1):1-160.

9. Migraine and Headache Diary Workbook. The Health Central Network. My Migraine Connection. Available at: www.helpforheadaches.com/lwfiles/Diary_Workbook.pdf. Accessed Aug. 3, 2011.

10. Millichamp JG, et al. The diet factor in pediatric and adolescent migraine. Pediatr Neurol 2003;28:9-15.

11. Silberstein SD. Practice parameter: Evidence-based guidelines for standards subcommittee of the American Academy of Neurology. Neurology 2000;55:754-762.

12. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2004;2:CD003225.

13. Tfelt-Hansen P. Prophylactic pharmacotherapy of migraine. Some practical guidelines. Neurol Clin 1997;15:153-159.

14. Schrader H, et al. Prophylactic treatment of migraine with angiotensin convertine enzyme inhibitor (lisinopril): Randomized, placebo-controlled, crossover study. BMJ 2001;322:1-5.

15. Trovnik E, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: A randomized controlled trial. JAMA 2003;289:65-69.

16. Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol 1979;36:695-699.

17. Buleit S, et al. Venlafaxine versus amitryptyline in the prophylaxis of migraine. A randomized, cross-over study. Clin Neurol Neurosurg 2004;107:44-48.

18. Artemenko AR, et al. Effects of toiramate on migraine frequency and cortical excitability in patients with frequent migraine. Cephalalgia 2008;28:203-208.

19. Mulleners WM, Chronicle EP. Anticonvulsants in migraine prophylaxis; a Cochrane review. Cephalalgia 2008;28:585-597.

20. Paiva T, et al. Chronic headaches and sleep disorders. Arch Intern Med 1997;157:1701-1705.

21. Scharff L, et al. Triggers of headache episodes and coping response of headache diagnostic groups. Headache 1995;35:397-403.

22. Bic Z, et al. The influence of a low-fat diet on incidence and severity of migraine headaches. J Womens Health Gend Based Med 1999;8:623-630.

23. Goldfarb AH, Jamiertas AZ. Beta-endorphin response to exercise. An update. Sports Med 1997;24:8-16.

24. Koseoglu E, et al. Aerobic exercise and plasma beta endorphin levels in patients with migrainous headache without aura. Cephalalgia 2003;23:972-976.

25. Bianchi A, et al. Role of magnesium, coenzyme Q10, riboflavin and vitamin B12 in migraine prophylaxis. Vitam Horm 2004;69:297-312.

26. Peikert A, et al. Prophylaxis of migraine with oral magnesium: Results form a prospective multicenter, placebo-controlled and double-blind randomized study. Cephalalgia 1996;16:257-263.

27. Fascchinetti F, et al. Magnesium prophylaxis for menstrual migraine: Effects on intracellular magnesium. Headache 1991;31:298-301.

28. Wang F, et al. Oral magnesium oxide prophylaxis of frequent migraine headaches in children. A randomized, double-blind, placebo-controlled trial. Headache 2003;43:601-610.

29. Demirkaya S, et al. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 2001;41:171-177.

30. Drugs.com monograph on magnesium. Available at: www.drugs.com/pro/magnesium-sulfate.html. Accessed Aug 6, 2011.

31. Evers S, et al. EFNS guideline on the drug treatment of migraine-revisied report of an EFNS task force. Eur J Neurol 2009;16:968-981.

32. Schoenen J, et al. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998;50:466-470.

33. Sparaco M, et al. Mitochondrial dysfunction and migraine: Evidence and hyothesis. Cephalalgia 2006;26:360-372.

34. Sandor PS, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: A randomized controlled trial. Neurology 2005;64:713-715.

35. Hershey AD, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache 2007;47:73-80.

36. Thomet OA, et al. Role of petasin in the potential anti-inflammatory activity of a plant extract of Petasites hybridus. Biochem Pharmacol 2001;61:1041-1047.

37. Lipton RB, et al. Petsites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology 2004;63:2240-2244.

38. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2004; DC002286.

39. Makheja AM, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew. Prostaglandins Leukotrienes Med 1982;8:653-660.

40. Diener HC, et al. Efficacy and safety of 6.25 mg tid feverfew C02 extract (MIG-99) in migraine prevention—A randomized, double-blind, multicenter, placebo-controlled study. Cephalalgia 2005;25:1031-1041.

41. Teran E, et al. Coenzyme Q10 supplementation during pregnancy reduces the risk of pre-eclampsia. Int J Gynecol Obstet 2009;105:43-45.

42. Firoz M, Graber M. Bioavailablity of US commercial magnesium preparations. Magnes Res 2001;14:257-262.

43. Durlach J. New data on the importance of gestational magnesium deficiency. J Am Col Nutr 2004;23:69S-70S.

44. Loder E. Migraine in pregnancy. Semin Neurol 2007; 27:425-433.

45. Silberstein SD. Headaches in pregnancy. Neurol Clin 2004;22:727-756.

46. Consumer Lab on Butterbur. Available at www.consumerlab.com/tnp.asp?chunkiid=21626&docid=/tnp/pg000417. Accessed August 8, 2011.

47. Heck AM, et al. Potential interaction between alternative therapies and warfarin. Am J Health Syst Pharm 2000;57:1221-1227.

48. ConsumerLab. Available at: www.consumerlab.com/reviews/Review-CoQ10-Supplements-and-Ubiquinol/CoQ10/. Accessed Aug. 2, 2011.

49. Grossmann W, Schmidramsl H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Alt Med Rev 2001;6:303-309.

50. Ernst E, Pittler, MA. The efficacy and safety of feverfew (Tanacetum parthemium L): An update of a systematic review. Public Health Nutr 2000:3:509-514.

51. 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;55:754-762. Available at: www.guideline.gov/summary/summary.aspx?docjd=2820. Accessed Aug. 3, 2011.

52. Mauskop A; Graff-Radford S. Special treatment situations: Alternative headache treatments. Standards of Care for Headache Diagnosis and Treatment. Chicago, IL: National Headache Foundation; 2004:115-122.