Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial

Catherine Buettner, Rony-Reuven Nir, Suzanne M Bertisch, Carolyn Bernstein, Aaron Schain, Murray A Mittleman, Rami Burstein, Catherine Buettner, Rony-Reuven Nir, Suzanne M Bertisch, Carolyn Bernstein, Aaron Schain, Murray A Mittleman, Rami Burstein

Abstract

Objective: The aim of this work was to assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine.

Methods: We performed a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period in 57 adults with episodic migraine. Participants were randomly assigned to simvastatin 20 mg tablets twice-daily plus vitamin D3 1,000 international units capsules twice-daily or matching placebo tablets and capsules.

Results: Compared to placebo, participants using simvastatin plus vitamin D3 demonstrated a greater decrease in number of migraine days from the baseline period to intervention weeks 1 to 12: a change of -8.0 (interquartile range [IQR]: -15.0 to -2.0) days in the active treatment group versus +1.0 (IQR: -1.0 to + 6.0) days in the placebo group, p < 0.001; and to intervention weeks 13 to 24: a change of -9.0 (IQR: -13 to -5) days in the active group versus +3.0 (IQR: -1.0 to + 5.0) days in the placebo group, p < 0.001. In the active treatment group, 8 patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and 9 (29%) at 24 weeks postrandomization. In comparison, only 1 patient (3%) in the placebo group (p = 0.03) experienced such a reduction. Adverse events were similar in both active treatment and placebo groups.

Interpretation: The results demonstrate that simvastatin plus vitamin D is effective for prevention of headache in adults with episodic migraine. Given statins' ability to repair endothelial dysfunction, this economical approach may also reduce the increased risk for vascular diseases among migraineurs.

Trial registration: ClinicalTrials.gov NCT01225263.

© 2015 American Neurological Association.

Figures

Figure 1
Figure 1
Flow of participants through the trial.

References

    1. Lipton RB, Stewart WF. Migraine in the United States: a review of epidemiology and health care use. Neurology. 1993 Jun;43(6 Suppl 3):S6–10.
    1. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2163–96.
    1. Gilmore B, Michael M. Treatment of acute migraine headache. American family physician. 2011 Feb 1;83(3):271–80.
    1. Wilkinson M. Migraine treatment: the British perspective. Headache. 1994 Sep;34(8):S13–6.
    1. Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2009 Jan-Feb;12(1):55–64.
    1. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007 Jan 30;68(5):343–9.
    1. Dahlof CG, Solomon GD. The burden of migraine to the individual sufferer: a review. European journal of neurology: the official journal of the European Federation of Neurological Societies. 1998 Nov;5(6):525–33.
    1. Terwindt GM, Ferrari MD, Tijhuis M, Groenen SM, Picavet HS, Launer LJ. The impact of migraine on quality of life in the general population: the GEM study. Neurology. 2000 Sep 12;55(5):624–9.
    1. Dodick DW, Silberstein SD. Migraine prevention. Practical neurology. 2007 Nov;7(6):383–93.
    1. Silberstein SDHS, Freitag F, Dodick DW, Argoff C, Ashman E Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337–45.
    1. Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. Journal of managed care pharmacy : JMCP. 2014 Jan;20(1):22–33.
    1. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II) Headache. 2013 Apr;53(4):644–55.
    1. Bigal ME, Kurth T, Santanello N, et al. Migraine and cardiovascular disease: a population-based study. Neurology. 2010 Feb 23;74(8):628–35.
    1. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Migraine and risk of cardiovascular disease in women. JAMA : the journal of the American Medical Association. 2006 Jul 19;296(3):283–91.
    1. Kurth T, Schurks M, Logroscino G, Gaziano JM, Buring JE. Migraine, vascular risk, and cardiovascular events in women: prospective cohort study. BMJ. 2008;337:a636.
    1. Sacco S, Ricci S, Carolei A. Migraine and vascular diseases: a review of the evidence and potential implications for management. Cephalalgia. 2012 Jul;32(10):785–95.
    1. Sacco SRP, Grassi D, Pistoia F, Ornello R, Carolei A, Kurth T. Peripheral vascular dysfunction in migraine: a review. J Headache Pain. 2013 Oct;1:14–80.
    1. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology. 2005 Feb 22;64(4):614–20.
    1. Stam AH, Haan J, van den Maagdenberg AM, Ferrari MD, Terwindt GM. Migraine and genetic and acquired vasculopathies. Cephalalgia. 2009 Sep;29(9):1006–17.
    1. Aird WC. Endothelial cell heterogeneity. Cold Spring Harbor perspectives in medicine. 2012 Jan;2(1):a006429.
    1. Mattace-Raso FU, van der Cammen TJ, Hofman A, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation. 2006 Feb 7;113(5):657–63.
    1. Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. The open cardiovascular medicine journal. 2010;4:302–12.
    1. Schindler TH, Nitzsche EU, Olschewski M, et al. Chronic inflammation and impaired coronary vasoreactivity in patients with coronary risk factors. Circulation. 2004 Aug 31;110(9):1069–75.
    1. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes care. 2009 Nov;32(Suppl 2):S314–21.
    1. Antoniades C, Bakogiannis C, Leeson P, et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation. 2011 Jul 19;124(3):335–45.
    1. Everett BM, Glynn RJ, MacFadyen JG, Ridker PM. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Circulation. 2010 Jan 5;121(1):143–50.
    1. Forero-Pena DA, Gutierrez FR. Statins as modulators of regulatory T-cell biology. Mediators of inflammation. 2013;2013:167086.
    1. Liao JK, Laufs U. Pleiotropic effects of statins. Annual review of pharmacology and toxicology. 2005;45:89–118.
    1. Tousoulis D, Psarros C, Demosthenous M, Patel R, Antoniades C, Stefanadis C. Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins. Journal of the American College of Cardiology. 2014 Jun 17;63(23):2491–502.
    1. Yanuck D, Mihos CG, Santana O. Mechanisms and clinical evidence of the pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in central nervous system disorders: a comprehensive review. The International journal of neuroscience. 2012 Nov;122(11):619–29.
    1. Musial J, Undas A, Gajewski P, Jankowski M, Sydor W, Szczeklik A. Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia. International journal of cardiology. 2001 Feb;77(2-3):247–53.
    1. Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. The New England journal of medicine. 2001 Jun 28;344(26):1959–65.
    1. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004 Jun 1;109(21 Suppl 1):II18–26.
    1. Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arteriosclerosis, thrombosis, and vascular biology. 2003 May 1;23(5):729–36.
    1. Zhou Q, Liao JK. Pleiotropic effects of statins. - Basic research and clinical perspectives. Circulation journal : official journal of the Japanese Circulation Society. 2010 May;74(5):818–26.
    1. Millar PJ, Floras JS. Statins and the autonomic nervous system. Clin Sci (Lond) 2014 Mar;126(6):401–15.
    1. Buettner C, Burstein R. Association of statin use and risk for severe headache or migraine by serum vitamin D status: A cross-sectional population-based study. Cephalalgia. 2014 Nov 25;
    1. Christakos S, Hewison M, Gardner DG, et al. Vitamin D: beyond bone. Annals of the New York Academy of Sciences. 2013 May;1287:45–58.
    1. Hewison M, Freeman L, Hughes SV, et al. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol. 2003 Jun 1;170(11):5382–90.
    1. Jeffery LE, Wood AM, Qureshi OS, et al. Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. J Immunol. 2012 Dec 1;189(11):5155–64.
    1. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Translational research : the journal of laboratory and clinical medicine. 2009 Jan;153(1):11–6.
    1. Palamaner Subash Shantha G, Ramos J, Thomas-Hemak L, Pancholy SB. Association of vitamin d and incident statin induced myalgia-a retrospective cohort study. PloS one. 2014;9(2):e88877.
    1. Morioka TY, Lee AJ, Bertisch S, Buettner C. Vitamin D status modifies the association between statin use and musculoskeletal pain: A population based study. Atherosclerosis. 2014 Nov 20;238(1):77–82.
    1. Buettner C, Rippberger MJ, Smith JK, Leveille SG, Davis RB, Mittleman MA. Statin use and musculoskeletal pain among adults with and without arthritis. The American journal of medicine. 2012 Feb;125(2):176–82.
    1. Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders (second edition) Cephalalgia. 2004;24(Suppl 1):1–160.
    1. Schafer JL. Multiple imputation: a primer. Statistical methods in medical research. 1999 Mar;8(1):3–15.
    1. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Topiramate for the prophylaxis of episodic migraine in adults. The Cochrane database of systematic reviews. 2013;6:CD010610.
    1. Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European journal of preventive cardiology. 2014 Apr;21(4):464–74.
    1. Ashina S, Bendtsen L, Lyngberg AC, Lipton RB, Hajiyeva N, Jensen R. Prevalence of neck pain in migraine and tension-type headache: A population study. Cephalalgia. 2014 May 22;
    1. Hauser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Deutsches Arzteblatt international. 2012 Jun;109(26):459–65.

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