Simvastatin and Vitamin D for Migraine Prevention
By Dara Jamieson, MD
Associate Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Jamieson reports she is a consultant for Bayer and Boehringer-Ingelheim.
SYNOPSIS: In a randomized, double-blind, placebo-controlled trial of 57 adults with episodic migraine, simvastatin plus vitamin D was effective in the prevention of headache in adults with episodic migraine.
SOURCE: Buettner C, et al. Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial. Ann Neurol 2015; Sep 29. DOI: 10.1002/ana.24534 [Epub ahead of print].
Despite somewhat effective acute migraine headache treatments, there continues to be a need for further treatments to prevent episodic migraine. Buettner et al performed a randomized, double-blind, placebo-controlled trial to assess the efficacy and tolerability of the twice-daily combination of simvastatin and vitamin D for migraine prevention in 57 adults with episodic migraine. Adults, recruited from the greater Boston area, had to have episodic migraine headaches, as diagnosed by the International Headache Society (ICHD-II) criteria for ≥ 3 years, with ≥ 4 headache days a month. Patients were not eligible if they had chronic migraine with ≥ 15 days of headache a month for 3 months. The majority had used multiple acute pain medications for abortive therapy. Approximately half had tried or were currently using a migraine-preventive medication. After a 12-week baseline data-gathering period, the migraineurs were randomly assigned to simvastatin 20 mg tablets twice daily plus vitamin D3 1000 IU capsules twice daily or to matching placebos for a 24-week intervention period. Headache characteristics were tracked by diary.
Compared to the placebo group, the active treatment group had statistically significantly older age, larger body mass index, and more headache days in the past 3 months (25.5 vs 18.0). Episodic migraineurs randomized to 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 days in the active treatment group vs +1.0 days in the placebo group (P < 0.001). In the second half of the treatment period, intervention weeks 13 to 24, there was a change of -9.0 days in the active group vs +3.0 days in the placebo group (P < 0.001). In the simvastatin plus vitamin D3 group, eight out of 28 migraineurs experienced a 50% reduction in the number of migraine days at 12 weeks, and nine out of 24 participants had the reduction at 24 weeks post-randomization. Only 1 out of 29 patients in the placebo group had a 50% reduction in the number of migraine days.
Adverse events were similar in both groups, treatment discontinuation rates were low, and blinding was successful. Creatine kinase levels were monitored with a significant elevation in one placebo group participant who was exercising vigorously and taking vitamin supplements. The results of this small preliminary study indicate that simvastatin plus vitamin D may be effective for prevention of headache in adults with episodic migraine. The authors speculated that because statins are believed to correct endothelial dysfunction, this economical approach may also reduce the risk for vascular diseases among migraineurs.
COMMENTARY
The authors noted that migraine is a neurological disorder associated with increased cerebrovascular and cardiovascular risk, not adequately explained, but with likely involvement of changes in the endothelial morphology. Statins have anti-inflammatory, antithrombotic, and antiplatelet properties that are independent of their more well-known lipid-lowering effect. Statins appear to stabilize the endothelium, accounting for their use in vascular risk reduction. The authors previously observed an association with statin use, with potential migraine benefit in those with higher vitamin D levels, and they postulate favorable synergism between vitamin D and statins. While these results show headache prevention with two relatively well-tolerated drugs in patients with episodic migraine, the real test of this treatment is in patients with chronic migraine. Patients who respond favorably to acute treatment with a triptan several times a month usually do not generally need to take a daily preventive medication for functional improvement. Statins are generally well tolerated, with muscle complaints noted in a small number of patients. This pilot study continues to explore that observation. But a larger study with a more diverse and better matched patient population is needed to confirm these promising results.
Migraine preventive treatment is essentially empiric, based on epidemiologic data rather than on cogent mechanistic explanation. The explanations offered to patients asking how these medications work are frustratingly vague. Any offerings on mechanisms for simvastatin and/or vitamin D are conjecture. Which of these two active treatments confers benefit is not known and the appropriate patient profile for their use is also unspecified. Low vitamin D levels are common in the United States, especially in northern climates, with lack of sun exposure in colder months. The participants’ vitamin D levels were not noted in the results to see if there was a correlation with treatment response. As the individual patient profile often dictates the choice of migraine preventive medication, if migraine patients are known to have untreated elevation of LDL, encouraging treatment with simvastatin plus vitamin D makes sense. The benefit of simvastatin is likely a class effect rather than a specific agent effect, so other statins may also be efficacious.
As a coda, two of the authors and Beth Israel Deaconess Medical Center have applied for a patent for the combination of a statin and vitamin D as a prophylactic treatment for migraine. This patent application is reminiscent of the past patenting of the combination of a triptan and a nonsteroidal anti-inflammatory agent for the acute treatment of migraine, with a branded single pill combination treatment eventually coming to market after the patent expiration on Imitrex. If the combination of simvastatin and vitamin D continues to show benefit, will Zocor be rebranded with an over-the-counter vitamin? However, the generic two-pill combination may be just as efficacious, as this study was performed with generic simvastatin and vitamin D from Trader Joe’s.
In a randomized, double-blind, placebo-controlled trial of 57 adults with episodic migraine, simvastatin plus vitamin D was effective in the prevention of headache in adults with episodic migraine.
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