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Statin for Migraine Headache: Is It Worthwhile?
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.299154
Keywords: Cholesterol-lowering agent, headache, migraine disorders, statins
Migraines are severe primary headache disorder that affects about 12% of the population, more frequent in women than in men, and it often occurs along with nausea, vomiting, and extreme sensitivity to light and sound.[1] Diagnostic criteria are according to the International Classification of Headache Disorders, third edition(ICHD-3). Migraine attacks can cause pulsating pain of moderate-to-severe intensity in the head that remains for at least 4 to 72 h, and the patients who suffer from intense pain should lie down and sleep in a quiet and dark place.[2] Some types of migraines may be accompanied by sensory warning symptoms, such as flickering lights in vision, and numbness or tingling hands and feet.[3] The peak age of onset of a migraine is among young people meanwhile women are affected more than men.[4] If there is a family history of migraine, the migraine may be increased.[5] However, repeated migraine attacks may vary in different individuals and overtimes; this difference may be related to the external and internal factors such as stress and hormones(especially estrogen), respectively.[6] Statins or 3-hydroxy-3-methyl-glutaryl-coenzyme A(HMG-CoA) reductase inhibitors are medicines that reduce the cholesterol content of liver cells and lead to low-density lipoprotein (LDL) uptake through the expression of the LDL receptor. The other statin mechanism is related to the reaction of very-LDL(VLDL) and LDL, of which temporary increase of the synthesis of HMG-CoA reductase following statin therapy led to preservation and reproduction of the cellular VLD; consequently, this improves the effect of statins on the expression of LDL receptors, reduces the amount of LDL l in plasma, and returns intracellular cholesterol to normal steady status.[7] Statins can also reduce VLDL by affecting the secretion of apolipoprotein B levels.[8],[9] Statins are different in the absorption and binding to plasma proteins, secretion, solubility, and their ability to reduce high-density lipoprotein(HDL). Statins can reduce triglycerides and increase HDL by 5% to 10%, but do not affect lipoprotein.[10] In addition, pleiotropic properties of statins cause improving endothelial function, increasing the stability of atherosclerotic plaques, reducing oxidative stress and inflammation, and inhibiting the thrombogenic response. Generally, the beneficial effect of statin's drugs has been shown that the effect of their mechanism is more than reducing lipid levels alone.
The researchers found that changes in the brain blood flow of these patients develop during the migraine phase such as a typical prodromal may be responsible for migraine attacks. Hypoperfusion(low blood flow to the tissue) occurs first and then hyperperfusion(excessive blood flow to the tissue), in which the patient experiences symptoms such as visual, sensory, or even linguistic disturbances [Figure 1].[11] In migraine attacks, the patient experiences different conditions depending on the type of migraine. It is usually painful and one-sided, and the patient tends to sleep or even anesthesia, which is sometimes accompanied by vomiting and photophobia. This headache remains for up to 72 h if treatment is done during 4 to 6 h, and if treatment is not successful or treatment is not committed, patients with asymptomatic migraine usually feel pain on both sides of the head that is accompanied by neck pain.[12],[13],[14],[15] After the headache has been healed, symptoms may remain for hours or even days and may annoy the patient. These symptoms often include excessive fatigue, weakness, slowness, and mood changes.
For the treatment of the patients who suffer from migraines, it is important to have a suitable solution, as well as to determine the necessary measures to treat the patients completely. Statin is cholesterol and triglycerides(blood lipids) lowering drug, but according to the pleiotropic effect of statins, especially improving endothelium function and antioxidant property, we should focus on the evidence that has a main role in the effect of statins on migraine headaches, especially in patients who do not respond to first-line prevention treatments. The hypothesis may show that drugs called statins could be effective in the treatment of patients with migraine.
Experimental evidence Migraine pathophysiology is just beginning to be known, which is assumed to comprise activation and sensitization of trigeminovascular nociceptive pathways. This activation innervates the cranial vasculature and leads to the activation of brain stem nuclei. Other theories include the sensitization of neurons, activation at serotonin receptors, calcitonin gene-related peptide, and vascular contributions. Over the last 30 years, our provided translational knowledge and a framework of the pathophysiology of migraine owe research conducted in animal models.[16] Yin et al.[17] performed an experimental study to explore whether atorvastatin attenuates NF-kappa B activation in trigeminal nucleus caudalis in a migraine animal model. They suggested that atorvastatin may be a novel and promising candidate for forthcoming presentation or treatment of migraine through activating NF-kappa B in trigeminal nucleus caudalis. Epidemiologic evidence Very limited epidemiologic studies about the use of statin in patients with migraine were conducted so far. Buettner and Burstein[18] conducted a cross-sectional, population-based study of US individuals aged ≥40 years to evaluate whether statin and vitamin D status is associated with migraine or not. In this study with a population of 5938 people, the rate of prevalence of migraine in people who use statins was calculated and showed that people with higher levels of vitamin D with statin use were less likely to have a migraine headache. Clinical evidence Liberopoulos and Mikhailidis[19] were among the first researchers who suggested that the potential beneficiary use of statins for migraine headache prevention in a 58-year-old man with frequent attacks of typical aura with migraine since he was 20-year old. Atorvastatin, 20 mg/day was prescribed considering his elevated level of low-density lipoprotein cholesterol(LDL-C); thus, interestingly he came back after three months with no migraine attacks and remains migraine episodes-free for two years. After this report, Ramsey and Snyder[20] described a 46-year-old airline captain with no prior history of chronic headaches or migraine who suffers migraine-type headaches after exposure to cabin altitudes (above 6000 feet) that began within days of starting pravastatin for hypercholesterolemia. This was the first report of migraine headaches triggered by the exposure to pravastatin along with reduced barometric pressure. To the best of our knowledge, there are a few clinical trials alongside various other studies on stain use in migraines so far [Table 1].
Buettner et al.[21] conducted a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period to assess the efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in 57 adults with episodic migraine. Their results suggest that simvastatin plus vitamin D is effective for the prevention of migraine headaches in adults with episodic migraine, as well as due to the ability of statins on endothelial dysfunction treatment, this approach may also reduce the risk of cardiovascular disease in patients with migraine. Moreover, Medeiros et al.[22] performed an open-label, prospective, parallel-group, active comparator study during a 90-day maintenance period on 25 women with migraine attacks, and reported a potential efficacy of statins for migraine prevention. Hesami et al. and Marfil-Rivera andFlores conducted a randomized clinical trial study using 40 mg daily atorvastatin for patients with episodic migraine and suggested that atorvastatin was effective, safe alternative drug with fewer adverse effects in the prevention of episodic migraine.[23],[24] Sahebnasagh et al. in 2020 show that 500-mg sodium valproate with 20 mg/d atorvastatin reduces the number of acute attacks and pain severity.[25] As well as the study of Mazdeh et al., 2020 shows that the numbers of attacks were significantly decreased in the intervention group, but for propranolol(10 mg twice a day) and rosuvastatin(10 mg/d).[26] These studies justify a need for more randomized, placebo-controlled trials to evaluate the efficacy and tolerability of statins for the preventive treatment of migraine. Trials ongoing In trial databases, there were two ongoing trial studies that recruitment completed [Table 2]. In this phase 3 clinical trial, patients with diagnostic migraine aged over 18 years, having at least four migraine attacks per month, and normal serum vitamin D3 levels(greater than 30 ng/mL) were included and divided into two groups of intervention(25 mg of nortriptyline and 40 mg of atorvastatin) and control(25 mg of nortriptyline and placebo tablets similar to atorvastatin) for 24 days. In other study, participants with physician-diagnosed migraine with or without aura who are treatment one dose within 6 months.
Today, for the relief and treatment of migraine headache, many methods and medications have been designed and proposed, of which each method has its advantages and disadvantages. The best methods to treat the disease are those with high durability and effectiveness for patients with medically complex conditions. Based on epidemiologic, clinical, and laboratory evidence mentioned, statin could be an effective drug in prophylaxis and treatment of patients with migraine headaches. In the previous studies, statin affects the cholesterol level and positively affects reducing the measure of cholesterol and triglycerides(blood lipids), as were the patients with migraine headache have no episode of attacks, possibly a connection between headache pains and high blood cholesterol levels, stating that reduce the incidence of migraine attack's frequency.[19] Several studies with a variety of dosage of statins in combination with vitamin D indicate that it may compose positive effect on the treatment of migraine headache; these studies have shown that people with migraine are less likely to develop migraine following the use of this combination.[18],[21] Experiments led on mice have demonstrated that the statin drug in cases where individuals have prophylaxis of migraines, the action of inhibitory drugs, can be panic attacks who get migraines be prevented, but this study wasin vitro and animal model, and need for more research on the human samples.[17] Statins may turn out to be beneficial drugs in the treatment or prophylaxis of migraine, due to two reasons, first, reducing the increased cardiovascular risk associated with migraine, and second, have a beneficial effect on the pathogenesis of migraine and consequently the symptoms associated with this condition.[19] The exact mechanism that increases the vascular risk associated with migraine is not fully known, but possibilities include endothelial dysfunction, platelet abnormalities, microemboli, and drug induction.[27] The proposed mechanism is the pleiotropic effects of statins that may play a role in reducing migraine attacks; besides, improving endothelial function, arterial stiffness and vascular tone by statins may reduce migraine attack frequency [Figure 2]. Other statin effects, including reducing inflammatory responses and decreasing platelet aggregation and thrombosis, also could contribute to the beneficial effect on migraine.[18]
According to this study, statins can be used at 20–40 mg/d doses to treat or reduce migraine attacks.
Taken together, epidemiologic, clinical, and experimental evidence suggest that statin may be a novel and promising candidate for future treatment or prophylaxis of migraine. We hope that the use of this drug as lowering cholesterol and triglycerides(blood lipids), as well as reducing migraine headaches episodes agent to enhance the role of this drug in cure or prevent migraine attacks or recurrence, and finally to improve the patient's quality of life. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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