Warfarin Institute of America
Dedicated To Your Health
Are Anticoagulants a Possible Treatment for Cluster Headaches?
Joseph T. Horsfall II, Pharm D. Candidate
Ohio Northern University
In recent scientific literature, there has been some discussion of the relationship between cluster headaches and anticoagulant therapy. The discussion has actually included some disagreement among researchers. Case reports exist both stating that warfarin relieves and causes cluster headaches.1,2 In addition, it has been suggested by case report that another anticoagulant which is a chemical relative of warfarin, acenocoumarol (available in many countries, however not approved by the FDA for use in the United states), can relieve cluster headaches caused by warfarin.2 Interestingly, it has also been suggested that vitamin K antagonists in general may be useful in prophylactic treatment of cluster headaches in some patients.3
In general, cluster headaches are characterized by at least five headache attacks associated with each other, occurring from one every other day up to eight headache attacks per day. For a diagnosis of cluster headache, headache attacks must not be attributable to any other disease state. In addition, headache attacks will cause severe to very severe one sided pain behind or around the eye, or in the temple region. The pain may radiate to the upper teeth, jaw, or neck. Headache attacks last 15 minutes to 3 hours if untreated. Other symptoms may include same-sided tearing, same-sided nasal congestion or drainage, same-sided eyelid swelling, same-sided forehead and facial sweating, same-sided miosis (constriction of the pupil which may lead to blurry vision), and a sense of restlessness or agitation.4
Cluster headache may be episodic in nature or chronic. Episodic cluster headache is defined as having at least 2 cluster periods, separated by at least one month of headache free remission, of at least 7 but not more than 365 days. Chronic cluster headache occurs if headache attacks occur over a period of time longer than one year without remission or occur as episodic attacks with remission lasting less than one month. Cluster headaches are often referred to as “suicide headaches” due to their excruciating severity and also as “alarm clock headaches” due to their nature of being periodic.4
Factors that may trigger the onset of a cluster headache may include sleep apnea, because sleep apnea can result in hypoxia, a condition where the body’s tissues are not receiving enough oxygen to perform cellular functions. In addition, chemical compounds such as nitroglycerin, alcohol, carbon dioxide and other agents with the ability to cause blood vessels to dilate may also trigger a cluster headache attack.4
Treatment for chronic headaches should be handled from two differing angles. Acutely, treating the headache attack at the onset (also known as abortive treatment) and prophylactically, treatment intended to prevent an attack from starting by raising the threshold needed to overcome in order for a headache attack to begin. Acute treatment could include oxygen and sumitriptan (US brand name, Imitrex). In addition, intranasal dihydroergotamine, intranasal lidocaine, and intranasal capsaicin have been used with some limited success. Abortive therapy is only needed, and therefore should only be used, when attacks arise. 4
Prophylactic treatment, on the other hand, is a chronic treatment, a therapy that is typically used all the time and that should not be discontinued without talking to your physician, regardless of the number of headache attacks you do or do not experience. Prophylactic treatment may include verapamil, a calcium channel blocker (CCB), and prednisone. It should be noted that verapamil is not as likely to trigger the onset of a headache attack as some other CCB’s. Other agents, such as divalproex, topiramate, ergotamine, methylergonovine maleate, and melatonin have also been used, but with limited success. Methylergonovine should not be used for more than six months continuously and should be restricted to use in refractory cases. It should not be used in hypertension and pregnancy and, if it is to be used at all, it should be used with caution in patients with cardiac or vascular disease and patients with kidney or liver insufficiency. In addition, Methylergonovine is a relative of the drug LSD, and therefore hallucinations may occur. 4
For treatment of chronic cluster headaches, the drug of choice is verapamil. Lithium has also been used with some success, and should be tried in patients intolerant to verapamil. Non-drug treatment has included microvascular decompression, a surgical technique which should only be used in the worst cases. 4
Warfarin is known for its ability to decrease liver production of vitamin K dependent clotting factors. It is through this mechanism that it has pharmacologic activity in slowing the rate at which clots are formed, a useful effect in disease states such as atrial fibrillation or in patients with a history of deep vein thrombus (DVT) or pulmonary embolism (PE). Warfarin has also been shown to have an anti-inflammatory effect in the rat model. It has been suggested that in addition to these activities, warfarin also halts the synthesis of vitamin K.1
Vitamin K is known to have a role in the central nervous system (CNS), inducing nitric oxide (NO), another chemical compound which can cause blood vessels to dilate. These compounds, as previously stated, may play a role in triggering the onset of a headache attack. The link between warfarin and its utility in cluster headaches may be through this mechanism. Kowacs et al. suggested that if warfarin can decrease vitamin K in the CNS, it may also decrease NO, leading to less vasodilation, and raising the threshold needed to trigger a headache attack. 1, 3 Warfarin has also been suggested to trigger or potentiate cluster headache attacks. 2 This article of case reports, however failed to propose a mechanism by which warfarin may have caused these attacks. Nevertheless, warfarin utility in this disease remains to be fully seen. 1-3
Acenocoumarol, as previously mentioned, is unavailable in the US. It is related to, although should not be substituted for, warfarin. Acenocoumarol has complex pharmacological effects, and as such must not be confused with warfarin. This point cannot be stressed enough; the two share some anticoagulation properties, but have pharmacological profiles very distinct from one another. It must however, be a part of this discussion in relation of anticoagulants and cluster headaches. It is used widely in other countries, in Canada and across Europe. In a study primarily looking at migraine headaches, acenocoumarol showed some benefit to all headaches, migraines, cluster headaches, and tension headaches included. 3 These results were attributed to acenocoumarol’s ability to act as a vitamin K antagonist, in a fashion similar to warfarin. However, these results are tainted by the fact that in the non-migraine-type-headache group (consisting of 100 persons), 38 claimed improvement among their headaches with anticoagulant therapy, 33 reported no change, and 29 stated that their headaches were exacerbated (17 of whom had no headaches before anticoagulant therapy was initiated). That means for each 4 persons whose headaches improved, approximately 3 persons experienced a worsening of their headache attacks. 3
Anticoagulants that act as vitamin K antagonists, such as warfarin or acenocoumarol, may indeed have anti-cluster headache properties. And the mechanism proposed by Kowacs et al. is pharmacologically reliable, as well as physiologically feasible. However, until it can be shown in a scientific study, it will remain a disputed theory. While these agents are certainly not the first line therapy as noted in current literature,4 they may have some utility in patients who are refractory to current main line therapy. 1, 3 Because these agents have such a complex pharmacologic effects, the clinical application of these therapies will remain a vague practice.
References:
1) Kowacs PA, Piovesan EJ, de Campos RWGR, Lange MC, Zetola VF, Werneck LC. Warfarin as a Therapeutic Option in the Control of Chronic Cluster Headache: a Report of Three Cases. Journal of Headache Pain. 2005;6:417-419.
2) Mainardi F, Maggioni F, Dainese F, Palestini C, Zanchin G. Cluster-like Headache Due to Warfarin Therapy? Cephalalgia. 2003;23:476-478.
3) Morales-Asin F, Iniguez C, Cornudella R, Mauri JA, Espada F, Mostacero E. Patients with Acenocoumarol Treatment and Migraine. Headache. 2000;40:45-47.
4) Beck E, Sieber WJ, Trejo R. Management of Cluster Headache. American Family Physician. 2005;71:717-724.
©2006 Joseph T. Horsfall II Used by permission
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Last updated June 13, 2007
