Warfarin as a therapeutic option in the control of chronic cluster headache: a report of three cases

Abstract

Chronic cluster headache remains refractory to medical therapy in at least 30% of those who suffer from this condition. The lack of alternative medical therapies that are as effective as, or more effective than, lithium carbonate makes new therapies necessary for this highly disabling condition. Based on a previous report, we gave oral anticoagulants to three patients with chronic cluster headache. Two of them remained cluster headachefree while taking warfarin. In the third patient, the use of warfarin for three weeks initially increased the frequency and intensity of cluster headache attacks but subsequently induced a prolonged remission. In spite of the paucity of data available, oral anticoagulation appears to be a promising therapy for chronic cluster headache. [PUBLICATION ABSTRACT]

J Headache Pain (2005) 6:417419

DOI 10.1007/s10194-005-0234-6BRIEF REPORTPedro A. KowacsElcio J. Piovesan

Ricardo W.G.R. de Campos

Marcos C. Lange

Viviane Flumingham Zetola

Lineu C. WerneckWarfarin as a therapeutic option in the control

of chronic cluster headache: a report of three

casesReceived: 17 April 2005

Accepted in revised form: 8 June 2005

Published online: 1 August 2005P.A. Kowacs () E.J. Piovesan

R.W.G.R. de Campos M.C. LangeV. Flumingham Zetola L.C. Werneck

Headache Section, Neurology Division,

Internal Medicine Department,

Hospital de Clnicas,

Universidade Federal do Paran,

Rua General Carneiro 181/1236,

80060-900 Curitiba, Brazil

e-mail: [email protected]

Tel.: [phone]

Fax: [phone]Abstract Chronic cluster headache

remains refractory to medical therapy in at least 30% of those who suffer from this condition. The lack of

alternative medical therapies that

are as effective as, or more effective than, lithium carbonate makes

new therapies necessary for this

highly disabling condition. Based

on a previous report, we gave oral

anticoagulants to three patients with

chronic cluster headache. Two of

them remained cluster headachefree while taking warfarin. In the

third patient, the use of warfarin for

three weeks initially increased the

frequency and intensity of cluster

headache attacks but subsequently

induced a prolonged remission. In

spite of the paucity of data available, oral anticoagulation appears to

be a promising therapy for chronic

cluster headache.Key words Cluster headache Chronic cluster headache Cluster

headache therapy Oral anticoagulants WarfarinIntroductionCluster headache is perhaps the best defined trigeminal

autonomic cephalalgia. Its less frequent form, chronic cluster headache, frequently eludes available medical therapies[1]. Three cases of chronic cluster headaches that were

responsive to oral anticoagulation are described. The paucity of effective therapies to treat this condition [1, 2], and the

puzzling effectiveness of warfarin in the cases described

here, justify reporting of this uncontrolled evidence.Case reportsPatient 1A 46-year-old white male presented with cluster headache

since the age of 32 years, and with chronic cluster

headache since the age of 35 years. He was submitted to

currently available prophylactic therapies for cluster

headache such as prednisone, deflazacort, verapamil,

lithium carbonate, methysergide, divalproate, pizotifen,

lamotrigine and topiramate, and to several other unconventional therapeutic drugs. He only responded to

steroids, which produced a partial and transitory response.

He took prednisone for a prolonged period, which may

have contributed to the chronification of his cluster

headache. A retrogasserian balloon compression led to a

transitory remission. In September 2003, after an earlier

communication of the case subsequently described by

Souza et al. [3], warfarin 2.5 mg/day up to 10 mg/day was

prescribed. Cluster headache attacks decreased during the

titration period and were followed by a sustained remission in the succeeding two months, allowing him to discontinue prednisone. The attacks recurred when warfarin

was withdrawn, but their frequency and intensity

decreased again from 6 daily full-blown episodes to a

headache-free condition after two mild episodes following418the re-introduction of warfarin at 2.5 mg/day (RNI=1.26).

The patient is on warfarin and remains headache free after

20 months of follow-up. A transcranial Doppler with agitated saline solution carried out during warfarin therapy

showed no evidence of a right-to-left shunt.Patient 2A 56-year-old man presented because of cluster headaches

that had started at the age of 45 years and had been chronic

since the age of 53 years. He had been unsuccessfully submitted to therapy with prednisone, lithium carbonate, verapamil, sodium valproate and methysergide. In September

2004, warfarin 2.5 mg/day was started and titrated up to 5

mg. The patients RNI reached 2.81 after 14 days. The intensity of his cluster headache attacks decreased, but the attacks

still occurred up to five times a day. When the warfarin dose

was increased to 10 mg/day, the intensity of his attacks

increased, but he would then remain up to two days without

attacks. As his RNI had increased to 7.4, the warfarin dose

was decreased to 5 mg/day (RNI: 3.4). At this time, the

patient became pain-free and five days later warfarin was

discontinued, allowing methysergide to be discontinued two

weeks later. He remained pain-free without medication at

the eighth month of follow-up. A transcranial Doppler with

agitated saline solution after warfarin was stopped revealed

evidence of an important right-to-left shunt.Patient 3A 45-year-old man presented with a 17-year history of

cluster headache. In 2004, he became unresponsive to the

usual medication (prednisone, ergotamine tartrate, verapamil, methysergide and lithium carbonate) and his cluster

headache became chronic. In December 2004 warfarin was

titrated from 2.5 mg/day up to 5 mg/day, with complete

remission of the cluster headache episodes on the third day

of therapy, allowing verapamil, methysergide and lithium

to be withdrawn. His RNI is being kept between 2.0 and3.0, and there were no recurrences at his last follow-up

visit seven months after the beginning of therapy. A transcranial Doppler with agitated saline solution during warfarin therapy revealed evidence of a right-to-left shunt.DiscussionTherapy for chronic cluster headache remains a debatable

issue for neurologists and headache specialists. In fact,

there is a lack of systematic trials in this field [1, 2].

Conversion to the episodic type has been reported to occur

in approximately one third of patients with chronic cluster

headache [46], and spontaneous remissions to occur in

only 5% [4]. The large number of different surgical procedures used in efforts to control the symptoms of chronic cluster headache illustrates the refractoriness of this

condition [1, 7]. A recent trial with acenocoumarol has

confirmed previous anecdotal reports of the efficacy of

anticoagulants in migraine prophylaxis [8], but, conversely, warfarin was reported to precipitate a cluster-like

headache in a single patient [9]. In 2003, Souza et al. [3]

reported that warfarin used to control deep venous thrombosis in a chronic cluster headache patient resulted in his

cluster headache attacks abating [3]. A placebo effect,

although possible, seemed unlikely in patients with the

chronic variety of the disease [10].Current concepts in cluster headache suggest that three

areas appear to be involved in the pathogenesis and

expression of cluster headache: the trigeminal nociceptive

pathways, the autonomic system and the hypothalamus.The most well-known pharmacological effect of warfarin, which is a derivative of 4-hydroxycoumarin, is its

inhibition of blood clotting as a result of interference with

the hepatic synthesis of the vitamin K-dependent clotting

factors. The K vitamins are fat-soluble substances that

belong to the naphthokinones group. Their main biological functions are those related to bone metabolism and to

their role as a cofactor of -glutamyl-carboxylase, which

catalyses the post-translational conversion of glutamic

acid to -carboxyglutamic acid in vitamin K-dependent

proteins [11]. These vitamins exist in two naturally occurring forms, K1 (phyllokinone) and K2 (menaquinone).

Although vitamin K1 is the predominant form of vitamin

K in the liver, heart and pancreas, vitamin K2 in its MK-4

form (menaquinone, with four isoprenoid rings) is the predominant form of vitamin K in the brain [11]. The role of

vitamin K in the CNS remains to be clarified, but several

effects on neuronal and glial metabolism have already

been identified [11]. Warfarin anti-cluster headache properties could be

explained by interference with both peripheral and central

mechanisms. Warfarin was reported to have a marked

anti-inflammatory effect in the formaldehyde- and carrageenan-induced rat paw oedema model. This effect

could be observed not only when warfarin was administered prior to the induction of inflammation, but also

when it was given to animals with inflammatory reactions

that had developed previously [12], a pattern of response

that suggests a peripheral effect. Interference with

menaquinones ability to induce inducible nitric oxide

synthase (iNOS) [13] could also be accounted for by a

peripheral effect, as iNOS plays a role in the neurogenic

inflammation model.419Conversely, the effects of quinones in the nervous system may occur through biochemical pathways other than

their action as a cofactor of the -glutamylcarboxylase.

Warfarin, by limiting the postribosomal carboxylation of

vitamin K precursors, and thus halting the synthesis of vitamin K, may interfere with the influence of the quinones in

PKA- and MAPK-mediated cellular processes [14], including the release of CGRP or other substances involved in the

inflammatory cascade by trigeminal neurons.Furthermore, both PKA and MAPK participate in cell

processes of different hypothalamic neuronal populations[15], which may render cluster headache-related hypothalamic neurons vulnerable to a warfarin-induced reduction in the availability of menaquinone. A central effect is

suggested by the extreme and consistent changes in the

clinical behaviour of the cluster headaches in the cases

described here.A third hypothesis for the efficacy of warfarin may be

related to its anticoagulant properties. As with migraine,

patent foramen ovale (PFO) has been reported to be more

prevalent in cluster headache patients than in controls [16].

In cluster headache patients, arterial desaturation is considered to be a trigger for cluster headache attacks in patients

with PFO and obstructive sleep apnoea syndrome. A rightto-left shunt was detected by contrast transcranial Doppler

(cTCD) in two of our three patients. Warfarin could perhaps

interfere with embolic phenomena rather than with arterial

desaturation [16], but this hypothesis seems unlikely

because in patient 2, who showed the most important rightto-left shunt, remission persisted after warfarin was discontinued. In spite of an insufficient understanding of the

mechanisms involved, the apparent efficacy of warfarin as

a new treatment for cluster headache sufferers points to new

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