Cox-2 Inhibitor for the Treatment of Idiopathic Stabbing Headache Secondary To Cerebrovascular Diseases

Abstract

The idiopathic stabbing headache (ISH) is characterized by a stabbing pain of short duration, variable localization and an errant evolution pattern. As its biological mechanisms are unknown and the treatment options are little effective, this disorder shows a strong impact on the patient's life. Two females and one male, aged 76, 66 and 72 years, respectively, started presenting ISH within 20 days after the onset of a stroke. All the patients were treated for the ISH with celecoxib, a COX-2 specific inhibitor, with full recovery from ISH up to 6 days after it was first administered. The interruption of the drug 60 days after the treatment with celecoxib induced again the appearance of algic symptoms in two patients. We concluded that cerebrovascular diseases (CD) can lead to ISH and that the COX-2 inhibitor can be an effective prophylactic drug for ISH after CD.

Introduction

Idiopathic stabbing headache (ISH) is a paroxystic disorder of short duration whose clinical criteria remain conflicting (1, 2). The mechanisms of this disorder are still unknown, but sporadic reports associating its onset with episodes of cerebrovascular diseases (CD) have been described (2). We describe three cases in which ISH was preceded by CD, as well its clinical response to the use of COX-2 inhibitors.

Case reports

A group of 32 patients suffering from idiopathic stabbing headache at our headache clinic at the Hospital de Clínicas of the Federal University of Paraná, Brazil, was evaluated from January to December 2000. From among them, three patients were included in this study, who reported ISH up to 30 days after a stroke, without previous history of ISH before the stroke.

Patient 1

A 76-year-old female had an ischaemia in the left median cerebral artery territory. She had migraine without aura until the age of 50. Sometimes she had episodic tensional-type headaches and used an angiotensin-converting enzyme inhibitor for hypertension, l-thyroxin for hypothyroidism and nivarstatin for dislipedemia. Twenty days before starting to present IHS, she developed a sudden right hemiparesis, associated with mental confusion and a somewhat impaired speech. A computerized axial tomography (CAT) of the head disclosed a generalized brain atrophy. A cerebral angiography (CA) revealed a 40% stenosis in the distal segment of the right carotid artery, occlusion in the left internal carotid artery and a critical stenosis (pre-occlusive) in the origin of the right vertebral artery by ateroma plaque. A heart catheterization revealed a subocclusive lesion in the right coronary artery and intense calcification of the anterior descendent trunk with a segmental lesion from 80% to 90% on the anterior descendent. A conservative treatment was chosen, due to the high risk of a surgical intervention. Phenprocoumon was started in order to keep the international normalized ratio (INR) between 2.5 and 3.5. Ten days after the stroke the patient presented a strong stabbing headache in her right temporal region, lasting fractions of a second (using a chronometer we asked the patient to press the physician's hand while the stabbing occurred, with its duration being measured). The patient's paroxysms were limited to the temporal regions, occurring mostly on the right-side (90% of the paroxysms) and less frequently on the left side (about 10%). She had 6–10 stabs per day, which led her to vocalization. The erythrocyte sedimentation rate (ESR) was 20 mm within the first hour and the temporal artery was normal. As an anticoagulant therapy was indicated, celecoxib 100 mg/day was chosen. She obtained partial relief of her symptoms. After a week, the celecoxib dose was increased to 100 mg b.i.d. and after 72 h the patient became asymptomatic, remaining in this condition for 30 more days. After this time period had elapsed we carried out a therapeutic test by withdrawing celecoxib, but after 6 days she started feeling the painful symptoms again. Celecoxib was reintroduced and there was no recurrence of the symptoms. She had a cardiac arrest during a coronary bypass procedure and the usual resuscitating techniques proved unsuccessful. The lack of a follow-up CT scan or MRI of the head did not allow a definitive conclusion about the location of the stroke, which was inferred on the clinical picture presented by the patient.

Patient 2

A 72-year-old male had a transient left side hemiparesis lasting 18 h. A similar episode occurred again 72 h after the patient sought medical attention. The neurological examination revealed a reduction of muscle strength on the left side, as well as confusion. CAT scan images disclosed a chronic hypodense lesion in the middle cerebral artery territory. He had had three episodes of transient ischaemic attacks (TIA) in the preceding 10 years, when he was submitted to a left carotid artery endarterectomy. He was using beta-adrenergic antagonists for hypertension and had smoked cigarettes for 30 years. The CA showed an ulcerated ateroma in the distal segment of the right common carotid artery, with a 40% stenosis. The patient refused to undergo surgery for this lesion and a conservative approach with phenprocoumon was adopted to keep the INR between 2.5 and 3. Fifteen days later the patient reported a severe pain in his left temporal region spreading to the retroauricular region, lasting about a second, two to four times a day, four times a week. For the treatment of the ISH we prescribed celecoxib 100 mg b.i.d. Six days after the treatment was started the patient became asymptomatic. After 60 days of effective therapy, celecoxib was withdrawn and the ISH reappeared on the fourth day after the drug was suspended, with the same characteristics as before. After celecoxib was reintroduced the patient became asymptomatic again, remaining so for the next 6 months.

Patient 3

A 66-year-old female had a sudden loss of muscle strength on the left side of her body. She used an angiotensin-converting enzyme inhibitor for hypertension and was an active smoker of 20 cigarettes per day until she suffered a stroke. Throughout her life she had had tension-type headaches. Upon examination, a full left-side hemiparesis with thermal and painful hypoesthesia was found. In the CAT scan a hypodense lesion of the right cerebral hemisphere in the distribution of the middle cerebral artery was observed. The CA was normal. Twenty days later she started to complain of a sudden pain in the head, unilateral and multifocal (temporal and occipital), now on the right, now on the left side. The sudden stabs of pain lasted about 2 s, were very severe, always frightened the patient and were followed by vocalization. She reported two to three episodes per day, without autonomic symptoms or any other manifestation. Celecoxib 100 mg b.i.d was started. After 2 weeks of treatment the patient was asymptomatic. The patient was followed-up for 120 days and did not show any other pain. The interruption of celecoxib did not cause the headaches to recur.

Discussion

The characteristics of idiopathic stabbing headache (ISH) are the only relevant elements for its diagnosis. The International Headache Society (IHS) characterizes ISH as a pain which (1): (A) is restricted to the first branch of the trigeminal (orbital, temporal and parietal) region, but recent works show that the symptoms can also be observed on the facial, occipital, retroauricular, temporal and even parietal regions (3, 4); (B) is a typical sudden pain (stab), lasting fractions of a second, presenting isolated stabs or a set of stabs; (C) reappears at regular intervals, from hours to days; (D) has a diagnosis which depends on the exclusion of structural alterations in the painful area and in the distribution of the affected nerve.

This disorder can be related to other types of headache. Studies show that some association occurs in 58% of the cases (with migraine 63%, tension-type headache 27.3% and other types 9.7%). Recent studies have shown that the association with migraine can exist in 40.4% of the cases (5). The association can also exist with the disautonomic trigemino-vascular headaches, hemicrania continua and chronic paroxysmal hemicrania (6–8).

The clinical presentation of the syndrome is usually characterized by a sudden start, with its evolution directly related to the frequency of the attacks. Occasionally, it may present a sporadic and irregular pattern, with erratic characteristics, alternating symptomatic and asymptomatic periods. As the frequency of the attacks may vary from once a year to 50 attacks a day, its evolution is extremely variable. The chronic pattern (over 80% of the days) occurs only in 14% of the cases (2). More than half of the patients report daily episodes (57%), while the others present weekly (14%), monthly (23%) and yearly episodes (6%) (2). The intensity of the paroxysms ranges from moderate to severe. They may last from fractions of a second (in 69% of the cases) to rarely more than 10 s (2, 9). In the Vaga study, in the vast majority of the cases the paroxysms lasted up to 3 s (94.6%) (10).

The beginning of the symptoms of the ISH seems to be spontaneous, but it may be related to cerebrovascular diseases, cranial trauma, ocular trauma and herpes zoster (2). Despite the relationship with primary headaches, as well the presence of some factors that may provoke them, such as cerebrovascular diseases (CD), the mechanisms involved in the physiopathology of this disease remain unknown.

The stabbing quality of the pain may suggest a pattern similar to that which is reported in trigeminal neuralgia (true paroxystic neuronal discharges). The aetiology may be associated with irritation of the peripheral roots of the trigeminal nerve or other cranial nerves (greater occipital nerve, for example), associated with a transitory deficit in the central inhibitory mechanisms for pain control. Thus, synchronic spontaneous discharges originating in the peripheral nerves are felt, producing algic symptoms with peculiar sensorial topographies.

The association between CD and ISH is more evidence that ISH is related to the loss of a cortical balance of the nociceptive control. Previous papers also show that stroke can bring about ISH (2). Although the response to a peripheral-acting drug could reinforce the role of a peripheral mechanism for the IHS, it is currently known that selective COX-2 inhibitors can also act over central nociceptive mechanisms (11–13).

Cyclooxygenase-2 (COX-2) is induced as an immediate early gene in a wide variety of cell types and in response to a wide variety of stimuli. In the nervous system it can play roles in the regulation of cerebral blood flow, fever, hypothalamic control of the stress response, the sleep/wake cycle, and in peripheral and central control of pain perception (14). COX-2 mRNA could be detected in dentate gyrus cells, pyramidal cell neurones in the hippocampus (CA4 through CA1), the piriform cortex, superficial cell layers (II and III) of the neocortex, the amygdala, and at low levels in the striatum, thalamus (subparafascicular nucleus) and hypothalamus (paraventricular and median preoptic nuclei), nucleus of the optic tract, the pontine reticular formation and the dorsal raphe nucleus (15). COX-2 inhibitor could attenuate the neuronal spreading depression that occurs in the seizure and the nociceptive excitotoxicity that is mediated by NMDA (16).

The treatment of this syndrome with indomethacin improves 35% of the cases but partial results are seen in 30% of the cases and no benefit at all in the 35% remaining cases (2). Mathew has reported a clinical recovery in five patients with indomethacin 50 mg, three times a day, but it elicited no clinical response to aspirin or a placebo (17). Medina reports good results from the use of indomethacin (18). On the other hand, Sjaastad found little clinical response to treatment with indomethacin (19). The use of specific inhibitors of ciclooxygenase (COX-2) in patients suffering from ISH after a stroke has never been reported before.

In our cases, the indomethacin therapeutic test was not carried out because some patients were on anticoagulant therapy (20). Besides, the long-term use of indomethacin in the elderly has been described to be associated with a greater risk of fatal adverse events such as bleeding or perforation of a gastric ulcer, and to bone marrow depression or leukaemia (21), while celecoxib has a good tolerability and safety (22).

The COX-2 inhibitor is essentially equipotent to indomethacin in vivo with a better tolerability (23, 24). Studies show that anti-inflammatory drugs that act on the COX-2 sites can be used as prophylactics in some trigeminal-autonomic headaches and in cases of hemicrania continua (25, 26). Recently Peres et al. have shown that COX-2 inhibitors can be very efficient when used in the prophylaxis of hemicrania continua (27).

The indomethacin-responding headaches may need a long-lasting therapy, thus making it possible for drug-related side-effects to emerge, sometimes with fatal outcomes (20). The good ISH response to the use of a selective COX-2 inhibitor is in accordance with previous reports of their use in other types of indomethacin-responding headaches. This fact, allied to the low side-effect profile of this class of drugs, places them as safe therapeutic options in this type of headache (25–27).

CD may have a relationship with ISH by impairing cortical modulation of nociception. Patients with this profile can obtain good results from a prophylactic treatment with a selective COX-2 inhibitor. The study has shown a full clinical response in three patients. In two patients the withdrawal of the drug resulted in a recurrence of ISH, and in the third case the symptoms did not recur even after the administration of celecoxib was interrupted. We cannot postulate whether this remission was secondary to therapy with celecoxib, as in many cases ISH shows an atypical pattern of evolution.