Chronic Bilateral Headache Responding to Indomethacin
Address all correspondence to Dr. Jan Hannerz, Department of Neurology, Karolinska Hospital, Stockholm, Sweden.
Three patients with bilateral chronic tension-type headache (meeting IHS diagnostic criteria) responded with complete control of the headache during the more than 2 years they were treated with indomethacin. The headache recurred within 12 to 26 hours after indomethacin was stopped. Fifty milligrams of intravenous indomethacin resulted in complete relief of headache for 6.5 to 25 hours, similar to results found earlier in patients with hemicrania continua. It is concluded that there may be a subgroup of patients with bilateral chronic headache who respond to indomethacin in the group of patients otherwise diagnosed as having chronic tension-type headache.
Indomethacin is the treatment of choice for episodic and chronic paroxysmal hemicrania.1,2 Response to indomethacin has even been included in the International Headache Society (IHS) criteria for the diagnosis.3 Furthermore, hemicrania continua has also been reported to respond to indomethacin.4 The proposed criteria for this diagnosis, not currently included in the IHS taxonomy, are: (1) strict unilaterality of the headache; (2) continuous character (persisting from morning until night) in the full-fledged form; (3) moderate severity; (4) relative paucity of clinical, attack-related autonomic symptoms and signs, when compared to chronic paroxysmal hemicrania and cluster headache; (5) lack of precipitation mechanisms; and (6) complete response to indomethacin.
Hemicrania continua is considered rare; only 18 patients were diagnosed in the 7 years after the diagnosis of the first patient.5 However, in a review of hemicrania continua by Bordini et al, 3 of the 18 met the criteria for bilateral hemicrania. Two of the patients started with unilateral hemicrania that progressed to bilateral headache. Intensity between the sides differed, with more intense pain on the original side. Furthermore, 1 patient initially had bilateral headache without any difference in pain intensity between the sides. This patient was considered to be experiencing bilateral hemicrania continua. In a recent article, another patient was also reported to initially have hemicrania continua but to develop bilateral symptoms later.6 This patient was helped by indomethacin, but treatment with 150 mg per day did not achieve complete relief. A second patient, reported in the same article, started initially with bilateral chronic headache that was relieved by indomethacin. However, an aggravation of the headache for 1 to 2 hours related to straining, coughing, and sneezing was reported in this patient; this has not been reported in other headache types responsive to indomethacin.
Although only one of these patients initially had bilateral chronic headache without any other symptoms, these histories suggest that there may be patients who suffer from bilateral chronic headache who could obtain relief with indomethacin.
The purpose of the present study was to investigate if there are bilateral chronic headaches that respond to indomethacin with similar control and temporal response as that observed in chronic paroxysmal hemicrania and hemicrania continua.7
PATIENTS AND METHODS
Forty consecutive patients with chronic tension-type headache, according to IHS diagnostic criteria,3 who were referred to the neurology polyclinics at Karolinska Hospital were asked to participate in the study. All the patients had tried physiotherapy and amitriptyline with unsatisfactory results. They all started with 25 mg of oral indomethacin three times a day for the headache and 600 mg per day of cimetidine for stomach protection.
In patients who responded with definite and permanent relief of headache to oral indomethacin, a parenteral indomethacin test was performed as earlier reported in patients with chronic paroxysmal hemicrania and hemicrania continua.7 The test was undertaken 36 hours after oral indomethacin had been stopped and the headache had returned. Because there was no great difference in the results when 50- or 100-mg indomethacin was used in patients with hemicrania continua, only 50-mg indomethacin was injected, although intravenous and not intramuscular indomethacin was administered in the former study.
Before the indomethacin injection, the intensity and the localization of the headache was recorded. The intensity of the pain was evaluated on a scale of 0 to 10 (0 = no pain, 10 = maximal, intolerable pain). Pain in the frontal, parietal, occipital, and cervical regions was recorded. After the injection of indomethacin, the localization and intensity of the headache were recorded every 15 minutes until the headache had completely disappeared. The patient also recorded when the headache reappeared after the indomethacin test.
The study was approved by the Ethics Committee of Karolinska Hospital, and consent was received from the patients who participated in the study.
When asked a week after initiating oral indomethacin, 25 mg, three times a day, 3 of 40 patients with symptoms corresponding to the IHS criteria for bilateral chronic tension-type headache3 reported complete relief or a definite decrease of their headache. Two other patients reported slight but only temporary improvement. The 3 patients who definitely responded to indomethacin, 1 woman aged 46 years and 2 men aged 55 and 42 years, had had their headaches for 21, 38, and 17 years, respectively. In 1 of the patients, the symptoms had started on a definite date and continued without intervals of relief. Such a definite start of the pain was not found in the other 2 patients who reported a more gradual onset of the symptoms.
Complete relief from headache was attained with 75 mg of indomethacin per day in patients 1 and 3 and with 150 mg per day in patient 2. After 1 year of treatment, complete relief was attained with 50 mg a day in patient 1 and with 100 mg a day in patient 2. The characteristics of their daily headaches had been the same during the years before the use of indomethacin. The symptoms were not aggravated by exertion, cough, or sexual activity. They had used different analgesics, mainly salicylates up to 6 grams a day, often combined with codeine. These were also the drugs they had used until the test with oral indomethacin was undertaken.
About every second month, the woman also had menstrual migraine without aura, which had not changed in intensity or frequency over the years. The two men had not had migraine attacks.
Both men had normal cerebrospinal fluid, although the lumbar pressure was somewhat high (25 and 26 cm H2O, respectively). None of the patients had papilledema. Computed tomography of the skull had been performed on all three, and two had magnetic resonance imaging of the brain with contrast. All results were normal.
Peroral indomethacin was stopped 36 hours before the intravenous indomethacin test. The headache recurred in 12 to 26 hours; in one patient it was not its usual intensity, but it was still increasing at the time of the test (patient 3) (Table 1).
Table 1.—. Temporal Aspects of Headache With Intravenous Indomethacin
|Patient||Time to Headache|
|Time to Complete|
The intensity and localization of the headache was recorded before the indomethacin injection (Table 2). All pain was bilateral and symmetrical in intensity. The time for complete relief of headache after intravenous indomethacin administration was 75 to 120 minutes (Table 1). The time for recurrence of headache after the indomethacin test was 6.5 to 25 hours (Table 1).
Table 2.—. Localization and Intensity of Headache Before Indomethacin Test*
The effects of indomethacin on the headaches have not changed during the more than 2 years that the patients have been treated. No side effects have been reported.
It is presumed that the entity chronic tension-type headache in the IHS classification consists of headaches that differ from each other in pathophysiology. Chronic daily headache is a new term that has been used for headaches that occur more than 15 days a month and for more than 4 hours per day.8,9 The chronic daily headache group has been suggested to include four types of headaches: transformed migraine,10 new daily persistent headache, hemicrania continua, and chronic tension-type headache. In all four subgroups, patients with and without medical overuse of analgesics are differentiated.
The criteria for transformed migraine are: (1) history of migraine, (2) history of increased frequency of migraine attacks before the chronic state is attained, and (3) successive transformation of the headache to daily or almost daily chronic tension-type headache (ie, a headache of less severe intensity than during regular migraine attacks and possible cessation of photophobia, phonophobia, nausea, and the need to lie down during the headache). However, occasional migraine attacks of the original severity and with accompanying symptoms may still occur in this later stage.
New daily persistent headache differs from transformed migraine due to the lack of a history of increasing migraine or tension-type headaches before the start of the new daily persistent headache. The start of the new daily persistent headache is often easily recalled by the patient. After starting, the headache is persistent with possible fluctuation in intensity but probably no change in location.
The criteria for hemicrania continua were described in the introduction, and the criteria for chronic tension-type headache are outlined in the IHS classification.3
The clinical characteristics of the three patients reported in this study were no different from other patients with chronic tension-type headache. The headaches did not conform to the criteria for transformed migraine because only one of the three patients had migraine previously and it had not changed before or after the start of the chronic headache. The cerebrospinal fluid pressure was somewhat increased, but pressures above 20 cm H2O have been reported, not only in transformed migraine,11 but also in chronic tension-type headache.12
The start of the headache was clearly recalled by only one of the three patients. In the other two, the headache increased successively with headache-free intervals in the beginning. The medical history is consistent with a diagnosis of new daily persistent headache in only one of the three patients. Except for the bilateral pain, the headache in each patient was similar to the characteristics of hemicrania continua, including the indomethacin response. In patients with hemicrania continua, the mean temporal delay for the headache to reappear after indomethacin treatment was stopped has been reported to be 16 ± 2 hours; the mean time for complete headache relief after intramuscular administration of 50-mg indomethacin was 73 ± 66 minutes, and the mean time for the pain to recur after the test was 13 ± 8 hours.6 Similar results were found in the three patients of the present study, although the indomethacin was injected intravenously and not intramuscularly as in the patients with hemicrania continua.
The incidence of chronic bilateral headache responding to indomethacin cannot be determined from this study because patients with headache who are seen by neurologists are a select group, only patients who did not benefit from physiotherapy and amitriptyline treatment were included, and only a small patient group was studied.
The complete relief of the headache with indomethacin and the nonrecurrence of the headache on this regimen (ie, complete control of the symptoms) represent a great improvement compared with earlier treatments with conventional analgesics. The tendency to need less indomethacin over time may permit discontinuation of indomethacin treatment, as this author has observed in patients suffering from chronic paroxysmal hemicrania. This is in contrast to the use of conventional analgesics in chronic tension-type headache.
The indomethacin response and the similarity of the findings to the temporal aspects of the effects on the headache in the indomethacin test in hemicrania continua suggest that hemicrania continua and the headaches in patients reported here have pathophysiologic mechanisms in common. It could be suggested that episodic and chronic paroxysmal hemicrania, hemicrania continua, and bilateral indomethacin-responding chronic headache could be grouped together as indomethacin-responding headaches. An entity that corresponds to the description of bilateral indomethacin-responding episodic headache will presumably be diagnosed in the future and should also be included in the group.