Abstract
Hemicrania continua is a daily headache disorder that is characterized by unilateral, constant pain with exacerbations of intensity accompanied by autonomic symptoms. Response to indomethacin is the diagnostic criterion for hemicrania continua, but efficacy of indomethacin in therapy is restricted because of gastrointestinal adverse events. Therefore, many patients are disqualified from treatment with indomethacin, creating a need to search for alternative therapy. In comparison with indomethacin, acemethacin seems to have a better therapeutic profile. It is associated with fewer gastrointestinal adverse events while having a good therapeutic effect. We present three patients effectively treated with acemethacin without adverse events of the gastrointestinal tract.
Introduction
Hemicrania continua belongs to the group of trigeminal autonomic cephalalgias, which are characterized by continuous, moderate, unilateral headache that usually intensifies several times a day. The exacerbations of pain may be accompanied by some typical features of migraine, such as throbbing pain, sound and light phobias or nausea. However, unilateral lacrimation, conjunctival injection, eyelid edema and other autonomic symptoms that accompany the pain are characteristic for trigeminal autonomic headaches (1). Despite past thinking, it turns out that hemicrania continua is not that rare, and the fact that a therapeutic effect of indomethacin is used as a diagnostic criterion has increased the number of diagnosed cases (2).
The chronic character of hemicrania continua influences the quality of patients’ lives, and the therapy that is applied should have more benefits than adverse effects. Hemicrania continua is known for its full response to indomethacin. However, indomethacin has many disadvantages, especially gastrointestinal adverse events. We present three cases of patients successfully treated with acemethacin, which seems to have a better therapeutic profile and should be considered a good alternative for indomethacin. Acemethacin is available in many European countries, the United Kingdom, the United States, Canada, Australia and Asia in the form of capsules, usually in 60 and 90 mg doses.
Case reports
Case 1
A 36-year-old female reported a three-month history of continuous, moderately severe headache in the left frontotemporal region, accompanied by exacerbations of pain lasting for one to several hours, especially in the left orbital area, associated with redness of left eye conjunctiva, left-sided lacrimation, eyelid edema, blepharophimosis and nasal congestion. During exacerbations, the patient reported the pain as very intense. There was no previous history of primary headache disorder. Neurological examination did not reveal any abnormalities. Blood cell count and biochemical results were normal. Computed tomography (CT) of the brain and electroencephalography revealed no aberrations. Duplex ultrasonography of carotid and vertebral arteries showed no features of stenosis. Diagnostic test with 150 mg of indomethacin divided into three doses caused total pain relief after the third dose. The clinical picture and therapeutic response to indomethacin led to the diagnosis of hemicrania continua. To continue the therapy with a drug that is similar to indomethacin, with its anti-inflammatory profile, but with a lower risk of gastrointestinal disorders, we chose acemethacin in 90-mg doses in retard form, given once a day. Therapeutic effects of acemethacin were observed after the first dose. The patient continued to use acemethacin in a 90-mg dose once a day. After this treatment, the headache occurred occasionally and did not disturb the daily activities. The follow-up examination after three months revealed no adverse events.
Case 2
A 36-year-old male reported a six-month history of continuous right-sided headache of moderate intensity. There were five to six pain exacerbations during the day in the right orbital region with throbbing, eye flashing, a feeling of higher pressure in the right eye and nasal congestion. There was no history of migraine or other primary headache disorder. Neurological examination did not reveal any deviation from the norm. CT of the brain revealed no aberrations. Duplex ultrasonography of carotid and vertebral arteries showed no features of stenosis. Because the non-steroidal anti-inflammatory drugs (NSAIDs) and triptans appeared to be inefficacious, the patient was given 150 mg of indomethacin, divided into three daily doses given every eight hours. The patient reported total pain relief after the third dose of the drug. During hospitalization the headache did not reappear. The clinical features of the pain and good response to indomethacin met the diagnosic criteria for hemicrania continua. As in Case 1, the patient was prescribed 90 mg of acemethacin in one retard form dose, given once a day. The expected beneficial effect appeared after the second dose. During the follow-up examination after four months, the patient mentioned occasional headache of moderate intensity that did not interfere with everyday activities and did not require additional analgesic drugs. No adverse events were reported.
Case 3
A 29-year-old male was hospitalized in the neurological ward with a 1.5-year history of left-sided continuous headache of moderate severity, with attacks of increased pain intensity lasting a few minutes to half an hour in the left orbital and temporal area accompanied by left-sided edema of orbital soft tissue and conjunctival injection, lacrimation and nasal congestion. No history of primary headache disorder was reported. The family medical history revealed that his grandfather had had headaches of similar features and severity. The patient did not respond to typical analgesic drugs except for 100 mg of nimesulide. The analgesic effect lasted several hours. Neurological examination revealed hyperesthesia in the area of the first left trigeminal branch. Ophthalmological and laryngological examination did not reveal any abnormalities. Results of MRI and magnetic resonance angiography (MRA) were normal.
During hospitalization, a diagnostic test with 150 mg of indomethacin was done. The headache subsided after the first dose. As in the two previous cases, the diagnosis of hemicrania continua was made and the patient was given acemethacin in retard form, in doses of 90 mg given once a day. Pain relief occurred after the second dose of the drug. In the follow-up examination after one month, the patient reported that pain-free days occurred for the most part of the month, and pain intensity during the headache attacks had diminished significantly.
Discussion
Hemicrania continua is a primary chronic headache, and like other chronic headaches has a negative impact on the quality of patients’ lives and so requires effective pharmacological prophylaxis (3). The essential diagnostic criterion for hemicrania continua is the therapeutic response to indomethacin. However, treatment of hemicrania continua with indomethacin involves high risk of peptic ulcer, bleeding and perforation (4), and up to 50% of patients with hemicrania continua treated with indomethacin experience gastrointestinal side effects, leading them to discontinue the therapy (5). Some drugs, including cyclo-oxygenase (COX)-2 inhibitors such as celecoxib, piroxicam and nimesulide; anti-epileptic drugs such as topiramate and gabapentine; and others such as melatonin and verapamil (6) are used in prophylaxis of hemicrania continua instead of indomethacin to eliminate the risk of its side effects. Indomethacin has an effective anti-inflammatory profile, and therefore is considered as the reference standard for some anti-inflammatory drugs, such as acemethacin, which is a glycolic acid ester of indomethacin (Figure 1).
Chemical structure of acemethacin (ACM) and indomethacin (IND).
Its anti-inflammatory effect consists of inhibition of prostaglandin synthesis and rapid bioconversion to indomethacin, the active metabolite of acemethacin. It is used against various rheumatic disorders. Studies on acemethacin have shown that its efficacy is similar to that of indomethacin. However, it appears to be better tolerated in comparison with indomethacin in the context of gastrointestinal adverse events, due to its lesser inhibitory effect on COX-1 compared with indomethacin (7). Acemethacin has been regarded as a preferential COX-2 inhibitor (8), and studies on the damaging influence on the gastrointestinal epithelium revealed good tolerance of acemethacin (9,10), probably because acemethacin does not increase the level of tumor necrosis factor (TNF)-α, leukotriene B4, and adhesion of leukocytes to the gastric epithelium and so does not increase the risk of gastrointestinal side effects to the same extent as indomethacin (9,11–13). In this study, acemethacin worked for our patients without introducing gastrointestinal adverse events, making it an alternative treatment for hemicrania continua.