Nitrate-induced headache in patients with stable angina pectoris: Beneficial effect of starting on a low dosage

Background: Nitrates, although important for the management of angina pectoris, cause significant headache in many patients. Methods: In a randomized, double-blind crossover study, 89 patients with stable angina pectoris were used to compare two different dosage strategies of isosorbide- 5-mononitrate (5-ISMN). Patients were randomized to either 60 mg 5-ISMN once daily (o.d.) for 2 weeks or 30 mg 5-ISMN o.d. for 1 week followed by 60 mg 5- ISMN o.d. for 1 week. A 2-week placebo wash-out ensued, after which the alternative treatment was given. We assessed the occurrence of angina pectoris and headache by diary cards while taking into account the numbers of isosorbide dinitrate sublingual puffs and paracetamole tablets required. Data were assessed for carryover and time effects. Results: The two dosage regimens were equally efficient for the relief of angina pectoris without development of tolerance. Thirty percent of the patients never experienced headache from the given dosages. The remainder showed a highly significant time-effect: The total numbers of headache attacks in the 1st period of active treatment were 2,380 vs 1,400 attacks in the 2nd period (p < 0.003), yet significantly fewer patients had headaches on low dosages than high ones (45 vs 57, p < 0.02). Conclusions: Starting on a low dosage was associated with reduced frequency and severity of headache and did not notably influence the beneficial effect of nitrates on angina pectoris. One in three patients never experienced headache from the given dosages. The overall number of headache attacks in the 1st period of active treatment was significantly higher than that of the 2nd period, irrespective of the dosages given.