Yes, headache is a well-established and common side effect of Pletal (cilostazol) 100 mg twice daily.
Headache is the most frequently reported adverse effect of cilostazol, occurring in up to 25% of patients within the first 2 weeks of treatment 1. According to ACC/AHA guidelines, headache is explicitly listed as one of the most common side effects of cilostazol, alongside diarrhea, abnormal stools, palpitations, and dizziness 1.
Evidence from Clinical Trials
Multiple large-scale randomized controlled trials consistently demonstrate this side effect:
Meta-analysis of 8 trials (2,702 patients): Cilostazol-treated patients reported a significantly higher incidence of headache compared to placebo 2
Comparative trial data: Patients taking cilostazol had 2.83 times higher odds of experiencing headache compared to placebo (OR 2.83; 95% CI 2.26-3.55) 3
Head-to-head comparison: Cilostazol caused more headaches than pentoxifylline, with 2.20 times higher odds (OR 2.20; 95% CI 1.16-4.17) 3
Specific incidence rates: One study comparing cilostazol to ISMN showed 30-40% of patients experienced headache 4
Clinical Characteristics of Cilostazol-Related Headache
The headache associated with cilostazol has several important features:
- Timing: Typically occurs within the first 2 weeks of starting treatment 5
- Severity: Generally mild to moderate in intensity 6
- Duration: Often self-limited or resolves with symptomatic treatment 7, 6
- Management: Rarely requires treatment discontinuation, though it does contribute to higher withdrawal rates (approximately 20% vs 12% for aspirin) 5
Mechanism
The headache is attributed to cilostazol's mechanism as a phosphodiesterase III inhibitor, which increases intracellular cyclic AMP, causing vasodilation 5. This same vasodilatory effect accounts for both its therapeutic benefit in claudication and its side effect profile.
Important Clinical Considerations
Counsel patients proactively about this side effect before starting therapy, as it is predictable and common. The headache typically improves with continued use, so patients should be encouraged not to discontinue prematurely unless symptoms are severe or intolerable.
Withdrawal rates due to adverse events (including headache) are approximately 14-20% across studies, but this is balanced against the significant clinical benefit of 40-60% improvement in walking distance 1, 7.
The benefit-risk profile remains favorable for most patients with intermittent claudication, as the headache is usually manageable and transient, while the functional improvements are substantial and sustained.