Comparative effects of pharmacological interventions in the prophylactic treatment of tension-type headache: systematic review and network meta-analysis

Tension-type headache (TTH) is the most common neurological disorder. The comparative effect of pharmacological interventions for TTH prophylaxis remains unclear. We aimed to assess the comparative effects of pharmacological interventions in the prophylactic treatment of TTH. Ovid Medline, Embase, and Cochrane were searched from inception to 12 December, 2025. Randomized controlled trials (RCTs) of medications compared to placebo or another medication for preventing TTH were included. The primary outcome was headache days per month. A Bayesian random-effect model was employed as the primary analysis of chronic TTH. Thirty-five RCTs were included, 33 (88.6%) RCTs involved chronic TTH patients, and 24 RCTs provided available data for meta-analysis. Amitriptyline 100 mg presented more reduction of monthly headache days than placebo at 4 and 8 weeks (4 weeks: MD −6.59, 95% CrI −11.22 to −0.64; 8 weeks: MD −6.14, 95% CrI −10.27 to −0.87). BTX-A 100 U can reduce monthly headache days (MD −3.79, 95% CrI −7.16 to −0.33). Amitriptyline 100 mg was the highest-ranked treatment for monthly headache days at 4 (SUCRA 0.85), 8 (SUCRA 0.85), and 24 (SUCRA 0.87) weeks; 12 weeks was lidocaine 25 ml (SUCRA 0.75). Amitriptyline 100 mg and BTX-A 500 U showed a higher adverse event rate than placebo. Amitriptyline 100 mg and BTX-A 100 U may be options to reduce monthly headache days in patients with chronic TTH. Given the low to very low certainty of evidence, high risk of bias, and high heterogeneity, more studies are needed. PROSPERO (CRD42025639586). There is a lack of a comprehensive review of the effectiveness of pharmacological interventions for the prophylactic treatment of tension-type headache (TTH).Low to very low certainty of evidence suggested that amitriptyline 100mg reduces headache days per month at 4 and 8 weeks, and it may also confer potential preventive benefits for patients with chronic TTH at 12 and 24 weeks.Amitriptyline 100mg and botulinum toxin type-A 500U showed a higher adverse event rate than placebo. There is a lack of a comprehensive review of the effectiveness of pharmacological interventions for the prophylactic treatment of tension-type headache (TTH). Low to very low certainty of evidence suggested that amitriptyline 100mg reduces headache days per month at 4 and 8 weeks, and it may also confer potential preventive benefits for patients with chronic TTH at 12 and 24 weeks. Amitriptyline 100mg and botulinum toxin type-A 500U showed a higher adverse event rate than placebo.