Cytokines in primary headache disorders: a systematic review and meta-analysis

BACKGROUND: The role of inflammation and cytokines in the pathophysiology of primary headache disorders is uncertain. We performed a systematic review and meta-analysis to synthesise the results of studies comparing peripheral blood cytokine levels between patients with migraine, tension-type headache, cluster headache, or new daily persistent headache (NDPH), and healthy controls; and in migraine between the ictal and interictal stages. METHODS: We searched PubMed/Medline and Embase from inception until July 2022. We included original research studies which measured unstimulated levels of any cytokines in peripheral blood using enzyme-linked immunosorbent assay or similar assay. We assessed risk of bias using the Newcastle-Ottawa Quality Assessment Scale. We used random effects meta-analysis with inverse variance weighted average to calculate standardised mean difference (SMD), 95% confidence intervals, and heterogeneity for each comparison. This study is registered with PROSPERO (registration number CRD42023393363). No funding was received for this study. RESULTS: Thirty-eight studies, including 1335 patients with migraine (32 studies), 302 with tension-type headache (nine studies), 42 with cluster headache (two studies), and 1225 healthy controls met inclusion criteria. Meta-analysis showed significantly higher interleukin (IL)-6 (SMD 1.07, 95% CI 0.40-1.73, p = 0.002), tumour necrosis factor (TNF)-α (SMD 0.61, 95% CI 0.14-1.09, p = 0.01), and IL-8 (SMD 1.56, 95% CI 0.03-3.09, p = 0.04), in patients with migraine compared to healthy controls, and significantly higher interleukin-1β (IL-1β) (SMD 0.34, 95% CI 0.06-0.62, p = 0.02) during the ictal phase of migraine compared to the interictal phase. Transforming growth factor (TGF)-β (SMD 0.52, 95% CI 0.18-0.86, p = 0.003) and TNF-α (SMD 0.64, 95% CI 0.33-0.96, p = 0.0001) were both higher in patients with tension-type headache than controls. CONCLUSIONS: The higher levels of the proinflammatory cytokines IL-6, IL-8 and TNF-α in migraine compared to controls, and IL-1β during the ictal stage, suggest a role for inflammation in the pathophysiology of migraine, however prospective studies are required to confirm causality and investigate the mechanisms for the increase in cytokine levels identified. Cytokines may also have a role in tension-type headache. Due a lack of data, no conclusions can be made regarding cluster headache or NDPH.