The Role of Biomarkers Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Vasoactive Intestinal Peptide (VIP) in Chronic and Episodic Migraines: A Meta-Analysis

Abstract

Background. Migraine is a neurological disorder that results in disability accumulation, and there are no blood-based markers for indicating migraine susceptibility. Here, we aimed to evaluate the possible biomarker role of neuropeptides, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) in chronic (CM) and episodic migraine (EM). Method. PubMed, medRxiv, and Google Scholar databases were searched up to the 7th of September 2022 using the search syntax to define all relevant articles addressing the plasma and serum levels of VIP and PACAP in migraineurs and controls. Concerning bias assessment, the risk of bias in nonrandomized studies-I (ROBINS-I) was assessed. Also, the standardized mean difference (SMD) was measured with a random effects model. Results. Five case-control studies with 503 migraine cases were included. CM patients had elevated VIP levels compared to controls ($\text{SMD}=0.44$, 95% CI 0.25-0.62, $p<0.00001$). In contrast, PACAP levels were lower in EM patients ($\text{SMD}=-0.30$, 95% CI -0.48 to -0.11, $p=0.002$). Overall, migraine cases had higher VIP levels ($\text{SMD}=0.25$, 95% CI 0.11-0.39, $p=0.0006$) but lower PACAP levels ($\text{SMD}=-0.16$, 95% CI -0.30 to -0.03, $p=0.020$) than controls. Conclusion. The results support the role of VIP and PACAP neuropeptides in migraine pathophysiology. CM patients have significantly higher serum VIP levels, while EM patients have lower serum PACAP levels compared to controls. Further studies should confirm these findings.