Headache After Vaccination: An Update on Recent Clinical Trials and Real-World Reporting

Abstract

Purpose of Review The aim of this review is to characterize headache as a vaccine adverse event (VAE) in clinical trials. Recent Findings Of the recent phase III vaccine RCTs (non-COVID-19), 53 studies reported on headache (13 infectious agents). The median rate (interquartile range) of headache was 15.6% ( IQR : 9.6–37.6%). Of these, 24.5% of the RCTs reported headache greater in the vaccine group compared to the placebo/control group. In the herpes zoster vaccination trials, headache was more common in all active groups: median rate 33.9% ( IQR : 29.7–40.5%) as compared to placebo: median rate 17.7% ( IQR : 15.4–23.8%). Influenza and HPV vaccination trials were the 2nd and 3rd most common to have headache as a VAE. Of the 6 widely distributed COVID-19 vaccinations, median rate of post-vaccination headache was 39% ( IQR : 28–50%). Summary Headache is a common VAE in vaccine trials. Standardized grading methods, predictors of persistence, and treatment regimens are warranted.

Headaches and facial pain attributed to SARS‐CoV‐2 infection and vaccination: a systematic review

“…Sixty‐two articles were identified (Appendix S4). According to the Vaccine Adverse Events Reporting System, headache was the fifth most reported AE post‐vaccination after administration of any SARS‐CoV‐2 vaccine [84]. Notably, headache is a frequent AE after any vaccination [85].…”

New Daily Persistent Headache

“…31 Purported mechanisms of headache and new daily persistent headache developing after vaccination include systemic reactogenicity with the release of prostaglandins (such as those in the E family), interleukin-6, and C-reactive protein, increased blood-brain barrier permeability, and the activation of trigeminal nociceptors. 30,32 A stressful life event may be the second most frequently reported inciting factor in new daily persistent headache, ranging from 10% to 20% in many series. 10,11,17 As stress or stress let down (moving from high-stress to low-stress environments) can be a strong migraine trigger, and a major stressful life event can incite migraine to progress to chronic migraine, this observation for new daily persistent headache could suggest underlying migraine biology.…”

“…29 Among non-COVID-19 vaccines, headache occurs most commonly after vaccination for varicella-zoster virus, followed by influenza and human papillomavirus. 30 However, it is important to note that in an analysis of the Vaccine Adverse Event Reporting System, the risk of experiencing headache is 500 times higher with COVID-19 infection relative to vaccination. 31 Purported mechanisms of headache and new daily persistent headache developing after vaccination include systemic reactogenicity with the release of prostaglandins (such as those in the E family), interleukin-6, and C-reactive protein, increased blood-brain barrier permeability, and the activation of trigeminal nociceptors.…”

“…In a systematic review of 84 studies including 1.57 million participants for mRNA COVID-19 vaccine trials, headache was experienced after the first dose in 22% (95% confidence interval: 18% to 27%) and after the second dose in 29% (95% confidence interval: 23% to 35%), but also after placebo in 10% to 12% 29 . Among non–COVID-19 vaccines, headache occurs most commonly after vaccination for varicella-zoster virus, followed by influenza and human papillomavirus 30 . However, it is important to note that in an analysis of the Vaccine Adverse Event Reporting System, the risk of experiencing headache is 500 times higher with COVID-19 infection relative to vaccination 31 .…”

Diferencias y similitudes entre la cefalea relacionada con la COVID-19 y la cefalea relacionada con la vacuna de la COVID-19. Un estudio de casos y controles

“…Headache is also one of the most frequent symptoms reported after COVID-19 vaccines, described in 39-59% of patients in pivotal studies [ 8 - 10 ]. A recent systematic review of phase III vaccine randomized clinical trials not related to COVID-19 reported a median rate of headache of 15.6% –interquartile range (IQR): 9.6-37.6%–, a lower rate than the 39% (IQR: 28-50%) reported following COVID-19 related-vaccines [ 12 ]. In a study that evaluated 314,610 neurological adverse events reported to the United States Vaccine Adverse Events Reporting System, out of 306,907,697 COVID-19 vaccine doses administered, headache was the most frequently reported adverse effects [ 13 ].…”