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Abstract

Objective

To examine SARS-CoV-2 vaccine-related headache characteristics and risk factors in migraine patients.

Methods

This retrospective cohort study included 732 migraine patients who had AstraZeneca Vaxzevria, Pfizer-BioNTech Comirnaty, or Moderna Spikevax vaccines. Participants provided information through questionnaires and headache diaries. Headache frequency before and after vaccination and factors associated with headache risk were examined.

Results

Approximately a third of patients reported increased headache the day after having primary and booster doses, with mean increase ± SD of 1.9 ± 1.2 and 1.8 ± 1.1 days/week, respectively. Proportions of migraine patients with headache (after vaccination vs. before vaccination) increased after having primary-dose Vaxzevria (35.3% vs. 22.8%, p < 0.001) but not Spikevax (23.8% vs. 26.7%, p = 0.700) or Comirnaty (33.2% vs. 25.8%, p = 0.058). Headache proportion increased after having all three boosters (Vaxzevria 27.1% vs. 17.9% p = 0.003; Comirnaty 34.1% vs. 24.5% p = 0.009; Spikevax 35.2% vs. 24.8% p = 0.031). For primary dose with Vaxzevria and Comirnaty, headache risk increased on the vaccination day, peaked on the day after vaccination, and subsided within a week, while for Spikevax headache risk rose gradually after vaccination, peaked on the seventh post-vaccination day and subsided subsequently. For booster dose, headache risk generally increased on the vaccination day, peaked on the day after vaccination, and subsided gradually with fluctuating pattern within a month. Our study also showed that headache increased on the day before primary dose but not booster dose vaccination and it may be attributable to stress associated with having to undertake new vaccines. Multivariable analyses showed that depression was associated with headache.

Conclusion

Prolonged headache with vaccine- and dose-specific headache pattern was found. Patients with higher risks of vaccine-related headache must be informed of the potential worsening headache.

Keywords

COVID-19 adverse event AstraZeneca Vaxzevria Pfizer-BioNTech Comirnaty Moderna Spikevax

Introduction

The Coronavirus Disease 2019 (COVID-19) has caused significant mortality and morbidity in human population through a global pandemic with an estimated 14.9 million direct or indirect excess death recorded between 2020 and 2021 (1). Several public health measures including isolation/quarantine of individuals with the disease, regional lockdown, and vaccinations against the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which causes COVID-19, have been introduced. While vaccination remained the single most effective method in reducing the negative impact of COVID-19, many vaccinated individuals reported local or systemic adverse effects such as headache, muscle ache, feverishness, diarrhea and others during the post-vaccination periods and a minority reporting serious adverse events including myocarditis, thrombosis, myelitis and others (2 –6).

Headache, alongside injection-site pain and fatigue, were among the top three common reported adverse events following vaccinations against the SARS-CoV-2 (6). The reported headache risks were generally higher in clinical trials than in community studies at 25–65% vs. 8–23% and 20–59% vs 13% after primary and booster doses, respectively (6 –9). To what extent the number was due to reporting bias in relation to active surveillance in trials or passive surveillance in community studies was unknown (10). Nevertheless, patients with migraine were shown more likely to have vaccine-related headache (69% vs. 38%), indicating potential common etiology between migraine attack and vaccine-related headache (11,12). Because repeated vaccinations are suggested to improve individual immune response against the developing SARS-CoV-2, the burden associated with vaccine-related headache cannot be overlooked.

In patients with migraine, headache associated with vaccinations against SARS-CoV-2 was higher in pain intensity and less responsive to usually effective painkillers (13). Studies suggested potential mechanism and trigger for vaccine-related headache included vaccine-induced activation and production of inflammatory mediators which may also play critical roles in migraine occurrence or worsening, and anxiety or stress associated with having to undertake vaccination (12,13).

We aimed to investigate characteristics and risk factors of headache associated with vaccination against SARS-CoV-2 in migraine patients. It is especially important to identify risk factors for vaccine-related headache to prevent debilitating headache in migraine patients. We studied headache around the vaccination period in a migraine cohort who regularly recorded their headache frequencies through headache diaries. We also examined the associations between increased headache and risk factors including personal and headache characteristics, anxiety and depression, and allodynia.

Methods

Participants and data collection

Information on consecutive patients with migraine who were diagnosed and followed at the headache clinics at Taipei Veterans General Hospital and Taipei Municipal Gan-Dau Hospital and who had at least two doses of vaccinations against SARS-CoV-2 between 1 April 2021 and 31 December 2022 was retrospectively extracted and analyzed in this study. Patients were included if they i) were aged 20 and above ii) fulfilled the International Classification of Headache Disorders, 3rd edition criteria (14), for migraine iii)provided baseline personal and headache data through questionnaires iv) provided updated headache frequency data through headache diary during the study period, v) had primary and second doses of AstraZeneca Vaxzevria, Pfizer–BioNTech Comirnaty, or Moderna Spikevax vaccines during the study period. Patients were excluded if they had two doses of vaccines of different type.

All participants provided personal and headache information through questionnaires. Details on the questionnaires and information collected were described before (15). Briefly, information on demographic, lifestyle, comorbid health condition, headache profile, psychological health (collected using the Hospital Anxiety and Depression Scale [HADS]) (16), and allodynia score (17) was collected. Participants regularly recorded their headache frequencies through headache diary. Headache frequencies around the vaccination period (from 28 days before to 28 days after vaccination) were extracted from headache diaries for analysis. Information on vaccinations against SARS-CoV-2 including date of vaccinations and types of vaccines received were acquired during migraine clinic visit.

Anonymized information was extracted for data analysis. Ethical approval (2022-11-010CC) was obtained from the Institutional Review Board of Taipei Veterans General Hospital and written informed consent from each participant was waived.

Vaccinations against SARS-CoV-2

Participants could freely select the vaccine of choice, subject to availability, from the three following types: AstraZeneca Vaxzevria (0.5 mL from a 5 mL multidose vial), Pfizer–BioNTech Comirnaty (0.3 mL from a 0.45 mL multidose vial diluted in its original vial with 1.8 mL 0.9% sodium chloride solution) and Moderna Spikevax (0.5 mL from a 5 mL multidose vial).

Statistical analysis

The demographic and clinical characteristics of patients were presented as number and proportion for categorical variables and mean and standard deviation (SD) for continuous variables, and their differences between vaccine types were compared using chi square test and one-way ANOVA test, respectively. Daily headache frequency and 3-, 7-, 28-day mean headache proportion before and after vaccination were presented.

Proportion of headache on the day before and after receiving vaccination, were presented, and compared using McNemar’s test. Mean weekly headache days (days/week) in the week before and after receiving vaccination were also presented and compared using paired t-test.

In exploratory analyses, we examined the risk of increased headache after primary or booster doses of vaccination against SARS-CoV-2 in relation to personal characteristics (age, sex, BMI, hypertension) and headache characteristics (headache frequency ≥ 15 days, migraine with aura), anxiety (HADS-A ≥ 11), depression (HADS-D ≥ 11), or allodynia (17-item allodynia score ≥ median) using age-and-sex logistic regression models. Risk of increased headache was defined as increased headache day(s) comparing the week following vaccination to the week before vaccination. Factors with p ≤ 0.05 in the age-and-sex model were further examined for associations with increased headache in multivariate logistic regression models.

Statistical significance was defined as a two-sided p of less than 0.05. All analyses were performed using Stata statistical software version 15.1 (StataCorp, College Station, TX, USA).

Results

Study population and baseline characteristics

A total of 732 patients with migraine who had two consecutive doses of vaccines against SARS-CoV-2, of which 410 (56.0%) had AstraZeneca Vaxzevria, 211 (28.8%) had Pfizer–BioNTech Comirnaty and 111 (15.2%) had Moderna Spikevax, were recruited (Table 1). The distribution of age at primary dose vaccination was dissimilar between participants, with younger mean age (±SD) recorded for those who had Vaxzevria (42.7 ± 10 years) or Comirnaty (39.4 ± 11 years) while older mean age recorded for those who had Moderna Spikevax (48.5 ± 13 years). There were also statistically significant differences between participants regarding proportions with hypertension (users of Vaxzevria 6.4%; Comirnaty 7.1%; Spikevax 18.2%) but they were not statistically significant after adjusting for sex and age.

Table 1.

Personal and headache characteristics of study participants.

	All participants	AstraZeneca Vaxzevria	Pfizer-BioNTech Comirnaty	Moderna Spikevax	P-value
No. of participants (%)	732 (100.0)	410 (56.0)	211 (28.8)	111 (15.2)	n/a
Clinical characteristics
Age at primary dose, mean (SD)	42.6 (11)	42.7 (10)	39.4 (11)	48.5 (13)	<0.001
Sex (men), n (%)	147 (20.1)	88 (21.5)	41 (19.4)	18 (16.2)	0.455
BMI, mean (SD)	22.9 (4)	22.9 (4)	22.7 (4)	23.5 (4)	0.298
Hypertension, n (%)	61 (8.4)	26 (6.4)	15 (7.1)	20 (18.2)	<0.001
Headache characteristics
Aura, n (%)	44 (6.0)	23 (5.6)	17 (8.1)	4 (3.6)	0.244
Monthly headache frequency, mean (SD)	5.7 (6)	5.4 (5)	6.2 (6)	5.7 (6)	0.326
Allodynia score, mean (SD)	2.4 (3)	2.5 (3)	2.1 (3)	2.7 (3)	0.244
Hospital Anxiety score, mean (SD)	8.1 (4)	8.0 (4)	8.1 (4)	8.1 (4)	0.967
Hospital Depression score, mean (SD)	6.4 (4)	6.4 (4)	6.1 (4)	6.6 (4)	0.489

BMI, body mass index; SD, standard deviation.

Headache pattern around primary dose vaccination period

Figure 1 shows daily headache pattern (%) around vaccination period ranging from 28 days before to 28 days after receiving a vaccination against SARS-CoV-2, with about a fifth of migraine patients regularly reporting having headache on each day (28-day-before-vaccination mean 21.1%, range 18.3%–24.2%) (Figure 2). The headache pattern for Vaxzevria and Comirnaty users were similar, which rose on the vaccination day (Vaxzevria 28.1%, Comirnaty 25.3%), peaked on the day after vaccination (Vaxzevria 35.3%, Comirnaty 33.2%), and subsided subsequently (Figure 1). For Spikevax users, headache rose gradually after having vaccination, peaked on the seventh day after vaccination (34.3%) and subsided subsequently (Figure 1). Interestingly, we observed a slight increase in headache for all three vaccine users on the day before their primary dose vaccination (Vaxzevria 22.8%, Comirnaty 25.8%, Spikevax 26.7%).

Figure 1.

Daily headache pattern (proportion with headache) around vaccination against SARS-CoV-2 period in migraine patients.

Figure 2.

Mean proportion of headache (%) by days before and after vaccination against SARS-CoV-2.

When compared to the day before vaccination, statistically significantly increased headache was found on the following day after vaccination in Vaxzevria users (35.3% vs. 22.8%, p < 0.001) but not in Spikevax users (23.8% vs. 26.7% p = 0.700) while there seem to be increased headache in Comirnaty users (33.2% vs. 25.8%, p = 0.058) (Figure 2). When compared to the week before vaccination, about a third of migraine patients (217/732, 29.6%) reported increased headache days in the week following vaccination with a mean of 1.9 days/week (p < 0.001) (by vaccine types: Vaxzevria 1.9 days/week, Comirnaty 2.1 days/week, Spikevax 1.9 days/week; all p < 0.001). In patient with increased headache (n = 217), 21.3% and 30.2% reported headache of moderate of severe intensity on the primary-dose vaccination day and the day after vaccination, respectively, while the proportions were between 3.2 and 9.7% in the week before (Figure 3). Collectively, 31.0% and 43.2% of these patients exhibited characteristic of migraine on the primary-dose vaccination day and the day after vaccination (Figure 3), respectively, while the remainders bore features of tension-type headache.

Figure 3.

Headache characteristics in migraine patients with SARS-CoV-2 vaccine-related increased headache by days of vaccination.

Headache pattern around booster dose vaccination period

For booster dose, the headache pattern before vaccination was similar to that of primary dose with the same 28-day-before-vaccination mean headache proportion of 21.1% (range 17.6%–24.3%) (Figure 2). For Vaxzevria users, headache rose on the vaccination day (24.3%), peaked on the day after vaccination (27.1%), and subsided gradually within 2 weeks (7^th day 24.6%, 14^th day 21.6%) (Figure 1). For Comirnaty users, headache increased on the vaccination day (29.7%), peaked on the day after vaccination (34.1%), and decreased gradually after 2 weeks (15^th day 24.9%) with fluctuating headache pattern (range: 20.1–27.9%) (Figure 1). For Spikevax users, headache increased and peaked on the day after vaccination (35.2%) and decreased gradually after a week (8^th day 25.6%) with fluctuating headache pattern (range: 22.4–30.4%) (Figure 1). We observed no increase in headache for all vaccine users on the day before their booster dose vaccination (Vaxzevria 17.9%, Comirnaty 24.5%, Spikevax 24.8%).

When compared to the day before vaccination, significantly increased headache on the following day after vaccination was found in all three vaccine users (Vaxzevria 27.1% vs. 17.9%, p = 0.003; Comirnaty 34.1% vs. 24.5%, p = 0.009; Spikevax 35.2% vs. 24.8%, p = 0.031) (Figure 2). When compared to the week before vaccination, about a third of migraine patients (257/732, 35.1%) reported increased headache in the week following vaccination with a mean of 1.8 days/week (p < 0.001) (by vaccine types: Vaxzevria 1.7 days/week, Comirnaty 1.9 days/week, Spikevax 1.8 days/week; all p < 0.001). In patients with increased headache (n = 257), 17.1% and 25.7% reported headache of moderate of severe intensity on the booster-dose vaccination day and the day after vaccination, respectively, while the proportions were between 4.3 and 8.2% in the week before (Figure 3). Collectively, 25.2% and 35.8% of these patients exhibited characteristic of migraine on the booster-dose vaccination day and the day after vaccination (Figure 3), respectively, while the remainders bore features of tension-type headache.

Risk factors for vaccination-related headache

Table 2 shows relative risks for vaccine-related headache in relation to personal and headache characteristics, anxiety and depression, and allodynia. In multivariable analyses, depression (HADS-D ≥11) was associated with increased headache in relation to both doses of vaccines [primary dose RR 1.76 (95% CI 1.03–3.02), p = 0.040;/booster dose RR 1.81 (95% CI 1.06–3.10), p = 0.030]. Being aged ≥55 was associated with increased headache risk (RR 1.52 [95% CI 1.00–2.29], p = 0.048) while monthly headache frequency ≥15 was associated with decreased headache risk (RR 0.33 [95% CI 0.16–0.70], p = 0.003) after booster dose.

Table 2.

Risk factors for vaccine-related headache.

Risk factors	Primary dose				Booster dose
	Age-and-sex model		Multivariate model		Age-and-sex model		Multivariate model
	RR (95% CI)	P-value	RR (95% CI)	P-value	RR (95% CI)	P-value	RR (95% CI)	P-value
Age ≥55	0.90 (0.59–1.35)	0.598			1.59 (1.08–2.36)	0.020	1.52 (1.00–2.29)	0.048
Male sex	0.91 (0.58–1.43)	0.678			0.82 (0.53–1.28)	0.379
Underweight (BMI <18.5)	1.20 (0.59–2.42)	0.621			1.43 (0.71–2.88)	0.322
Obesity (BMI >25)	0.48 (0.28–0.80)	0.002	0.50 (0.24–1.05)	0.067	1.21 (0.76–1.92)	0.424
Hypertension	0.43 (0.20–0.92)	0.029	0.48 (0.22–1.04)	0.065	1.10 (0.60–2.04)	0.754
Migraine with aura	1.18 (0.54–2.55)	0.680			0.31 (0.11–0.81)	0.018	0.39 (0.14–1.07)	0.069
Monthly headache frequency ≥15	0.66 (0.34–1.28)	0.217			0.34 (0.17–0.70)	0.003	0.33 (0.16–0.70)	0.003
Anxiety (HADS-A ≥11)	1.39 (0.91–2.11)	0.129			1.52 (1.00–2.29)	0.048	1.42 (0.93–2.18)	0.108
Depression (HADS-D ≥11)	1.83 (1.09–3.10)	0.023	1.76 (1.03–3.02)	0.040	1.92 (1.14–3.24)	0.014	1.81 (1.06–3.10)	0.030
Allodynia	1.04 (0.71–1.52)	0.848			0.96 (0.66–1.39)	0.837

BMI, body mass index; HADS, Hospital Anxiety and Depression Scale; RR, relative risk; CI, confidence interval.

Because depression (HADS-D ≥11) was associated with headache after both primary and booster doses, we examined further for associations between depression score (HADS-D score was categorized in three groups of about the same size: upper/middle/lower thirds) and headache risk in a post-hoc analysis. Figure 4 showed linear associations between increasing scores for depression and headache risk after primary dose (p for linear trend = 0.027) and booster dose (p for linear trend = 0.001).

Figure 4.

Increasing depression score and risk of increased headache after vaccination against SARS-CoV-2.

Discussion

About a third of migraine patients reported an additional 1.8–1.9 headache days in the week following vaccination against SARS-CoV-2 comprising either AstraZeneca Vaxzevria, Pfizer-BioNTech Comirnaty, or Moderna Spikevax vaccines. Prolonged headache with distinctive headache pattern specific to each type and dose of vaccine received was found. For primary dose of Vaxzevria or Comirnaty vaccine, headache started to increase on the vaccination day, peaked on the day after receiving the vaccine and generally subsided within a week. For primary dose of Spikevax vaccine, headache increased gradually after having the vaccination, peaked on the seventh day post-vaccination and subsided thereafter. For booster dose of Vaxzevria vaccine, headache increased on the vaccination day, peaked on the day after vaccination and subsided thereafter. For Comirnaty or Spikevax booster dose, headache peaked on the day after vaccination and there was a prolonged period with fluctuating headache pattern for about a month. Multivariable analyses showed that depression was associated with vaccine-related headache, whether it be primary or booster doses, with consistent linear associations also found between increasing depression score and headache risk.

Our study extracted and analyzed information on vaccination against SARS-CoV-2 in a migraine cohort who regularly recorded their headache frequencies through headache diary, which avoided reporting bias related to high frequency of adverse event as a result of active surveillance commonly seen in clinical trials (or low frequency as a result of passive surveillance in community studies) (10). Nevertheless, we showed that vaccinations against SARS-CoV-2 disproportionately affected migraine patients with lengthier post-vaccination headache recorded here (mean increase 1.9 days after primary dose and 1.8 days after booster dose) when compared to 0.3–0.7 days reported in published literatures of general populations receiving SARS-CoV-2 vaccinations (3). The proportions with vaccine-related headache in our study of migraine patients were higher (30.4%–33.1%) than those reported by a large recent meta-analysis of published studies of general population (22%–29%), providing additional evidence that migraine patients were more likely than others to experience vaccine-related headache (3,12). In migraine patients, we observed a vaccine- and dose-specific difference in headache pattern similar to those of general populations in that more headache was recorded after primary dose Vaxzevria when compared to booster dose while more headache was recorded after booster dose Comirnaty or Spikevax when compared to primary dose (18).

While vaccine-induced inflammatory reactions such as cytokine/chemokine release contributed to development of individual immunity against SARS-CoV-2, some of which may possibly provoke headache. Studies suggested that possible mechanism for vaccine-related headache include vaccine-induced innate immunity acute phase cytokine release, which was shown to begin within hours after vaccine administration and decrease within days (19,20), paralleling the occurrence and period of vaccine-related headache (6,13,21,22). Interestingly, higher concentrations of innate immunity cytokines were also detected after booster dose of vaccine injection, which parallel the higher proportion of headache after booster dose of vaccine users reported here (proportion with increased headache days: 35.1% after booster dose >29.6% after primary dose) and by published studies (3,6 –8,19,20). Besides, studies suggested vaccine-induced spike protein may bind to angiotensin-converting enzyme 2 (ACE2) which disrupt the normal cleavage of angiotensin (Ang) II, downregulating ACE2/Ang 1-7 pathway and leaving pathogenic Ang II/AT1R actions unopposed, which may result in increased sympathetic activity, blood pressure, oxidative stress, inflammation, nociception activity and subsequent headache (23). Higher serum Ang II was shown to be associated with increased circulating levels of calcitonin gene-related peptide (24), which may explain the observed higher headache frequency in migraine patients when compared with non-headache or less severe counterparts. Further studies are needed to directly correlate these molecular measures with clinical headache features.

Our exploratory analyses showed that depression (HADS-D ≥ 11) was associated with increased risk of vaccine-related headache in migraine patients. Emotional distress was suggested by studies to serve as an upstream driver of neurogenic inflammation (25). Besides, both depression and migraine shared features suggestive of central sensitization (26). It could be postulated that migraine patients with depression are more susceptible to stress response and vaccinations against SARS-CoV-2 triggered cascades of systemic inflammatory reactions and exacerbated central neuroinflammation, which lead to central sensitization. Whether or not depression and increased risk of vaccine-related headache was related to increased central sensitization or neurogenic inflammation requires clarification in further study. Interestingly, our study also showed that headache rose on the day before primary dose vaccination (not seen in booster dose) and it might be associated with anxiety or stress related to undertaking the vaccine (a newly developed vaccine) but more data are needed.

Strengths of our study include the large sample size of migraine patients and the unbiased information on headache recorded through headache diary. Our study participants were not asked to report headache objectively during the pre/post vaccination periods. Rather, we followed a migraine cohort, extracted and analyzed information on COVID-19 vaccines and headache frequency around the primary and booster dose injection period, preventing reporting bias commonly seen in adverse event study. We were also able to identify underlying or existing conditions which may predispose migraine patients to vaccine-related headache so that appropriate advice or treatments may be given to these patients before and after vaccinations. The main limitation of the current study is all participants were conveniently recruited from two headache clinics, which may reduce the generalizability of study findings on general migraine populations. Conversely, all migraine diagnoses were made by board-certified neurologists based on the ICHD-3 criteria so misclassification bias is low. For headache risk and pattern associated with booster dose, the findings may not be applicable to doses after the second dose because only headache information around the second dose vaccination period were analyzed in the current study. Secondly, we have no information on medications used by participants around the vaccination period so further studies are needed to identify the optimal treatment for vaccine-related headache in migraine patients. Additionally, the unexpected decreased risk of vaccine-related headache in patients with more frequent pre-vaccination headache (monthly headache frequency ≥15) may be related to the medications used in the post-vaccination period and further studies are needed to clarify this observed association. Third, results from the current analysis may be subject to residual confounding as seen in demographic differences between the three vaccine users due to a non-randomized setting. Nevertheless, headache pattern and mean increased headache days were also presented by each vaccine type and data before and after vaccination were compared using dependent data statistical tests while risk factor analyses were all controlled for age and sex initially and vaccine type plus other statistically significant factors subsequently in multivariable analyses, which may reduce the effect of confounding.

In conclusion, vaccinations against SARS-CoV-2, comprising both primary and booster doses of Vaxzevria, Comirnaty or Spikevax vaccines, increase headache days in about a third of migraine patients. Prolonged headache with distinctive headache patterns specific to each dose and type of vaccine received was found and this information is valuable to primary care physician and headache specialist when evaluating the impact of vaccine-related headache. Patients with depression are at risk of increased headache and should be warned of the potential worsening headache.

Clinical implications

Both primary and booster doses of vaccine against the SARS-CoV-2 increased headache days in about a third of migraine patients.

Migraine patients with depression are more vulnerable to vaccine-related headache.

Increased headache was noted as early as the day before primary dose vaccination and it may be attributable to anxiety or stress associated with having to undertake new vaccines and must not be overlooked.

Footnotes

Acknowledgements

We are thankful to the staff of Taipei Veterans General Hospital headache group for data collection and data management.

Author contributions

ASK and S-JW conceived the study. All authors contributed to the design of the study. S-PC, Y-FW, and S-JW recruited and interviewed the study participants. ASK did the literature search, performed the analysis, and drafted the manuscript. All authors read, provided comments, and approved the final manuscript.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ASK reported no disclosures relevant to the manuscript. S-PC, Y-FW and S-JW received grants or speaking honoraria, all outside the submitted work. S-PC received research grants from Taipei Veterans General Hospital and the National Science and Technology Council of Taiwan. Y-FW received grants from Taipei Veterans General Hospital and the National Science and Technology Council of Taiwan. S-JW has served on the advisory boards of Pfizer, Allergan, and Elli Lilly Taiwan; received speaking honoraria from local companies (Taiwan branches) of Pfizer, Elli Lilly, Boehringer Ingelheim, and GlaxoSmithKline; and received research grants from the National Science and Technology Council of Taiwan, Taipei Veterans General Hospital, Taiwan Novartis Company, and Taiwan Headache Society.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by grants from Taipei Veterans General Hospital (V112E-004-1, V112C-113, VGHUST112-G1-2-1), Ministry of Science and Technology of Taiwan (NSTC112-2321-B-075-007, MOST111-2314-B-075-086-MY3), and Brain Research Center, National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

ORCID iDs

Ai Seon Kuan

Shih-Pin Chen

Shuu-Jiun Wang

References

WHO (2022) Global excess deaths associated with COVID-19, January 2020–December 2021, https://www.who.int/data/stories/global-excess-deaths-associated-with-covid-19-january-2020-december-2021 (2022, accessed 1 July 2023).

Beatty

Peyser

Butcher

, et al. Analysis of COVID-19 vaccine type and adverse effects following vaccination. JAMA Netw Open 2021; 4: e2140364.

Castaldo

Waliszewska-Prosół

Koutsokera

, et al. Headache onset after vaccination against SARS-CoV-2: a systematic literature review and meta-analysis. J Headache Pain 2022; 23: 41.

Diaz

Parsons

Gering

, et al. Myocarditis and pericarditis after vaccination for COVID-19. JAMA 2021; 326: 1210–1212.

Franchini

Liumbruno

Pezzo

COVID-19 vaccine-associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome. Eur J Haematol 2021; 107: 173–180.

Menni

Klaser

May

, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis 2021; 21: 939–949.

Baden

El Sahly

Essink

, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021; 384: 403–416.

Polack

Thomas

Kitchin

, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020; 383: 2603–2615.

Ramasamy

Minassian

Ewer

, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 2021; 396: 1979–1993.

10.

Pohlman

Carroll

Tsuyuki

, et al. Comparison of active versus passive surveillance adverse event reporting in a paediatric ambulatory chiropractic care setting: a cluster randomised controlled trial. BMJ Open Qual 2020; 9: e000972.

11.

Ekizoglu

Gezegen

Yalınay Dikmen

, et al. The characteristics of COVID-19 vaccine-related headache: Clues gathered from the healthcare personnel in the pandemic. Cephalalgia 2022; 42: 366–375.

12.

Sekiguchi

Watanabe

Miyazaki

, et al. Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study. Cephalalgia 2022; 42: 266–272.

13.

Silvestro

Tessitore

Orologio

, et al. Headache worsening after COVID-19 vaccination: An online questionnaire-based study on 841 patients with migraine. J Clin Med 2021; 10: 5914.

14.

IHS. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

15.

Kuan

Chen

Wang

, et al. Risk factors and psychological impact of syncope in migraine patients. Cephalalgia 2019; 39: 1838–1846.

16.

Zigmond

Snaith

RP.

The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–370.

17.

Ashkenazi

Silberstein

Jakubowski

, et al. Improved identification of allodynic migraine patients using a questionnaire. Cephalalgia 2007; 27: 325–329.

18.

Caronna

van den Hoek

Bolay

, et al. Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review. Cephalalgia 2023; 43. DOI: 10.177/3331024221131337.

19.

Bergamaschi

Terpos

Rosati

, et al. Systemic IL-15, IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients. Cell Rep 2021; 36: 109504.

20.

Collignon

Bol

Chalon

, et al. Innate immune responses to chimpanzee adenovirus vector 155 vaccination in mice and monkeys. Front Immunol 2020; 11: 579872.

21.

Göbel

Heinze

Karstedt

, et al. Clinical characteristics of headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2 mRNA vaccine: a multicentre observational cohort study. Brain Commun 2021; 3: fcab169.

22.

Göbel

Heinze

Karstedt

, et al. Headache attributed to vaccination against COVID-19 (Coronavirus SARS-CoV-2) with the ChAdOx1 nCoV-19 (AZD1222) Vaccine: A multicenter observational cohort study. Pain Ther 2021; 10: 1309–1330.

23.

Bolay

Gül

Baykan

COVID-19 is a real headache! Headache

2020; 60: 1415–1421.

24.

Portaluppi

Vergnani

Margutti

, et al. Modulatory effect of the renin-angiotensin system on the plasma levels of calcitonin gene-related peptide in normal man. J Clin Endocrinol Metab 1993; 77: 816–820.

25.

Littlejohn

Guymer

Neurogenic inflammation in fibromyalgia. Semin Immunopathol 2018; 40: 291–300.

26.

Nijs

George

Clauw

, et al. Central sensitisation in chronic pain conditions: latest discoveries and their potential for precision medicine. Lancet Rheumatol 2021; 3: e383–e392.

Prolonged headache with vaccine- and dose-specific headache pattern associated with vaccine against SARS-CoV-2 in patients with migraine

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Methods

Participants and data collection

Vaccinations against SARS-CoV-2

Statistical analysis

Results

Study population and baseline characteristics

Headache pattern around primary dose vaccination period

Headache pattern around booster dose vaccination period

Risk factors for vaccination-related headache

Discussion

Clinical implications

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

ORCID iDs

References