Pain Ther (2021) 10:1309–1330 https://doi.org/10.1007/s40122-021-00296-3 ORIGINAL RESEARCH Headache Attributed to Vaccination Against COVID- 19 (Coronavirus SARS-CoV-2) with the ChAdOx1 nCoV-19 (AZD1222) Vaccine: A Multicenter Observational Cohort Study . Axel Heinze . Sarah Karstedt . Mascha Morscheck . Carl H. Go¨bel Lilian Tashiro . Anna Cirkel . Qutyaba Hamid . Rabih Halwani . Mohamad-Hani Temsah . Malte Ziemann . Siegfried Go¨rg . Thomas Mu¨nte . Hartmut Go¨bel Received: June 14, 2021 / Accepted: July 15, 2021 / Published online: July 27, 2021 (cid:2) The Author(s) 2021 ABSTRACT Introduction: The most frequently reported neurological adverse event of ChAdOx1 nCoV- 19 (AZD1222) vaccine is headache in 57.5%. Several cases of cerebral venous thrombosis (CVT) have developed after vaccination. Head- ache is the leading symptom of CVT. For the C. H. Go¨bel (&) (cid:2) A. Cirkel (cid:2) T. Mu¨nte Department of Neurology, University Hospital Schleswig-Holstein, Campus Lu¨beck, Ratzeburger Allee 160, 23538 Lu¨beck, Germany e-mail: carl.goebel@neuro.uni-luebeck.de C. H. Go¨bel (cid:2) A. Heinze (cid:2) S. Karstedt (cid:2) M. Morscheck (cid:2) L. Tashiro (cid:2) A. Cirkel (cid:2) H. Go¨bel Kiel Migraine and Headache Centre, Kiel, Germany Q. Hamid (cid:2) R. Halwani Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates Q. Hamid (cid:2) R. Halwani Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates M.-H. Temsah College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia M. Ziemann (cid:2) S. Go¨rg Institute of Transfusion Medicine, University Hospital Schleswig-Holstein, Campus, Lu¨beck, Germany differential diagnosis of headaches attributed to this vaccine and headaches attributed to CVT, it is of central clinical importance whether and, if so, how the phenotypes and course of these headaches can be differentiated. The study aims to examine in detail the phenotype of headache attributed to this vaccine. Methods: Data on the clinical features and corresponding variables were recorded using a standardized online questionnaire in this mul- ticenter observational cohort study. The pri- mary outcomes of this study are the clinical features of headaches after vaccination. Findings: A total of 2464 participants reported headaches after vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine. On average, headaches occurred 14.5 ± 21.6 h after vacci- nation and lasted 16.3 ± 30.4 h. A bilateral location was described by 75.8% of participants. This is most often found on the forehead (40.0%) and temples (31.4%); 50.4% reported a pressing and 37.7% a dull pain character. Headache intensity was most often severe (38.7%), moderate (35.2%), or very severe (15.5%). Accompanying symptoms were most (36.1%), commonly fatigue (44.8%), chills exhaustion (34.9%), and fever (30.4%). Conclusion: Headaches attributed to COVID- 19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine demonstrate an extensive and characteristic complex of symptoms. The 1310 Pain Ther (2021) 10:1309–1330 findings have several important clinical impli- cations for the differentiation of post-vaccinal headache and other primary as well as sec- ondary headaches. Novel Keywords: COVID-19; coronavirus SARS-CoV-2; ChAdOx1 nCoV-19 (AZD1222) vaccine; Vaccination; Side effects; Cerebral International venous thrombosis; Headache; Classification of Headache Disorders; ICHD-3 The findings have several important clinical implications for the differentiation of post-vaccinal headache and headache due to cerebral venous thrombosis as a complication of vaccination. On the basis of this analysis and by analogy to the ICHD-3, we are proposing new diagnostic criteria of headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine. Key Summary Points Why carry out this study? The most frequently reported neurological adverse event of ChAdOx1 nCoV-19 (AZD1222) vaccine is headache in 57.5%. Several cases of cerebral venous thrombosis (CVT) have developed after vaccination. Headache is the leading symptom of CVT. For the differential diagnosis of headaches attributed to this vaccine and other primary or secondary headaches, it is of central clinical importance whether and, if so, how the phenotypes and course of these headaches can be differentiated. The study aims to analyze and describe in detail the phenotype of headache attributed to ChAdOx1 nCoV-19 (AZD1222) vaccine. What was learned from the study? Headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine demonstrate an extensive complex of symptoms. The specific set of accompanying symptoms, along with the temporal and spatial headache characteristics describe a characteristic headache phenotype for headaches attributed to COVID-19 vaccination. INTRODUCTION syndrome respiratory In December 2019, cases of atypical viral pneumonia of unknown cause became known in Wuhan, China. A novel coronavirus, severe acute coronavirus 2 (SARS-CoV-2), was identified as the causative agent of this coronavirus disease (COVID-19). The virus has been spreading pandemically since then [1, 2]. The most common symptoms are fever, cough, fatigue, breathing difficulties, and loss of smell and taste. While the infection may present with mild to moderate intensity in some patients, severe forms may result in pro- nounced dyspnea, respiratory failure, and ulti- mately death [3]. In addition to behavioral interventions, such as social distancing, newly developed vaccinees that are available since the second half of 2020 are the most important countermeasures to prevent the spread of the virus [4]. According to the available data, vaccinees approved by regulatory authorities so far have a positive efficacy and side effect profile [4–11]. Worldwide, there are currently 66 vaccinees in clinical and 176 in preclinical development [4], some of which are already approved. This study is part of a series of analyses of headache as a side vaccination against COVID-19 with various vaccinees. Here we report on the phenotype of headache attributed to vaccination against COVID-19 (coronavirus following effect Pain Ther (2021) 10:1309–1330 1311 SARS-CoV-2) with the ChAdOx1 nCoV-19 (AZD1222) vaccine. ChAdOx1 nCoV-19 (AZD1222) vaccine is a monovalent vaccine composed of a single recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1) vector encoding the S glycoprotein of SARS-CoV-2 [9, 12–21]. The vaccine is administered intramuscularly in two doses given between 4 and 12 weeks apart. It is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older [9, 14]. According to the data available, the most frequently reported neurological adverse event attributed to vacci- nation against COVID-19 (coronavirus SARS- CoV-2) with the ChAdOx1 nCoV-19 (AZD1222) vaccine is headache in 57.5% of those vacci- nated [9, 14, 16, 22]. Detailed information about the clinical characteristics of this head- ache has not yet been described. The phase 3 clinical trial results only mention that mild headaches occur in 37.6%, moderate headaches in 17.6%, and severe headaches in 2.4% [14]. Several cases of cerebral venous thrombosis thrombotic events with and other unusual thrombocytopenia have developed after vacci- nation with ChAdOx1 nCoV-19 (AZD1222) vaccine [23]. This has led to extensive age in many countries around the restrictions world, including the complete cessation of the use of this vaccine. Headache is the leading symptom of cerebral venous thrombosis [24]. the differential diagnosis of headaches For attributed to this vaccine and headaches attributed to cerebral venous thrombosis, it is of central clinical importance whether and, if so, how the phenotypes and course of these head- aches can be differentiated. Vaccination-associated headaches are not yet classified by the International Classification of Headache Disorders ICHD-3, nor are diagnostic criteria provided [25]. Furthermore, the ChA- dOx1 nCoV-19 (AZD1222) vaccine is a novel vaccine not previously used [14]. A detailed clinical phenotype of vaccination-associated headaches is not known to date, including for example the precise latency between vaccina- tion and occurrence of the headache, its dura- localization, tion, character pain and symptoms, pain-modulating accompanying factors as well as possible comorbid conditions. The currently undergoing global vaccination campaign against COVID-19 allows this new form of headache to be studied alongside. The aim of this study is thus to delineate the detailed clinical characteristics of headaches occurring after vaccination against COVID-19 (AZD1222) with the ChAdOx1 nCoV-19 vaccine. METHODS Study Design and Setting continuous multicenter observational This study accompanying the COVID-19 cohort vaccination campaign aims to analyze the headache phenotype after vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine. The ethics committee of the University of Kiel approved the study (D403/21), which was per- formed in accordance with the principles of the Declaration of Helsinki of 1964 and its subse- quent revisions. All subjects gave their informed consent prior to participation. Specific aspects of the headache phenotype and related variables are collected using a pub- licly available online questionnaire. The ques- tionnaire is available in multiple languages, and it consists of 43 questions about the clinical characteristics of headaches after the COVID-19 vaccination. The questions are divided into the following groups: type of vaccine used, the occurrence of headaches after vaccination, possible headaches after previous vaccinations against other diseases, temporal parameters of the headache, headache localization, headache characteristics, headache intensity, accompa- nying symptoms, previous history of head- aches, and comorbid sociodemographic variables. diseases, other Here we present data collected from the vaccinees between January 8, 2021 and April 4, 2021. According to the German ordinance on the entitlement the SARS-CoV-2 coronavirus, vaccinations were given with the highest priority to people over the age of 80, as well as to inhabitants and to vaccination against 1312 Pain Ther (2021) 10:1309–1330 employees at residential care homes for the elderly. Healthcare workers at a very high risk of exposure to the SARS-CoV-2 coronavirus also received the highest priority for vaccination. Since direct contact with the vaccines is not possible because of data protection regulations, the management of the residential care homes was contacted by email and asked to pass on the information about the study to the residents and staff. Twelve thousand residential care homes in Germany were contacted. In addition, the departments responsible for organizing COVID-19 vaccinations at the university hos- pitals in Germany and the United Arab Emirates were contacted, asking to inform the employees about the study. Attention was also drawn to the study via the institutes’ websites and social media platforms. This evaluation reports the clinical headache those patients who received ChAdOx1 nCoV-19 (AZD1222) vaccine. characteristics of Data Collection (questionnaire link: Subjects The data on the clinical features and corre- sponding variables were recorded using a stan- dardized online questionnaire, the answers of which were collected in an online database https:// system schmerzklinik.de/impfung). were informed at the beginning of the questionnaire that data were collected anonymously, meaning that as a result of this anonymization it would not be possible to revoke participation in the study after any answers have been sent. Partic- ipants could complete the questionnaire at any time after the onset of headache, there was no time limit. Since data collection was initiated immediately with the start of the vaccination campaign, the answers generally refer to the first dose. Outcomes The primary outcomes of this study are the clinical features of headache after vaccination against COVID-19 with the ChAdOx1 nCoV-19 (AZD1222) vaccine. In addition, comorbidities, treatment with medication, and sociodemo- graphic variables are analyzed. Bias and Missing Data Medical staff in tertiary university hospitals and people being cared for in residential care homes for the elderly are overrepresented in this study compared to the general population, as both belonged to the groups with the highest vacci- nation priority in Germany. The study cannot analyze headache characteristics from people who did not voluntarily participate in this study. Complete data were not available for all variables, so the denominators differ between individual analyses. Missing data were not assumed for this descriptive analysis. Statistical Analysis The arithmetic mean and standard deviations are used to represent continuous variables. Fre- quency (%), unless otherwise stated, is used to represent categorical variables. Statistical anal- ysis for significant differences or continuous variables was done using the t test. The statisti- cal information is based on non-missing data. The 5% significance level (alpha = 0.05) was Table 1 Demographic data of patients Parameter n Sex, no. (%) Female Male Age at vaccination (years) Arithmetic mean Standard deviation Median Range Height (cm) Body weight (kg) Value 2464 1534 (84.7%) 276 (15.2%) 39.0 12.7 39 18–78 170.2 ± 8.1 75.8 ± 18.6 Pain Ther (2021) 10:1309–1330 1313 considered to be statistically significant. Statis- tical analyzes were carried out using SPSS 27. RESULTS Participants During the study period from January 8, 2021 till April 4, 2021, 2464 participants reported that headaches had occurred after vaccination against COVID-19 with the ChAdOx1 nCoV-19 (AZD1222) vaccine (Table 1). The participants consisted of 84.7% women and 15.2% men. The mean height was 170.2 ± 8.1 cm and the mean body weight 75.8 ± 18.6 kg. The mean age was 39.8 ± 12.7 years at the time of vaccination, the median was 39 years, and the range was 18–- 78 years the participants reported that they had not experienced any following previous vaccinations headaches (Fig. 2) and 7.4% of the participants indicated that In the latter group, 90.2% reported that the headache after COVID-19 vaccination was different from previous head- aches after previous vaccinations, so only 9.8% similar of (Fig. 1); 92.6% of experienced participants they had. the headaches after their COVID-19 vaccination compared to previous vaccinations. No prior history of headache disorders was reported by 35.3% of the participants; 26.9% of participants reported a tension-type headache, 15.3% a migraine, and 12.6% the coexistence of both tension-type headache and migraine; 0.9% reported cluster headaches; 8.7% reported a history of other headache disorders (Fig. 3). The most common other comorbid diseases were metabolic/hormonal pulmonary (20.8%), and mental disorders (13.0%). A com- plete list of frequencies can be found in Fig. 4. (22.7%), Temporal Parameters of Headache after Vaccination Against COVID-19 average The latency between vaccination against COVID-19 and the onset of headaches was 14.5 ± 21.6 h. Over half of the vaccinees experienced the headache after less than 10 h and 80% within 20 h after the vaccination. In less than 6.3% of the participants, the head- aches only began more than 2 days after the vaccination (Fig. 5). Fig. 1 Age distribution (years) of participants 1314 Pain Ther (2021) 10:1309–1330 Fig. 2 Relative frequency distribution of headaches after previous vaccinations Fig. 3 Frequency distribution of history of other headache disorders Pain Ther (2021) 10:1309–1330 1315 Fig. 4 Frequency distribution of comorbid diseases Fig. 5 Cumulative frequency distribution of latency (h) between vaccination and onset of headache 1316 Pain Ther (2021) 10:1309–1330 Fig. 6 Cumulative frequency distribution of duration (h) of headache attributed to COVID-19 vaccination The headache duration was 16.3 ± 30.4 h on average. In 50% of the vaccinees the headache duration was less than 6 h, and in 74.9%, it was less than 22 h. The headache lasted longer than 48 h in just 4.8% of the participants. The long- est headache duration reported in a single case was 504 h (Fig. 6). Overall, 67.4% of participants indicated that the headache occurred continuously as a single episode without interruption; 32.6% reported that the headache occurred in multiple phases. Headache Location and Radiation The headache was most frequently located in the forehead area (40.0% left, 39.7% right) fol- lowed by the temple region (30.4% left, 31.4% right) and the back of the head (24.1% left, 24.6% right). Retro-orbital pain was reported by 24.7%. Pain on the top of the skull was indi- cated by 21.6%, on the left side of the neck by 17.8%, and on the right side by 19.6% (Fig. 7). A bilateral headache occurred in 75.8% of the participants. A non-varying unilateral pain was indicated by 17.2% of the participants. An alternating one-sided headache was reported by 7.0% of the participants (Fig. 8). No radiation of pain was experienced by 56.6% of the participants, pain radiating to the neck and shoulder by 26.6%, and to the fore- head and temples by 16.7% (Fig. 9). Headache Character Overall, 50.4% of the participants indicated a pressing and 37.7% a dull pain character (Fig. 10). Less commonly, 18.0% of the patients experienced a pulsating pain (wave-like fluctu- ations of pain with every heartbeat) and 17.3% a stinging pain (repeated short stabs of pain) character. A throbbing pain (pulsing, beating sensation happening over and over again) was reported by 16.28%, a pounding pain by 14.4%, and a pulling pain by 13.1% of the participants. Other pain characters were reported by less than 10% of the participants. Pain Ther (2021) 10:1309–1330 1317 Fig. 7 Frequency distribution of headache location Fig. 8 Frequency distribution of headache side lateralization 1318 Pain Ther (2021) 10:1309–1330 Fig. 9 Frequency distribution of radiation of pain Fig. 10 Frequency distribution of headache character Pain Ther (2021) 10:1309–1330 1319 Fig. 11 Frequency distribution of headache intensity Fig. 12 Frequency distribution of effect of routine physical activity on headache 1320 Pain Ther (2021) 10:1309–1330 Headache Intensity After COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine, the headache intensity was documented as severe by 38.7% of the participants, moderate by 35.2%, and very severe by 15.5%. A mild headache was docu- mented by 9.1% and a very mild headache by 1.5% of the participants (Fig. 11). Overall, 45.6% of the participants found that routine physical activity did not affect head- ache intensity; 49.6% indicated that routine physical activity did indeed worsen the head- ache, while 4.7% found that routine physical activity actually relieved the headache (Fig. 12). Accompanying Symptoms We evaluated migraine-typical accompanying symptoms and other accompanying symptoms separately. Sensitivity to noise (33.4%), sensi- tivity to light (31.8%), and nausea (28.1%) were the most frequently reported symptoms typical (24.2%), of of migraine. appetite Loss hypersensitivity to smell (3.7%), and vomiting (4.0%) were less common (Fig. 13). The most frequently reported other accom- panying symptoms were fatigue (44.8%), chills (36.1%), exhaustion (34.9%), and fever (30.4%) (Fig. 14). With a frequency between 10.6% and 28.2%, the participants experienced weakness, joint pain, dizziness, neck pain, increased per- spiration, poor concentration, and reddening of the vaccination site. Sensitivity to touch, mus- cle pain, unsteadiness when walking, neck stiffness, irritability, anxiety, pale skin, tearful- ness, and visual disturbances were experienced with a frequency between 5% and 10%. Other accompanying symptoms experienced by less than 5% are listed in Fig. 14. Association with Pre-existing Headache Disorders We also investigated the effect of pre-existing headache illnesses on quantitative parameters of headaches after COVID-19 vaccination to uncover a possible connection between pre-ex- isting headache disorders and headache occur- ring after COVID-19 vaccination (Table 2). In Fig. 13 Frequency distribution of migraine-like accompanying symptoms Pain Ther (2021) 10:1309–1330 1321 Fig. 14 Frequency distribution of further accompanying symptoms participants with a history of migraine, there was no effect on the time between the vacci- nation and the onset of the headache compared to participants who had no primary headache. However, headache duration after COVID-19 vaccination was significantly longer in patients with a history of migraine than in participants without primary headache (20.9 ± 32.6 vs. 13.0 ± 18.5 h; p = 0.002). Furthermore, patients 3.2 ± 0.9; (3.7 ± 0.8 with migraine p \ 0.001) headache (3.5 ± 0.8 vs. 3.2 ± 0.9; p \ 0.010) reported a significantly higher headache pain intensity on the verbal rating scale (VRS 0–5) after COVID-19 vaccination compared to participants who had no history of migraine. vs. tension-type and Participants with a history of tension-type headache or cluster headache showed no dif- ference in the time interval between vaccina- tion and the onset of headache as well as the duration of the headache after COVID-19 vac- cination compared to participants without pri- mary headache (Table 2). Gender Differences There were no significant differences in the latency between vaccination and onset of headache and the duration of the headache between women and men (Table 3). The same was true regarding the headache intensity (VRS 0–5) attributed to COVID-19 vaccination (3.6 ± 0.9 in women vs 3.2 ± 0.8 in men; p \ 0.000). Age Effect To analyze an age effect, we split up participants into a group of up to 55 years of age and older than 55 years of age. We found no significant differences regarding the interval between vac- cination and onset of the headache, as well as the duration of the headache (Table 4) between these two age groups. However, the headache intensity was significantly higher in vaccinated people under 55 years of age than 55 years of (3.2 ± 0.9 vs. 3.6 ± 0.8; age p \ 0.000). and above 1322 Pain Ther (2021) 10:1309–1330 Table 2 Comparison of patients with pre-existing primary headaches (migraine, tension-type headache, or cluster head- ache) with patients without pre-existing primary headaches with regard to quantitative parameters of headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine Latency between vaccination and onset of headache 14.3 ± 20.6 14.2 ± 20.0 9.4 ± 4.5 14.8 ± 22.9 Duration of headache attributed to COVID-19 20.9 ± 32.6 16.8 ± 35.2 22.0 ± 35.6 13.0 ± 18.5 Intensity of headache attributed to COVID-19 3.7 ± 0.8 3.5 ± 0.8 3.6 ± 0.9 3.2 ± 0.9 Migraine Tension-type headache Cluster headache No primary headaches n = 274 n = 497 n = 16 n = 1060 p = 0.719 p = 0.582 p = 0.343 n = 201 n = 361 n = 11 n = 490 p = 0.002 p = 0.159 p = 0.333 n = 247 n = 501 n = 16 n = 602 p \ 0.001 p = 0.010 p = 0.479 (hours) vaccination (hours) vaccination (VRS 0–5) Arithmetic mean and standard deviation. Statistical analysis using t test Treatment DISCUSSION Regarding acute headache medication, 53.1% of the participants used paracetamol, followed by ibuprofen (50.7%) and metamizole (12.0%). Other medications used are listed in Fig. 15. Participants taking multiple drugs were asked to rank for the most effective drug. Fig- ure 16 shows the relative frequency with which an active ingredient was rated as the most effective drug. Accordingly, acetylsalicylic acid was most frequently named as the most effec- tive treatment option by 46.2%. Headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine show an extensive complex of symptoms with concise clinical characteristics. The specific set of accompanying symptoms along with the temporal and spatial headache characteristics characterize a unique headache phenotype for headaches attributed to COVID-19 vaccination. This phenotype is different from that of primary headaches. These headaches occur with similar symptoms across all age groups. Less than 8% of Table 3 Group comparison of women and men with regard to quantitative parameters of headaches attributed to COVID- 19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine Latency between vaccination and onset of headache (hours) 14.3 ± 20.9 15.6 ± 23.8 p = 0.342 Women Men t test Duration of headache attributed to COVID-19 vaccination (hours) 17.3 ± 33.4 13.7 ± 16.6 p = 0.130 Intensity of headache attributed to COVID-19 vaccination (VRS 0–5) 3.2 ± 0.8 p \ 0.001 n = 1518 n = 274 n = 1086 3.6 ± 0.9 n = 207 n = 1533 n = 276 Arithmetic mean and standard deviation. Statistical analysis using t test Pain Ther (2021) 10:1309–1330 1323 Table 4 Age group comparison of participants aged C 55 years and \ 55 years with regard to quantitative parameters of headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine ‡ 55 < 55 t test Latency between vaccination and onset of headache (hours) 15.4 ± 19.9 14.3 ± 21.7 p = 0.473 Duration of headache attributed to COVID-19 vaccination (hours) 15.7 ± 22.4 16.9 ± 32.7 p = 0.609 Intensity of headache attributed to COVID-19 vaccination (VRS 0–5) p \ 0.001 n = 271 n = 1519 n = 191 3.2 ± 0.9 n = 273 n = 1101 3.6 ± 0.8 n = 1533 Arithmetic mean and standard deviation. Statistical analysis using t test those affected experienced headaches resulting from previous vaccinations. And of these, over 90% report that the headache after COVID-19 vaccination is different from the headache fol- lowing previous other vaccinations. On average, headache attributed to COVID-19 vaccination occurs 15 h after vaccination with a duration of 17 h. In around two-thirds the headache lasts between 1 and 12 h. Over 67% experience a monophasic headache. The headache occurs bilaterally in more than 75%, the main local- ization being the forehead, temples, back of the head, and retro-orbital region. They do not commonly radiate to other regions. The pain character is most commonly described as pressing and dull, with pain intensity being most often moderate to severe. Routine physical activity can aggravate the pain. The most fre- quent accompanying symptoms are fatigue, chills, exhaustion, sensitivity to noise, and sensitivity to light. In women, the intensity of headache is significantly greater than in men. People younger than 55 years of age have sig- nificantly higher headache intensities than those who are vaccinated aged 55 or above. In the clinical approval studies, the use of paracetamol was recommended prophylacti- cally prior to vaccination in all trials (except in introduced as an study COV005; amendment during study COV001 [14]. The vaccinees were recommended to continue with 1000 mg of paracetamol in 6-h intervals for 24 h to reduce vaccine-induced side effects. The of analyzed COV001 it was study effect the paracetamol on immunogenicity using a stan- dardized ELISA on participants [19]. When study participants who received paracetamol were compared with those who did not, differ- ences in the generation of anti-S responses were not observed. However, it is possible that the headache phenotype was mitigated in these studies by the prophylactic administration of paracetamol. In the open application within the scope of this study, no prophylactic adminis- tration of paracetamol took place. In Germany, the preventive use of paracetamol was not rec- ommended. It is also not included in the pack- age insert. The headache phenotype recorded here can therefore provide a more realistic, unmasked picture. The uncovered headache phenotype in our study is neither that of migraine nor that of a tension-type headache. It may be possible that clinical symptoms of these two primary head- aches are included in the questionnaire reports and overlap with the headache phenotype attributed to COVID-19 vaccination. However, the described symptom complex of headache attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) differs markedly from the aforementioned primary headaches. The International Classification of Headache lists headaches attributed to Disorders [25] intracranial and systemic infections, either bacterial, viral, fungal, or parasitic. Headaches attributed to systemic viral infection are also described. A specific headache phenotype, is not described in these cases. however, 1324 Pain Ther (2021) 10:1309–1330 Fig. 15 Frequency distribution of medication used Fig. 16 Frequency of medication rated as most effective Pain Ther (2021) 10:1309–1330 1325 Table 5 Proposal for diagnostic criteria of headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine ----------------------------------------------------------------------------------------------------------------------------------- Acute headache attributed to Covid-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine Diagnostic criteria: A. Any new headache fulfilling at least three of the following five characteristics: 1. bilateral localisation 2. pressing or dull headache character 3. moderate to severe intensity 4. Sensitivity to noise and/or light 5. Routine physical activity does not alleviate B. Vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine has been carried out C. Evidence of causation demonstrated by at least two of the following: 1. headache developed within 24 h after vaccination 2. headache has developed in close temporal relation to other symptoms and/or clinical signs of the vaccination at least two of the following fatigue chills exhaustion fever 3. headache has significantly improved in parallel with stabilization or improvement of other symptoms and/or clinical signs of the vaccination. D. Either of the following: 1. headache has resolved within 72 h 2. headache has not yet resolved but 72 h have not yet passed E. Not better accounted for by another ICHD-3 diagnosis. ----------------------------------------------------------------------------------------------------------------------------------- Persistent headache attributed to Covid-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine Diagnostic criteria: A. Headache previously diagnosed as acute headache attributed to Covid-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine B. Headache has persisted for > 72 h after onset of headache C. Not better accounted for by another ICHD-3 diagnosis ----------------------------------------------------------------------------------------------------------------------------------- Headaches after vaccination are not yet listed in the International Classification of Headache Disorders. In particular, no detailed knowledge exists about the form of headaches occurring after vaccination with a single recombinant, replication-deficient adenovirus (ChAdOx1) vector encoding the S glycoprotein of SARS-CoV-2 in general and specifically with chimpanzee the ChAdOx1 nCoV-19 (AZD1222) vaccine. For the first time, the findings described in this report provide an overview of the phenotype of this headache, which can occur in more than 57% of the participants after vaccination as the most frequent neurological symptom [9, 14]. In Table 5, we summarize the results, and we pro- pose diagnostic criteria for acute and persistent 1326 Pain Ther (2021) 10:1309–1330 headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine by analogy to the current ICHD-3 criteria [25], subject to further empirical studies. Knowledge of these diagnostic criteria is crucial because these headaches may occur in patients who have no other headache disorder. It also allows one to differentiate vaccination- attributed headaches from other spontaneously occurring headache causes. While headaches in relation to a systemic viral infection typically have no specific headache characteristics regarding temporal aspects, pain character, location, and accompanying symptoms, the findings of this study delineate a specific head- ache phenotype with characteristic accompa- nying symptoms. thrombosis Our findings have several important clinical implications for the differentiation of headache after vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine, which can occur in over 57% of vaccinated persons [14] and headache due to cerebral venous (CVT). Headache is by far the most frequent symptom of CVT, present in 80–90% of cases, and also the most frequent inaugural symptom [25]. These headaches show no specific characteristics, but most often are diffuse, progressive and severe, and associated with other signs of intracranial hypertension. CVT can also mimic other pri- mary and secondary headaches. In over 90%, CVT is associated with focal neurological signs and/or signs of intracranial hypertension, sub- acute encephalopathy, or sinus syndrome. cavernous Post-vaccination headaches occur on average within 15 h and last for 16 h. Only less than 5% of those vaccinated have headaches that last longer than 3 days. Focal neurological signs such as speech disorders, sensory disorders, or double vision occur in less than 3%. The head- aches are usually monophasic and do not show an undulating course. The headaches are mainly present in the forehead and temple area and show a dull, pressing character. In contrast, venous or arterial thrombosis can develop approximately 5–20 days after vaccination [23]. If headaches only commence at this point after the vaccination (or recur after the initial post- vaccinal headache has subsided), accompanied by thrombocytopenia and focal neurological signs, this may indicate CVT. Headaches attributed to a systemic viral infection require, according to ICHD-3 [25], diagnostic evidence of a systemic viral infection without evidence of meningitis or encephalitis. The headache must be closely related to the onset of the viral infection, aggravate as the viral infection worsens, and improve as the viral infection disappears. The pain is described as diffuse and of moderate or severe intensity. However, headaches attributed to vaccination against COVID-19 with the ChAdOx1 nCoV-19 (AZD1222) vaccine are not due to a systemic viral infection. For the first time, we describe the precise time between vaccination and onset of the headache, the headache duration, the headache character, the location, and the specific accompanying symptoms in this study. These characteristics have not yet found their headache way classification. international into the The pathophysiological mechanisms of headache attributed to vaccination against COVID-19 remain unclear. Whether the S gly- coprotein of SARS-CoV-2, synthesized intracel- lularly using the gene supplied by the vaccine, is itself responsible for the headache or whether it is due to the resulting immune response trig- gered by that protein [8, 26–32] must remain open at present. The intracellular formation of the spike protein and the triggered immune response could be directly related to the devel- opment of the headache phenotype described, including the accompanying symptoms of fati- gue, chills, exhaustion, weakness, joint pain, and dizziness. It is speculated that microorgan- isms may activate anti-inflammatory substances such as nitric oxide, prostaglandins, and cytokines [29]. During a COVID-19 infection, vast amounts of proinflammatory cytokines can be released. According to our results, 36.1% of subjects with headaches attributed to vaccina- tion reported chills and 30.4% fever as an accompanying symptom. Therefore, it can be assumed that inflammatory mediators are also involved in the development of headaches attributed to COVID-19 vaccination. Pre-exist- such as ing primary headache disorders migraine lead to an increased duration and pain Pain Ther (2021) 10:1309–1330 1327 intensity of the headache attributed to COVID- 19 vaccination. It is possible that the sensitiza- tion with hyperexcitability of trigeminovascular neurons existing in primary headaches causes an increase in pain sensitivity and that this is relevant for the increased duration and pain intensity of headaches attributed to COVID-19 vaccination. This study has a number of limitations. Par- ticipants with particularly pronounced head- aches might have preferentially participated in this voluntary recruitment. The discovered clinical headache phenotype could thus repre- sent particularly severe forms. However, we tried to capture the headache phenotype in the most detailed way possible by recruiting a very large number of participants. The vaccinations were not started until the age of 18 years. Therefore, it is unlikely that new-onset primary headaches are confounded with the data. Regarding the gender ratio with more women than men, a definitive statement is not possible. As study participation was voluntary and the population of vaccinees is unknown, it is pos- sible that an excessive number of headache sufferers from the group of women participated in the study, given a disproportionate propor- tion of female vaccinees in the study. The responder rate of patients from residential care homes was than the responder rate of university hospital staff. In addition, vaccination among hospital staff was initially very rapid. This explains the higher age distribution of the working participants. The high proportion of female participants can be explained by the high number of female employees in hospitals (female doctors, nurses, administrative staff, assistants). Because head- aches occur very frequently irrespective of any vaccination, the data may be confounded by these other headaches. We did not attempt to delineate the frequency of headache occurrence after the COVID-19 vaccination. The phase 3 clinical trials of the various vaccination candi- dates provide this information by recording the frequency of possible side effects of the vacci- nation [5, 7–11, 16, 33–38]. Contrarily, no pre- cise clinical phenotype is contained in these studies. Whe- ther the headache phenotype described here significantly lower information regarding the occurs in the same way or in a different form with other vaccines against COVID-19 remains still open and is subject to further subgroup analyses in this study series [39]. CONCLUSIONS Headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine demonstrate an extensive and characteristic complex of symptoms. The set of accompany- ing symptoms, along with the temporal and spatial headache characteristics describe a unique headache phenotype for headaches attributed to COVID-19 vaccination. The find- ings have several important clinical implica- tions for the differentiation of post-vaccinal headache and other primary as well as sec- ondary headaches. On the basis of the findings, new diagnostic criteria for this form of head- ache can be developed. ACKNOWLEDGEMENTS We thank the participants of the study. Funding. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. No funding was received for the publication of this article. Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Authors’ Contributions. Dr. Carl H. Go¨bel— design and conceptualization of the study, interpretation of the results, contributed to statistical analysis, writing of the first draft of the manuscript. Dr. Axel Heinze—contribution to interpretation and analysis. Sarah Karstedt— contribution to interpretation and analysis. Mascha Morscheck—contribution to interpre- Tashiro— tation analysis. Lilian and 1328 Pain Ther (2021) 10:1309–1330 contribution to interpretation and analysis. Dr. Anna Cirkel—contribution to interpretation and analysis. Prof. Qutyaba Hamid—contribu- tion to interpretation and analysis. Prof. Rabih Halwani—contribution to interpretation and analysis. Dr. Mohamad-Hani Temsah—contri- bution to interpretation and analysis. Dr. Malte Ziemann—contribution to interpretation and analysis. Prof. Siegfried Go¨rg—contribution to interpretation and analysis. Prof. Thomas Mu¨nte—design and conceptualization of the study, contribution to interpretation and anal- ysis. Prof. Hartmut Go¨bel—design and concep- contributed to tualization of statistical the of manuscript. the analysis, co-writing study, Disclosures. Dr. Carl H. Go¨bel, Dr. Axel Heinze, Dr. Sarah Karstedt, Mascha Morscheck, Lilian Tashiro, Dr. Anna Cirkel, Prof. Qutyaba Hamid, Prof. Rabih Halwani, Dr. Mohamad- Hani Temsah, Dr. Malte Ziemann, Prof. Sieg- fried Go¨rg, Prof. Thomas Mu¨nte and Prof. Hartmut Go¨bel declare no financial conflicts and no competing interests. Compliance with Ethics Guidelines. The ethics committee of the medical faculty of the Christian-Albrechts University Kiel approved the study (D403/21). All subjects gave their informed consent prior to participation. The study was performed in agreement with the Declaration of Helsinki. Data Availability. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Open Access. This article is licensed under a Creative Commons Attribution-NonCommer- cial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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