355

ORIGINAL
Assessment of multiple domains of pain following BNT162b2
mRNA COVID-19 vaccination
Masashi Izumi1, 2, Toru Morimoto1, Shota Oda2, Dai Ohishi2, Yoshihiro Hayashi2, Takahiro Shimokawa2, Kazuki Ozaki1,
Anzu Nakamae1, Ryota Saito3, Yoshiki Fujii3, Naoki Komatsu4, Hiromi Seo4, and Masahiko Ikeuchi1, 2
Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Kochi, Japan, 2Department of Rehabilitation, Kochi Medical
School Hospital, Kochi University, Kochi, Japan, 3Center for Innovative and Translational Medicine, Kochi Medical School, Kochi University,
Kochi, Japan, 4Department of General Medicine, Kochi Medical School Hospital, Kochi University, Kochi, Japan
1

Abstract : Pain at the injection site is the most frequent reaction among COVID-19 vaccine recipients, but its
characteristics were not fully described yet. The purpose of this study was to investigate multiple domains ofpain following BNT162b2 mRNA vaccination. We included 107 subjects undergoing primary shot of the vaccination twice into deltoid muscle with a 3-week interval. They completed 6 sessions of pain assessments, one before
the first and second dose (1-0, 2-0), and 1st / 7th day after the first and second dose (1-1 / 1-7, 2-1 / 2-7). Pain visual analog scale (VAS), pain distribution, and pressure pain threshold (PPT) on deltoid muscle were evaluated in eachsession. The mean VAS (at rest / shoulder motion) was 6.0 / 27.6 mm at 1-1, and 12.8 / 34.0 mm at 2-1. Approximately,
90% of recipients showed localized pain within the upper arm. Percentage change of PPTs at 1-1 and 2-1 was bilaterally (ipsilateral / contralateral) decreased to 87.4 / 89.4% and 80.6 / 91.0%, which was recovered to the baseline
level at 1-7 and 2-7. Temporary, mild-to-moderate intensity, localized distribution, concomitant with bilateral mechanical hyperalgesia on the deltoid muscle, were typical pain characteristics following this vaccination. Thesefindings provide a rationale that will be informative for future recipients. J. Med. Invest. 70 : 355-360, August, 2023
Keywords : COVID-19, Vaccine, Vaccination, Pain, Pressure pain threshold

INTRODUCTION
Coronavirus disease 2019 (COVID-19) has posed as a serious threat to public health and economy worldwide. Since
there is still a lack of specific treatment, vaccination would be asignificant tool against the pandemic of this virus. BNT162b2(Comirnaty : Pfizer / BioNTech) is the first mRNA-based vaccine
in human history, which has proven to be 85% effective and is
expected to prevent the spread of COVID-19 infection in earlyreports (1, 2).
In Japan, this vaccine was the first to be authorized for
emergency use by the Ministry of Health, Labor, and Welfare ofJapan in February 2021, however, there was much concern about
reactogenicity following the vaccine. It is probably associatedwith an incident in 2013, where the Japanese government suspended proactive recommendation of the human papillomavirus
vaccine because of safety concerns raised by the general public(3). According to a recent cross-sectional internet survey completed by 2956 Japanese people, the proportion of participants
with a high likelihood of getting a COVID-19 vaccine was 62.1%,
and multiple logistic regression analysis showed that vaccine acceptance was lower among several sociodemographic groups (4).
Musculoskeletal pain is often included among extrapulmonary expression of COVID-19, and they can occur during theacute phase but also as short or long-term complications (5). A
recent literature review showed that the incidence rate rangeof myalgia / arthralgia was 1.5-61.0% (6). Another prospective
follow-up study by phone interview revealed that 92.3%, 72.7%,
Received for publication November 11, 2022 ; accepted April 10, 2023.
Address correspondence and reprint requests to Masashi Izumi, MD,
PhD., Department of Orthopaedic Surgery, Kochi Medical School,
Kochi University, 185-1 Kohasu, Oko-cho, Nankoku-City, Kochi Pref,
783-8505, Japan and Fax : +81-88-880-2388. E-mail : izumim@
kochi-u.ac.jp

and 56.3% of COVID-19 patients reported any musculoskeletal
symptoms at hospitalization, 2-week, and 1-month, respectively(7). The most common symptom was fatigue, followed by backpain, arthralgia, myalgia, low back pain, and neck pain (7).
Although molecular mechanisms underlying this ‘COVID-pain’
have not been elucidated yet, the issue of direct viral damage,
the role of macrophage activation, and the features of cytokine-induced damage are addressed (5).
Pain at the injection site was the most frequent reaction
among COVID-19 vaccine recipients. Regarding BNT162b2
recipients (n = 8183), mild-to-moderate pain at the injection
site within 7 days after the first / second dose were reported
as : 71% / 66% among recipients older than 55 years of age, and
83% / 78% among younger recipients, which were mostly resolved
within 1 to 2 days (8). According to a Japanese online survey(n > 3000), approximately 90% of participants reported pain at
the injection site, however, number of days absent from theirwork was less than 3 days in almost all cases (9). Thus, it is nota serious problem in general, however, detailed characteristics ofpain after this vaccination were not fully described yet and misinformation may cause unnecessary fear and subsequent vaccine
hesitancy for future recipients. The purpose of this study was toprovide clear and unbiased information about multiple domainsof pain following the BNT162b2 mRNA COVID-19 vaccination.

METHODS
Subjects

This observational study was conducted with a prospective manner. We announced the outline of this project to 471
consecutive subjects undergoing primary shot of the BNT162b2
mRNA COVID-19 vaccination twice from April to May 2021 in
our hospital. Based on inclusion and exclusion criteria, healthy
subjects who were willing to participate in this study were

The Journal of Medical Investigation Vol. 70 2023

M. Izumi, et al. Pain following COVID-19 vaccination

356

included, and subjects who were diagnosed as having painful
shoulder disorders, neurological disorders, psychiatric diseases,
skin disorders at examination sites, and taking pain killers 24hours before the experiment were excluded. At first, 138 recipients were enrolled. Among them, 107 recipients had completed
6 consecutive sessions of pain assessments, one before the firstdose (1-0), 1-day after the first dose (1-1), 7-days after the firstdose (1-7), before the second dose (2-0), 1-day after the second
dose (2-1), 7-days after the second dose (2-7), and were finally
included in the analysis (Figure 1). We did phone interviews
later and confirmed that most dropouts happened due to theirpersonal reasons which were not associated with adverse eventsof the vaccination except for 2 recipients who had a high fever
1-day after the injection. Background of the participants was
summarized in Table 1. The study protocol was approved by theInstitutional Review Board of Kochi Medical School (No : 2020162). All participants received verbal explanation of the study
and provided written informed consent prior to the investigation.
This study was conducted in compliance with the Declaration of
Helsinki.
Table 1. Background of the study participants. Height, Body
weight, and BMI are presented as mean ± SD.
VariableN

107

Age (years)

44.1 ± 13.9

Sex, n (%)
Male

51 (48)

Female56 (52)Right-handed, n (%)

102 (95)

Height cm

163.7 ± 13.9

Body weight kg

62.2 ± 11.9

BMI kg/m2

23.1 ± 3.6

Injected side, n (%)
Left

100 (93)

Right

7 (7)

Vaccination
Vaccination was injected into the lower deltoid muscle using
a 25-gauge (25 mm length) needle at the level of axillary line,

which was a completely standardized technique to prevent
possible bursitis around the shoulder (10). Then, recipients were
given 15-minute rest to confirm that there was no acute adverse
event such as anaphylaxis. They were given 2 tablets of 300 mg
acetaminophen (Tylenol A®, Johnson and Johnson) available touse depending on their pain, and were asked the number of tablets used between the sessions. Three-week interval was secured
between the first and second dose. This vaccination protocol wasstandardized for all recipients throughout the study period.

Pain assessments
In each session, body temperatures were checked prior to
the assessment. Recipients indicated pain intensity at rest andduring active shoulder elevation on a 100 mm visual analogue
scale (VAS). The VAS was anchored with “no pain” and “worst
pain imaginable” at 0 mm and 100 mm, respectively. If the VAS
was 0 mm after the injection, we additionally interviewed when
their pain had disappeared. Recipients were also asked to markthe pain distribution by filling in a body chart. They confirmed
their ongoing pain at each session and drew the distribution
by themselves. The occurrence of pain in 5 different areas was
registered as depicted in Figure 2. Additionally, the quality ofpain was assessed using the Japanese version of the Short-Form
McGill Pain Questionnaire (SF-MPQ) (11) at the session 2-1.
They selected all words that would be suitable for describing
their pain quality.
For assessment of mechanical hyperalgesia around the injection site and remote area, a handheld algometer (Somedic,
Hörby, Sweden) with a 1-cm 2 probe was used to record thepressure pain threshold (PPT) on the bilateral deltoid muscle ofrecipients in a sitting position (Figure 3). Assessment site wasdetermined as a midpoint between the lateral edge of acromionand the injection site. Pressure was increased gradually at a rateof 30 kPa / s until the pain threshold was reached and the subjectpressed a button. The PPT was defined to the subject as ‘‘thetime point at which the pressure sensation changed into pain.’’
The recording was repeated 3 times with a minimum interval of
20s in each session. Trained physiotherapists assessed the PPTs
and mean value of the recordings was obtained. Then percentagechange of PPT (each PPT value was divided by baseline PPT at
1-0 × 100) was calculated and used for analyses. Distance fromthe lateral edge of acromion to the assessment site was measured
to ensure that PPTs were recorded on a similar site as possible
in each session.

Figure 1. Schematic time course of vaccinations and pain assessment sessions. Number of recipients

participated in each session and dropouts are also shown. 107 cases who completed 6 consecutive sessions
were finally included in the study.

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The Journal of Medical Investigation Vol. 70 August 2023

frequency of male and female participants who showed higher
pain VAS and wider pain distribution after the second dose than
the first one was analyzed using the Fishers’ exact test.
Effect of acetaminophen on pain VAS and PPTs at each session was analyzed using the Mann-Whitney U test. Correlations
among age, height, weight, BMI, body temperatures, pain VAS,
and PPTs were analyzed using the Spearman’s correlation coefficients. All analyses were performed with SPSS version 26.0
software (IBM Corp. Armonk, NY, USA) and P < 0.05 indicatedstatistical significance.
Figure 2. Patterns of pain distribution after the vaccination. ①
Well-localized around the injection site, ② Proximally spread withinupper arm, ③ Distally spread within upper arm, ④ Distally spreadbeyond the elbow, ⑤ Spread to neck and trunk. × : injection site

RESULTS
There were no life-threatening adverse events such as anaphylaxis and no recipients showed hives, swelling of mouth,
lips, tongue, or throat ; shortness of breath, wheezing, or chest
tightness ; or low blood pressure or loss of consciousness(14)throughout the study period. Eight recipients took acetaminophen (6 persons : 1 tablet, 2 persons : 2 tablets) from the firstdose to 1-1, while it was 57 recipients (19 persons : 1 tablet, 38
persons : 2 tablets) from the second dose to 2-1. The body temperature was significantly higher at 2-1 compared with the othersessions (Table 2). Nineteen recipients (17.8%) showed ≧ 37.5℃
at 2-1 while there were no recipients that presented such a fever
increase at the other sessions.

Pain intensity

Figure 3. Recording of pressure pain threshold (PPT) on the deltoid
muscle. Assessment site was determined as a midpoint between thelateral edge of acromion and the injection site (×).

Analysis
Body temperatures, pain VAS, and PPTs were not normally
distributed and analyzed by the Friedman test followed by the
Wilcoxon signed rank test with the Bonferroni collection. To
address the effects of acetaminophen use on the time course ofpain VAS and PPTs, additional Friedman tests were done after
adjustment of subjects with or without taking acetaminophen.
Difference of pain VAS and distribution of pain was investigatedbetween sessions after the first and second dose. According toprevious reports, clinically significant difference of pain VAS
was considered as > 13 mm (12, 13). Frequency of pain distribution patterns was analyzed using Fishers’ exact test. Also,

The pain VAS at rest and during active shoulder elevation
was significantly higher at 1-1 and 2-1 compared with theother sessions (Table 2). This result was the same after adjustment of subjects with or without taking acetaminophen. (restpain ; P < 0.0021, motion pain ; P < 0.012). The number (percentage) of recipients who had rest pain / motion pain / both restand motion pain, was 40 (37.4%) / 100 (93.5%) / 40 (37.4%) at 1-1,
and 44 (41.1%) / 97 (90.7%) / 43 (40.2%) at 2-1, respectively. No
recipients complained pain in the other sessions except for one
person at 2-7. The mean estimated duration for disappearance of
pain after the vaccination was 2.7 ± 1.3 days. Younger recipients
showed higher pain intensity at 1-1 (motion pain : r = -0.273,
P = 0.005), and at 2-1 (rest pain : r = -0.255, P = 0.009, motion
pain : r = -0.280, P = 0.004). Rest pain VAS at 2-1 was negatively correlated with height (r = -0.305, P = 0.001), but not withweight and BMI. Body temperatures were positively correlatedwith pain VAS at 2-1 (rest pain : r = 0.248, P = 0.012, motion
pain : r = 0.285, P = 0.004). There was no significant differenceof pain VAS between 1-1 and 2-1, but 45 participants (42.1%)
showed higher pain intensity (> 13 mm) in 2-1 than 1-1, andthis trend was more common in females compared with males(P = 0.033). Other background data were not associated with theworsening of pain between the sessions. The motion pain VAS at
2-1 was higher in recipients who received acetaminophen thanthose without (39.6 [32.8-46.4] vs 27.6 [22.2-33.1], P = 0.024).

Table 2. Median [interquartile range] of body temperature and shoulder pain VAS. * : P < 0.00003 compared with the other sessions.
†: P < 0.0003 compared with 1-0, 1-7, 2-0, and 2-7

Body temperature (℃)

1-0

1-1

1-7

2-0

2-1

2-7

36.3

36.3

36.4

36.4

36.6 *

36.4[36.2-36.5][36.2-36.5][36.2-36.5][36.2-36.5][36.4-37.3][36.2-36.5]

0 [0-0]0 [0-9]†0 [0-0]0 [0-0]0 [0-26]†

0 [0-0]Shoulder Pain VAS (mm)Rest
Active motion

0 [0-0]†25 [15-40]

0 [0-0]0 [0-0]35 [24-52]†

0 [0-0]M. Izumi, et al. Pain following COVID-19 vaccination

358
Pain distribution and quality

Patterns of pain distribution at 1-1 and 2-1 were summarizedin Table 3. Approximately, 90% of recipients showed localized
pain around the injection site or the spread pain within theupper arm, however, some cases demonstrated widespread pain
to the neck and trunk (beyond the arm). This pattern was similar between 1-1 and 2-1, but 21 recipients (19.6%) revealed wider
pain distribution in 2-1 than 1-1, and this trend was more common in females compared with males (P = 0.016). Other background data were not associated with the spread of pain between
the sessions. The most 5 common words describing the qualityof pain after vaccination were tender (36.1% of participants),
aching (15.6%), heavy (6.7%), sharp (6.7%), and throbbing (5.6%).
Table 3. Patterns of pain distribution after the first and second vaccination. Number of participants (percentage) are displayed.
Pain distribution

1st vaccination

2nd vaccination

P-valueNone

6 (5.6)6 (5.6)1.00①

66 (61.7)

63 (58.9)

0.78②

15 (14)8 (7.5)0.19③

14 (13.1)

15 (14)

1.00

②+③

0 (0)

4 (3.7)0.12( ① or ② or ③ ) + ④

1 (1)

0 (0)

1.00

( ① or ② or ③ ) + ⑤

5 (4.6)9 (8.4)0.41( ① or ② or ③ ) + ④ + ⑤

0 (0)2 (1.9)0.50

Pressure pain sensitivity
PPTs were recorded on the deltoid muscle where 3.2 ± 0.5 cm
distal from the lateral edge of acromion. The baseline value of
PPT at 1-0 [mean (95%CI)] was 293 (268-319) kPa on ipsilateralside and 316 (285-346) kPa on contralateral side. Percentagechange of PPTs at 1-1 and 2-1 was bilaterally (ipsilateral / contralateral) decreased to 87.4 / 89.4% and 80.6 / 91.0%, respectively,
however, this change was recovered to the baseline level at 1-7
and 2-7 (P < 0.05, Figure 4). There were no significant differences
between the PPTs at 1-1 and 2-1. This result was the same after
adjustment of subjects with or without taking acetaminophen.
(ipsilateral side ; P < 0.016, contralateral side ; P < 0.023). Age
was positively correlated with PPT on the ipsilateral deltoid at
2-1 (r = 0.200, P = 0.043). There were no significant correlations
between the percentage change of PPTs and pain VAS at 1-1 and
2-1, however, a weak negative correlation was found between

the baseline value of PPT at 1-0 on the ipsilateral side and motion pain VAS at 1-1 (r = -0.293, P = 0.002) and 2-1 (r = -0.223,
P = 0.021). PPT on ipsilateral deltoid was lower (i.e. more painful) in recipients who received acetaminophen than those without (68.1 [46.1-90.0] % vs 88.9 [83.2-94.6] %, P = 0.029) at 1-1.

DISCUSSION
This report mainly focuses on multiple domains of pain following primary shot of the BNT162b2 mRNA COVID-19 vaccination including pain intensity, distribution, quality, and pressure
pain sensitivity over time. All recipients were Japanese andmost of them were non-obese subjects. Since this is a novel mRNA-based vaccine than ever before, there is much concern about
misinformation focused on its adverse effects in social media(15), and that’s why we aimed to provide a rationale for possible
pain reaction based on a scientific approach.
In this series, most recipients showed mild-to-moderate pain
at rest and during shoulder motion, which was localized aroundthe injection site and disappeared within a few days. Younger
and shorter recipients tended to show higher pain intensity.
These findings were roughly consistent with published investigations with larger cohorts (8, 9). The age-related differences inlocal reactions can be explained by the varying levels of binding
antibodies, which were reportedly lower among seniors andolder adults (16). Similarly, non-obese status was significantly
associated with a greater frequency of post-vaccine side effects
and higher levels of antibody titers were detected in non-obese
participants compared with obese ones (17). Since most of theparticipant were non-obese Japanese in our study, shorterheight, but not weight and BMI, might be associated with worse
pain. Additionally, it became clear that the pain manifestation
was similar between the two injections overall, however, 40% ofrecipients reported higher pain intensity and 20% showed wider
pain distribution after the second dose compared with the firstone, and this trend was more common in females compared withmales.
Mechanisms underlying pain following COVID-19 vaccination is quite unclear, however, a plausible explanation isimmune-mediated inflammation due to a higher humoral response after exposure to the spike protein of SARS-CoV-2. In
fact, a recent observational study of over 600 healthy Japanesecohorts demonstrated that participants who experienced adverse
reactions (i.e., fever and general fatigue) demonstrated a higher
antibody titer after BNT162b2 vaccination than those without
adverse reactions (18). It could be speculated that subsequent

Figure 4. Mean (±  95% CI) of PPT recorded on ipsilateral (black circle) and contralateral (gray square) deltoid.
* : P < 0.05 compared with session 1-0, 1-7, 2-0, and 2-7

The Journal of Medical Investigation Vol. 70 August 2023
macrophage activation and cytokine-induced damage, whichwere considered as essential molecular mechanisms of pain due
to COVID-19 infection itself (5), would also contribute to the pain
after the vaccination. However, further research is required to
discuss the difference between the ‘infection-associated’ and‘vaccine-associated’ COVID-pain.
Cases of shoulder injury related to vaccine administration(SIRVA), defined as atypical shoulder pain and limited rangeof motion after vaccination, have been reported particularly in
the influenza vaccine (19, 20). SIRVA usually occurs due to an
inappropriate injection technique such as ‘‘too high” or ‘‘too deep”
needle insertion, which typically causes subacromial-subdeltoid
bursitis (21). Recently, there has been some case reports presenting similar condition following the COVID-19 vaccination(22-25). In addition, another very rare conditions with painful
shoulder such as the Personage-Turner syndrome (26) andpolymyalgia rheumatica (27) have also been reported after the
BNT162b2 mRNA vaccination. In this regard, our study demonstrated a typical time course and characteristics of pain after thenovel vaccination in detail, which will help differentiate diagnosing atypical pain conditions as above.
PPT has been widely used for assessing altered mechanistic
pain profile in musculoskeletal pain disorders (28). Interestingly,
PPTs were significantly decreased from the baseline value andnot only on the injected side but also on contralateral side at 1-1
and 2-1. In general, localized hyperalgesia may indicate tissue
damage and subsequent sensory dysfunction at peripheral level,
whereas widespread hyperalgesia to remote non-painful area
seems to be a proxy for abnormalities in central nervous systemprocessing (28). As far as we had investigated, there were noreports including quantitative assessment of mechanical hyperalgesia following COVID-19 and any other vaccines. Although
exact mechanisms of altered nervous system are unknown,
Widyadharma et al. (29) reported that COVID-19 virus enters
the brain circulation which facilitates the interaction of the virus
spike protein with angiotensin-converting enzyme 2 (ACE-2).
Then the virus come to the neuron, they will interact with theACE-2 receptor expressed in the neurons and lead to nervous
system damage. Fortunately, our experience was a temporary
phenomenon and recovered to the baseline value within a week,
however, bilateral mechanical hyperalgesia was quite uniquecharacteristics and it may partly explain underlying mechanisms of systemic myalgia that has been reported commonly
after the BNT162b2 mRNA vaccination (8, 30-32). In addition,
monitoring of PPT may help predicting motion pain intensity
after vaccination from the aspect of inherent mechanical pain
hypersensitivity. Furthermore, it may detect precursory symptoms of above-mentioned, abnormal shoulder pain condition
though further studies are warranted.
Higher pain VAS and lower PPTs were observed during thenext day for recipients who received acetaminophen than those
who did not, suggesting that more painful recipients would likely
receive the drug after the vaccination, but it was not so effective
for relieving the pain. Although the pain would be mild-to-moderate and disappear naturally within a few days in normal
course, it concerns some people who have excruciating pain after
the vaccination and an alternative drug should be discussed forthem.
Several limitations should be noted in this study such as asmall sample size with relatively young recipients, lack of standardization for acetaminophen use, lack of multivariate regression analysis for considering possible confounders, and a lack ofcomparison with another vaccines. There was a possibility thatparticipants received other analgesic medications by themselves
without reporting. However, this is a preliminary report with the
exploratory nature of the design focused on a timely topic, which359

will provide directions for further investigations.
In conclusion, temporary pain with mild-to-moderate intensity and localized distribution, concomitant with bilateralmechanical hyperalgesia on the deltoid muscle, were typicalcharacteristics of pain after the vaccination. This manifestation
was similar between the two injections overall, however, 40% ofrecipients reported higher pain intensity and 20% showed wider
pain distribution after the second dose compared with the firstone. Inherent mechanical pain hypersensitivity may predict motion pain intensity after the vaccination. These findings provide
a rationale for possible pain reaction after this novel vaccination,
which will be informative for future recipients.

DISCLOSURESThe authors have no conflicts of interest to declare.

AUTHORS’ CONTRIBUTION
Study design : M Izumi, TM, SO, NK, HS. Data collection : M
Izumi, TM, SO, DO, YH, TS, KO, AN, RS, YF. Data analysis : M
Izumi, TM, SO, M Ikeuchi. Drafting or revising manuscript : M
Izumi, TM, SO, NK, HS, M Ikeuchi. All authors made substantial contributions to conception and design, acquisition of data,or analysis and interpretation of data ; took part in drafting
the article or revising it critically for important intellectual content ; agreed to submit to the current journal ; gave final approval of the version to be published ; and agree to be accountable for
all aspects of the work.

ACKNOWLEDGEMENT
We are grateful to Shinichiro Kanda, Takaaki Sano, Misato
Nagao, Ryo Maehara, Sakura Yamaoka, Junpei Kamishima,
Hitomi Watanabe, Ayako Yoshimura, Matsuzaki Yuki, andYumi Takeda for their invaluable assistance regarding datacollection. We would also like to thank all participants who took
part in this study at Kochi Medical School Hospital.

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