Expert Opinion on Drug Safety

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Safety of mirogabalin and pregabalin in Japanesepatients with neuropathic pain: a retrospective
cohort study
Rie Nakajima, Nobuhiro Ooba, Miwako Kamei, Hajime Hashiba & Choichiro
Miyazaki
To cite this article: Rie Nakajima, Nobuhiro Ooba, Miwako Kamei, Hajime Hashiba &Choichiro Miyazaki (2023): Safety of mirogabalin and pregabalin in Japanese patientswith neuropathic pain: a retrospective cohort study, Expert Opinion on Drug Safety, DOI:
10.1080/14740338.2023.2193395
To link to this article: https://doi.org/10.1080/14740338.2023.2193395© 2023 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.

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EXPERT OPINION ON DRUG SAFETY
https://doi.org/10.1080/14740338.2023.2193395

ORIGINAL RESEARCH

Safety of mirogabalin and pregabalin in Japanese patients with neuropathic pain:a retrospective cohort study
Rie Nakajimaa, Nobuhiro Oobab

, Miwako Kameic,d, Hajime Hashibac and Choichiro MiyazakicaDepartment of Pharmacy Practice in Primary Care, Nihon University School of Pharmacy, Chiba, Japan; bDepartment of Pharmacoepidemiology,
Nihon University School of Pharmacy, Chiba, Japan; cJapan Pharmaceutical Association, Tokyo, Japan; dFaculty of Pharmaceutical Sciences, Teikyo
Heisei University, Tokyo, Japan
ABSTRACT

Background: Few studies have compared the safety risks between the gabapentinoids, pregabalin, andmirogabalin in post-marketing clinical settings. We assessed reported events associated with gabapen­
tinoid use in patients with neuropathic pain.
Research design and methods: We conducted a retrospective cohort study between September 2020and December 2020 using the community pharmacies records in Japan. The pharmacists identified newvs. prevalent users of mirogabalin and pregabalin in September 2020 and reported data regarding
baseline and adverse events to the Japan Pharmaceutical Association using web-based questionnaires.
The incidence of events and hazard ratio (HR) were consequently compared.
Results: New users of mirogabalin and pregabalin were identified (n = 1,650 and 2,244; mean age(SD): 69 (15) and 68 (16) years; women: 59% and 56%, respectively). Although serious events were
not reported, a marked difference in HRs of common adverse events, including somnolence (1.6),
dizziness (1.3), nausea (2.8), edema (3.1), and acetaminophen (2.0)/antidepressant (2.4) addition,
was observed.
Conclusion: No new serious safety concerns were found for mirogabalin and pregabalin use in patientswith neuropathic pain, although the HR of some events indicated increased risk among mirogabalinusers. However, further studies are needed as estimates for events occurring in small numbers withwide confidence intervals.

1. Introduction
Neuropathic pain is defined as pain caused by a lesion or diseaseof the somatosensory system [1]. The most common pattern is
distal sensory polyneuropathy (DSP), which typically reduces thequality of life (QOL) due to pain, gait instability, and associateddepression [2]. Neuropathic pain is relatively common amongolder individuals aged > 60 years and women [3]. Its prevalenceis 2.4%–10.9% in the Netherlands, 6.9% in France, and 14.6% in
the United States [4–8]. In Japan, the prevalence of neuropathic
pain in the general population with a mean age of 53 years is
3.2% [9], while that in the community-dwelling population witha mean age of 64 years is 5.2%, which is slightly higher [10]. In
addition, the incidence of neuropathic pain is higher in indivi­
duals aged 70–74 years than in those aged 20–39 years [11]. The
estimated proportion of the population aged > 65 years in
Europe and the United States (18.3% in 2020 to a projected22.2% in 2030) and Japan (28.4% in 2020 to a projected 30.9%
in 2030) is increasing [12]. Since neuropathic pain is associatedwith poor health status [13] and QOL both physically and men­tally regardless of pain intensity [14], therapeutic management
and monitoring of neuropathic pain may become essential in theolder population.

ARTICLE HISTORY

Received 29 November 2022
Accepted 15 March 2023
KEYWORDS

drug event monitoring;mirogabalin; pregabalin;
primary data collection;
retrospective cohort study

According to guidelines [15,16] and reviews [17,18], thegabapentinoid pregabalin is recommended as a first-line phar­macological treatment for neuropathic pain. Its analgesic
effect may be due to the reduction in excitatory neurotrans­mitter release and inhibition of synaptic transmission by bind­ing to the α2δ subunit of voltage-gated calcium channels [19].
Pregabalin is widely used in some countries, including Japan[20], Australia [21], and the United Kingdom [22]. Serious
adverse events may be rare; however, dizziness, peripheral
edema, somnolence, and weight gain are the most common
adverse events [23].
A novel selective ligand for the α2δ calcium channel
subunit, mirogabalin [24,25], was first approved for periph­eral neuropathic pain in Japan in 2019. In a study using rat
models of neuropathic pain [26], the analgesic effects ofmirogabalin were more potent and longer lasting thanand its safety indices were superior to those of pregabalin.
However, in randomized controlled studies comparing mir­ogabalin and pregabalin, the incidence proportion of som­nolence [27,28], dizziness [27,28], headache [27,28], nausea[27], vomiting [28], weight gain [27,28], peripheral edema[28], and constipation [27] were more frequent in the

CONTACT Nobuhiro Ooba
ooba.nobuhiro@nihon-u.ac.jp
Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, 274-8555, Chiba, Japan
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2193395© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

2

R. NAKAJIMA ET AL.

mirogabalin and pregabalin groups than in the placebogroup. Moreover, somnolence, dizziness, and weight gain
are described as important risk factors in the risk manage­
ment plan (RMP) for mirogabalin in Japan [29]. However,these events were more common with the use of pregabalinthan with that of a placebo in a previous study [30]. As
randomized controlled studies have strict inclusion andexclusion criteria, the generalizability of these findings may
be limited. Further, previous studies [27,28] mainly included
male patients with a mean age of approximately 60 years. In
addition, the follow-up period of these previous studies was
short (≤9 weeks) [27,28].
In real-world settings, the incidence of common adverse
events due to mirogabalin and pregabalin use may be incon­
sistent. Therefore, this retrospective cohort study involving
community pharmacists aimed to assess the safety of the
newly approved mirogabalin and pregabalin as active com­parators in a real-world setting.

patients who switched between the study drugs during thestudy period in the questionnaire. The study lasted for
4 months (1 September 2020, to 31 December 2020). Followup was conducted for at least 3 months after study drug
initiation. Patients who had never visited the pharmacy after
the date of study drug initiation were excluded because they
could not be followed up.
Using pharmacy records, including data on health insur­
ance, prescriptions (drug name, dispensing date, daily dose,and days’ supply), follow-up regarding effectiveness andadverse drug reactions during treatment by pharmacists, anddemographic data of patients, including information on cur­rent smoking status, alcohol consumption, over-the-counter(OTC) drug use, co-medications, and comorbidities, the phar­macists collected the baseline data for 6 months before study
drug initiation (baseline period).

2.2. Definition of events

2. Patients and methods
2.1. Study design
A retrospective cohort study with concurrent active control
using new-user design [31] to prevent bias, such as healthyuser bias and healthy adherer bias, in the schema of drug
event monitoring (DEM) by the Japan Pharmaceutical
Association (JPA) was conducted in February 2021. In thefiscal year 2020, of the 60,951 community pharmacies inJapan [32], 48,395 were affiliated with the JPA (as ofFebruary 2021), accounting for 79% of all pharmacies inJapan. The JPA sent paper-based questionnaires to all com­munity pharmacies. The questionnaires were completed bypharmacists working in 6,486 pharmacies affiliated with the
JPA. The questionnaires were used to identify all patientsusing the study drugs (mirogabalin or pregabalin), distinguishnew users from prevalent users, and collect baseline and event
data [33,34]. When data from the paper-based questionnaires
were entered into the web-based online form by pharmacists,
the personal information of patients was anonymized using
study identification data for each pharmacy, similar to that inprevious studies [33,34].
Among the 6,486 participating community pharmacies, 938
and 1,128 community pharmacies identified new users ofmirogabalin and pregabalin in September 2020, respectively,
based on pharmacy records. Patients who did not receive any
prescribed drugs from a given pharmacy before February 2020
were excluded from the total prevalent users. This is because
unless the patient is a regular user of the same pharmacy, the
6-month prescribing record for judging whether the patient is
a new user of the study drug is not available. Additionally, as
part of the overall study cohort, patients who started taking
the study drugs in September 2020 after a period (March–
August 2020) of using neither mirogabalin nor pregabalin
were deemed new users by pharmacists; new users [31] ofany study drug did not include patients who were prescribed
either study drug within 6-months period prior to
September 2020. To maintain comparability between groupsof study drug users, we asked pharmacists not to include

Using a methodology similar to that used in previous stu­
dies [33,34], we defined an event, including adverse events,
during the follow-up period as any suspected drug reaction,
unexpected deterioration in concurrent illness, or reasonsfor discontinuing the study drug (if discontinued) or addi­
tion of a new drug (if added). Information on add-on drugs
or drug discontinuation was considered to be complimen­
tary to event data. To encode events reported by pharma­cists, we used the Medical Dictionary for Regulatory
Activities (MedDRA) version 23. We selected the lowestlevel terms in MedDRA, which were converted to the pre­ferred term level and counted as an event [35]. In addition,
pharmacists reported data on events and their incidence
dates using pharmacy records.

2.3. Statistical analysis
Summary statistics for the overall cohort were used todescribe demographic characteristics (age, sex, alcohol con­sumption, current smoking status, OTC drug use, and historyof hospitalization), comorbidities (hypertension, diabetes mel­litus, dyslipidemia, myocardial infarction, cancer, and rheuma­
toid arthritis), and co-medications (antihypertensives,
antidiabetics, lipid-lowering drugs, antidepressants, hypnotic
drugs, antipsychotic drugs, antiulcerative drugs, steroid drugs
except those for external use, and antirheumatic drugs) during
the baseline period. To assess the difference in baseline char­acteristics between the groups, we calculated the standar­
dized difference [36]. When the absolute standardized
difference was > 0.1, the difference was considered important.
We calculated the incidence of events reported at least
once. The crude risk ratio (RR) of mirogabalin for the reported
total events was estimated and compared with that of prega­
balin as a reference. We then calculated the incidence of fiveor more events reported for either drug. However, serious
events were considered even if the number of reported eventswas fewer than five. In addition, if the same event wasreported more than once by the same patient, only the firstevent was counted. As somnolence and dizziness were

EXPERT OPINION ON DRUG SAFETY

preidentified risks in the RMP of mirogabalin, the time to onsetof these events was depicted using the Kaplan–Meier curveand compared using the log-rank test.
In the primary analysis of the overall cohort using a Cox
proportional hazards model, unadjusted, age–sex-adjusted,
and multivariate-adjusted hazard ratios (HRs) for common
events in both groups and their 95% confidence intervals(CIs) were estimated. The proportional hazards assumption
regarding the most frequently reported events was then con­firmed. To adjust the HR, we used covariates, including age,sex, comorbidities, and co-medications, as shown in
Supplementary Table S1. In addition, to estimate the multi­
variate-adjusted HR, logistic regression was used to calculate
the propensity score (PS) using baseline characteristics, suchas comorbidities and co-medications, and incorporate it asa covariate in our model; PS is a convenient and effective
tool for adjusting many covariates [37]. The observation period
for assessing an event was defined as the period from the dateof study drug initiation to the incidence date of the event,date of switching or discontinuation of the study drug, date ofaddition of the other study drug, last visit date, or
31 December 2020, whichever occurred first. For sensitivity
analyses, we created a PS-matched cohort (matched cohort)using 1:1 matching and the estimated HR. For matching, weused sex and PS as matching factors between the 2.5th and
97.5th percentiles of the PS for mirogabalin.
No statistical sample size calculations were conducted, as
new users (study population) were selected from all patientsprescribed study drugs during the time period to identify
study patients from September 2020 for prevention of selec­tion bias. However, the total sample size was estimated to be

3,550 assuming that the incidence proportion of event at
control group was 1.3% when α = 0.05, power = 0.8, andrelative risk = 2.0. Statistical significance was set at p < 0.05.
All analyses were performed using SAS 9.4 (SAS Institute Inc.,
Cary, NC, USA).

2.4. Ethical consideration
This retrospective cohort study was performed in accordancewith the principles of the Declaration of Helsinki, and thestudy protocol was approved by the ethics review committeeof the JPA (no. 2020–001), which waived the need for indivi­
dual informed consent because the study data were fully
anonymized.

3. Results
In total, 9,182 and 26,504 prevalent users of mirogabalin andpregabalin, respectively, were identified in September 2020.
Among them, 1,650 (18%) and 2,244 (9%) patients wereselected as new users of mirogabalin and pregabalin,respectively.

3.1. Patient characteristics
Table 1 shows baseline characteristics of new users of thestudy drugs. In the overall cohort, the mean age (SD) andproportion of women were 68.7 (14.7) years and 58.6%,
respectively, for mirogabalin users and 68.1 (15.5) years and56.1%, respectively, for pregabalin users. The mean follow-up

Table 1. Baseline characteristics of new users of mirogabalin or pregabalin.
Matched cohorta

Overall cohort

Mean age, years (SD)
Women (%)
Mean follow-up period (days)
Mean daily dose
Current smoking (%)
Yes
Missing
Alcohol consumption (%)
Yes
MissingOver-the-counter drug
History of hospitalization
Comorbidity (%)
Hypertension
Diabetes mellitus
Dyslipidemia
Myocardial infarction
CancerRheumatoid arthritis
Co-medication (%)
Antihypertensives
Antidiabetics
Lipid-lowering drugs
Antidepressants/hypnotic drugs/antipsychotic drugs
Antiulceratives
Steroids except those for external use
Antirheumatic drugs except methotrexate
MethotrexateaMirogabalin Pregabalin
Mirogabalin Pregabalin(n = 1,650) (n = 2,244) Standardized difference (n = 1,532) (n = 1,532) Standardized difference
68.7 (14.7) 68.1 (15.5)
0.039
68.4 (4.6) 67.7 (15.6)
0.049
967 (58.6) 1,260 (56.1)
0.050
891 (58.2) 891 (58.2)
88.4
88.8
87.8
87.7
8.0
76.2
8.0
75.5
181 (11.0)
282 (17.1)

269 (12.0)
388 (17.3)−0.032−0.005169 (11.0)
264 (17.2)

154 (10.1)
256 (16.7)

0.032
0.014

415 (25.2)
290 (17.6)
30 (1.8)
20 (1.2)

561 (25.0)
403 (18.0)
41 (1.8)45 (2.0)

0.004−0.010−0.001−0.063394 (25.7)
273 (17.8)
28 (1.8)
9 (0.6)385 (25.1)
262 (17.1)
16 (1.0)
11 (0.7)

0.014
0.019
0.066
−0.016784 (47.5)
238 (14.4)
481 (29.2)
31 (1.9)109 (6.6)
41 (2.5)

1,100 (49.0)
367 (16.4)
667 (29.7)
55 (2.5)
113 (5.0)
56 (2.5)−0.030−0.054−0.013−0.0390.067−0.001736 (48.0)
219 (14.3)
456 (29.8)
24 (1.6)
51 (3.3)
17 (1.1)

734 (47.9)233 (15.2)
470 (30.7)
19 (1.2)
47 (3.1)
11 (0.7)

0.003−0.026−0.020
0.028
0.015
0.041

789 (47.8)235 (14.2)
490 (29.7)
273 (16.5)
356 (21.6)
490 (29.7)
45 (2.7)
15 (0.9)

1,111 (49.5)
364 (16.2)
695 (31.0)
397 (17.7)
569 (25.4)
619 (27.6)
86 (3.8)
33 (1.5)−0.034−0.055−0.028−0.030−0.0890.047−0.062−0.052741 (48.4)
217 (14.2)
459 (30.0)
255 (16.6)
313 (20.4)
457 (29.8)
23 (1.5)
7 (0.5)737 (48.1)
238 (15.5)
481 (31.4)
244 (15.9)309 (20.2)
447 (29.2)
19 (1.2)
3 (0.2)0.005−0.039−0.031
0.019
0.007
0.014
0.023
0.046

1:1 matching by propensity score and sex was conducted.

34R. NAKAJIMA ET AL.

period was approximately 90 days for both drugs. Among
women in both groups, history of hospitalization; diabetes
mellitus; cancer; and use of antidiabetic, antiulcerative, anti­
rheumatic drugs other than methotrexate, and methotrexate
showed absolute standardized differences of approximately
0.1 (i.e. dissimilarities between groups were evident).

3.2. Proportion and reason for discontinuation
The proportions of drug discontinuation were 36.4% (n = 600)
and 35.2% (n = 790) in the mirogabalin and pregabalingroups, respectively. The crude RR for discontinuation of mir­ogabalin was 1.03 (95% CI: 0.95–1.12). The crude RRs for
improvement, any suspected adverse drug reaction, and lackof effectiveness as reasons of drug discontinuation were 0.99
(95% CI: 0.84–1.17), 1.09 (95% CI: 0.84–1.41), and 1.22 (95% CI:
0.88–1.68), respectively.

3.3. Incidence of events
The incidence of adverse drug reactions reported at least once
was 30.2% for mirogabalin and 26.5% for pregabalin. The
crude RR for any adverse reaction to mirogabalin was 1.10
(95% CI: 1.03–1.18) and was compared with that of pregabalin
as reference. For mirogabalin and pregabalin, the incidencesof reported events, HR, and its 95% CI are shown in Table 2. In
mirogabalin users, preexisting conditions improved (14.7%),
and somnolence (7.1%) and dizziness (6.8%) were most fre­quently reported, while in pregabalin users, preexisting condi­
tions improved (15.7%), and nonresponse to therapy (5.8%)

and dizziness (5.3%) were most frequently reported. No ser­ious events were reported in either group of patients.

3.4. Preidentified important risks in RMP
The Kaplan–Meier curves for time to onset of somnolence(p < 0.001 for log-rank test) and dizziness (p = 0.03 for logrank test) for each study drug are shown in Figure 1. The
hazard function for the time to these events showeda considerable difference throughout the follow-up period.

3.5. Comparison of common events between study drugs
Table 2 shows the unadjusted, age–sex-adjusted, and multi­
variate (PS)-adjusted HRs for events with mirogabalin com­pared with those with pregabalin as reference. The
incidence of somnolence (HR = 1.60; 95% CI: 1.23–2.09),
dizziness (HR = 1.31; 95% CI: 1.01–1.70), nausea(HR = 2.81; 95% CI: 1.48–5.33), edema (HR = 3.06; 95% CI:
1.25–7.54), and hypoesthesia (HR = 3.32; 95% CI: 1.04–10.63)
was considerably higher among mirogabalin users thanamong pregabalin users. HR for common events adjusted
by PS only and that adjusted by multiple confounders weresimilar (Supplementary Table S1).

3.6. Comparison of common events for any add-on
drugs
Table 3 shows the unadjusted, age–sex-adjusted, and multi­
variate (PS)-adjusted HRs for the incidence of add-on drug

Table 2. Incidence and HR of common events reported among mirogabalin and pregabalin users.
Overall cohort
Event (%)
Preexisting condition improved
Somnolence
Dizziness
Therapy nonresponder
NauseaPain
Edema
Constipation
MalaiseTherapeutic response decreased
Therapy cessation
Abdominal discomfort
Fall
Blood pressure increased
Feeling abnormal
Hypoesthesia
Back pain
Diarrhea
Peripheral edema
Weight gain
HeadacheDry mouth
Vomiting

Mirogabalin(n = 1,650)
243 (14.7)
117 (7.1)
112 (6.8)
99 (6.0)29 (1.8)
21 (1.3)
15 (0.9)9 (0.5)8 (0.5)7 (0.4)7 (0.4)6 (0.4)6 (0.4)7 (0.4)6 (0.4)10 (0.6)
6 (0.4)6 (0.4)4 (0.2)4 (0.2)4 (0.2)3 (0.2)1 (0.1)Pregabalin(n = 2,244)
353 (15.7)
102 (4.5)
119 (5.3)
130 (5.8)
14 (0.6)30 (1.3)
7 (0.3)11 (0.5)
9 (0.4)8 (0.4)15 (0.7)
9 (0.4)3 (0.1)13 (0.6)
7 (0.3)4 (0.2)5 (0.2)6 (0.3)3 (0.1)6 (0.3)3 (0.1)2 (0.1)3 (0.1)

Unadjusted HRa(95% CI)
0.96 (0.82–1.13)
1.61 (1.23–2.10)
1.31 (1.01–1.69)
1.06 (0.82–1.38)
2.85 (1.51–5.40)
0.98 (0.56–1.71)
3.02 (1.23–7.41)
1.14 (0.47–2.75)
1.24 (0.48–3.20)
1.23 (0.44–3.38)
0.65 (0.26–1.59)
0.93 (0.33–2.61)
2.76 (0.69–11.02)
0.75 (0.30–1.88)
1.18 (0.40–3.52)
3.53 (1.11–11.27)
1.70 (0.52–5.55)
1.38 (0.45–4.27)
1.87 (0.42–8.37)
0.93 (0.26–3.31)
1.85 (0.41–8.28)
2.09 (0.35–12.53)
0.45 (0.05–4.35)

Age–sex-adjusted
HRa (95% CI)
0.96 (0.81–1.13)
1.61 (1.23–2.10)
1.29 (1.00–1.67)
1.07 (0.83–1.39)
2.79 (1.48–5.28)
0.99 (0.56–1.72)
3.02 (1.23–7.40)
1.13 (0.47–2.73)
1.20 (0.46–3.12)
1.28 (0.47–3.55)
0.65 (0.26–1.59)
0.92 (0.33–2.60)
2.58 (0.64–10.38)
0.79 (0.31–1.98)
1.16 (0.39–3.44)
3.66 (1.15–11.67)
1.80 (0.55–5.92)
1.39 (0.45–4.32)
1.90 (0.43–8.49)
0.92 (0.26–3.28)
1.80 (0.40–8.05)
2.04 (0.34–12.19)
0.44 (0.45–4.24)

CI: confidence interval, HR: hazard ratio, a with pregabalin users as reference. b Adjusted by propensity score.

Matched cohort
Multivariateb-adjusted
HRa (95% CI)
0.95 (0.80–1.11)
1.60 (1.23–2.09)
1.31 (1.01–1.70)
1.09 (0.84–1.41)
2.81 (1.48–5.33)
0.94 (0.54–1.65)
3.06 (1.25–7.54)
1.11 (0.46–2.70)
1.28 (0.49–3.32)
1.29 (0.47–3.59)
0.70 (0.28–1.71)
0.93 (0.33–2.63)
2.96 (0.73–11.91)
0.80 (0.32–2.01)
1.21 (0.40–3.62)
3.32 (1.04–10.53)
1.59 (0.48–5.25)
1.38 (0.44–4.30)
2.07 (0.46–9.33)
0.87 (0.24–3.09)
1.71 (0.38–7.69)
2.24 (0.37–13.53)
0.49 (0.05–4.78)

Unadjusted
HRa (95% CI)
0.99 (0.83–1.18)
1.58 (1.18–2.13)
1.27 (0.94–1.72)
1.12 (0.83–1.51)
2.72 (1.31–5.63)
0.93 (0.51–1.69)
4.48 (1.27–15.78)
1.15 (0.44–3.01)
0.88 (0.29–2.63)
1.03 (0.36–2.95)
0.46 (0.16–1.33)
0.58 (0.17–1.99)
Not presented
1.19 (0.40–3.57)
1.21 (0.37–3.96)
1.81 (0.53–6.18)
2.06 (0.52–8.23)
1.27 (0.34–4.71)
4.09 (0.46–36.44)
0.82 (0.22–3.09)
0.68 (0.11–4.09)
1.53 (0.26–9.17)
1.00 (0.06–16.00)

EXPERT OPINION ON DRUG SAFETY

5

Figure 1. Cumulative incidence of (a) somnolence and (b) dizziness among mirogabalin and pregabalin users HR: hazard ratio; CI: confidence interval.

administration with mirogabalin compared with those withpregabalin as reference. Nonsteroidal anti-inflammatory
drugs (2.4%), antacids (1.6%), acetaminophen (1.3%), andantidepressants (1.3%) were most frequently administered as
add-on drugs in the mirogabalin group, whereas nonsteroidal
anti-inflammatory drugs (2.5%), antacids (1.4%), and opioids(1.4%) were most frequently administered as add-on drugs in
the pregabalin group. The events of addition of acetamino­
phen (HR = 1.95, 95% CI: 1.01–3.77) and antidepressants(HR = 2.42, 95% CI: 1.19–4.93) were significantly (p < 0.05)
higher for mirogabalin users than for pregabalin users. HR ofcommon events for any add-on drugs adjusted by PS only andthat adjusted by multiple confounders were similar(Supplementary Table S2).

3.7. Sensitivity analysis using the matched cohort
To assess the consistency of our results, we conducteda similar analysis to the main analysis using the PS-matchedcohort. Among the baseline characteristics of the matchedcohort, only the absolute standardized difference of OTC
drug use was approximately 0.1 (Table 1). Compared withthose associated with pregabalin use as reference, the eventsof somnolence (HR = 1.58, 95% CI: 1.18–2.13), nausea(HR = 2.72, 95% CI: 1.31–5.63), edema (HR = 4.48, 95% CI:
1.27–15.78), addition of acetaminophen (HR = 2.49, 95%

CI: 1.03–6.03), and addition of antidepressants (HR = 2.14,
95% CI: 1.03–4.44) were more associated with mirogabalin use.

4. Discussion
We conducted a retrospective cohort study on the safety ofmirogabalin and pregabalin using the DEM project conducted
in 2020 by the JPA. In clinical settings, the crude RR for any
adverse drug reaction was higher (RR = 1.10, 95% CI: 1.03–
1.18) for mirogabalin users than for pregabalin users, although
the crude RR for drug discontinuation was similar between
both groups. In particular, the events of somnolence, dizzi­
ness, nausea, edema, addition of acetaminophen, and additionof antidepressants were more associated with mirogabalin use
in the overall cohort. If mirogabalin is initiated for neuropathic
pain, patients should be counseled and actively monitored by
medical staff and family members.
In Japan, somnolence and dizziness have been identified
as important risks in RMP for mirogabalin. In randomized
trials between mirogabalin and placebo, the crude RR ofmirogabalin for somnolence and dizziness was 2.2–2.8 and2.1–2.3, respectively [38,39]. These events were most com­monly reported in a review of clinical trials for pregabalin [40]and in mirogabalin studies [38,39]. In randomized trials car­ried out in the United States as well as in Asian countries,
including Japan, the crude RR for somnolence and dizziness

Table 3. Incidence and HR for any add-on drug reported for mirogabalin and pregabalin users.
Overall cohort
Add-on drug (%)
Nonsteroidal antiinflammatory drug
Antacid
Acetaminophen
AntidepressantsOpioidAntiepileptic
Vitamin B12
Laxative
Antiulcerative
Anticoagulant
Diuretic

Mirogabalin Pregabalin(n = 1,650) (n = 2,244)
39 (2.4)
55 (2.5)
26 (1.6)
22 (1.3)
21 (1.3)
19 (1.2)
13 (0.8)
12 (0.7)
10 (0.6)
9 (0.5)7 (0.4)5 (0.3)32 (1.4)
15 (0.7)
12 (0.5)
32 (1.4)
8 (0.4)13 (0.6)
12 (0.5)
13 (0.6)
8 (0.4)3 (0.1)

Matched cohort

Unadjusted HRa(95% CI)
0.99 (0.66–1.49)

Age–sex-adjusted H a(95% CI)
1.01 (0.67–1.52)

Multivariateb-adjusted HRa(95% CI)
1.00 (0.66–1.51)

Unadjusted HRa(95% CI)
0.97 (0.63–1.50)

1.14 (0.68–1.91)
2.06 (1.07–3.97)
2.44 (1.20–4.95)
0.82 (0.47–1.45)
2.28 (0.94–5.49)
1.29 (0.59–2.83)
1.16 (0.50–2.68)
0.96 (0.41–2.25)
1.23 (0.45–3.40)
2.38 (0.57–9.97)

1.14 (0.68–1.92)
2.09 (1.09–4.03)
2.47 (1.21–5.02)
0.84 (0.48–1.48)
2.29 (0.95–5.52)
1.27 (0.58–2.79)
1.17 (0.51–2.71)
0.97 (0.42–2.27)
1.32 (0.48–3.64)
2.59 (0.62–10.90)

1.16 (0.69–1.95)
1.95 (1.01–3.77)
2.42 (1.19–4.93)
0.83 (0.47–1.46)
2.28 (0.94–5.53)
1.22 (0.55–2.68)
1.14 (0.49–2.64)
1.06 (0.45–2.49)
1.21 (0.44–3.34)
2.45 (0.58–10.30)

0.98 (0.57–1.71)
2.49 (1.03–6.03)
2.14 (1.03–4.44)
0.69 (0.37–1.28)
2.22 (0.84–5.84)
0.84 (0.35–2.03)
1.02 (0.40–2.57)
1.02 (0.38–2.72)
2.07 (0.52–8.30)
1.75 (0.42–7.36)

CI: confidence interval, HR: hazard ratio, a with pregabalin users as reference. b Adjusted by propensity score.

6

R. NAKAJIMA ET AL.

was directly compared between mirogabalin and pregabalinusers and was found to be similar between both groups[27,28]. However, in our retrospective cohort study, using
pregabalin users as a reference, the risk of somnolence inmirogabalin users was high in the overall (HR = 1.60, 95%CI:
1.23–2.09) and matched (HR = 1.58, 95% CI: 1.18–2.13)
cohorts. Additionally, the risk of dizziness in mirogabalinusers tended to increase in the overall (HR = 1.31, 95% CI:
1.01–1.70) and matched (HR = 1.27, 95% CI: 0.94–1.72)
cohorts. Although further studies are needed to evaluate
the risk between these groups, the study population in ran­domized trials [27,28] was slightly younger, included fewer
women, and had a shorter follow-up period than that in ourstudy, which may have contributed to these findings.
No significant difference in the risk of headache, vomiting,constipation, peripheral edema, and weight gain (a preidenti­
fied risk) was found between groups; however, the risk ofnausea was higher in mirogabalin users than in pregabalinusers (HR = 2.81, 95% CI: 1.48–5.33 in the overall cohort). Ina real-world setting, medical staff might need to monitor
nausea development in mirogabalin users, although thesefindings differed between the present study and previous
randomized trials [27,28].
The additional risk of requiring acetaminophen (HR = 1.95,
95% CI: 1.01–3.77) and antidepressants (HR = 2.42, 95% CI:
1.19–4.93) was higher among mirogabalin users than amongpregabalin users. However, the reason why acetaminophen
requirement for mirogabalin users was high is unclear.
According to a study by Acker et al., patients with neuropathic
pain administered acetaminophen for painful neuropathic
symptoms [14]. Acetaminophen may enhance the analgesic
activity of anti-neuropathic drugs [41], although no highquality reports represent the association of acetaminophenwith neuropathic pain [16]. On the other hand, antidepres­sants are commonly used as first-line drugs in patients withneuropathic pain [15,17,18]. Since antidepressants are highly
effective in reducing pain [42], they may be prescribed as pain
relievers [14]. Therefore, antidepressants might have been
added in situations where monotherapy was insufficient [43],although the concomitant use of the drug at baseline wassimilar in both groups.
This study has several strengths. First, this was a postmarketing cohort study with a mean follow-up period of
3 months that used primary data from community pharmacies
to compare the incidence of any adverse drug reaction
between mirogabalin and pregabalin users. Previous phase 2
randomized trials comparing mirogabalin and pregabalinusers in the United States had a follow-up period of 5–
7 weeks [27,28]. Second, to prevent channeling bias, we
excluded patients with a history of mirogabalin or pregabalin
use within 6 months before the date of study drug initiation.
In a previous cohort study [44], patients who were switchedfrom pregabalin to mirogabalin had a high incidence of som­nolence and dizziness, although the incidence of peripheral
edema was low. However, in a retrospective cohort study ofpatients who switched from pregabalin to mirogabalin,patients who discontinued mirogabalin had a higher incidenceof dizziness (p = 0.01) and edema (p = 0.02) than those who
continued to use mirogabalin [45]. In addition, incidence ofsomnolence (p = 0.84) was not significant regardless of mir­ogabalin continuation/discontinuation [45]. Had patients forwhom the drugs were switched been not excluded from ourstudy population, appropriate comparison of the incidence of
events between the groups might have been difficult.
This study, however, has some limitations. First, the dose
relationship for individual events could not be considered inthis study. As our study population involved new users of thestudy drugs, the mean doses of both study drugs were low.
Further studies with larger sample sizes and longer follow-up
periods are needed to assess the association between doses
and events. Second, baseline characteristics may have differed
between the groups as the absolute standardized difference insome variables was approximately 0.1. Therefore, we esti­
mated adjusted HR using many confounders (Supplementary
Tables S1 and S2). In addition, we created a matched cohort
using PS and sex matching for sensitivity analysis andobtained almost the same findings as those of the main
analysis in the overall cohort. However, there might be resi­
dual confounding. Third, the proportions of older patients andwomen were higher in our study population compared withthose of study populations of previously reported randomized
trials [27,28]. Therefore, the generalizability of our findings toyoung patients and men may be limited. However, the popu­
lation is likely to be representative of the target population in
the real world as neuropathic pain is relatively common
in older individuals (aged >60 years) and women [3]. Fourth,in patients taking co-medications, it is up to the pharmacist at
each pharmacy to decide whether this is an event; thus,
events from concomitant medications may be misinterpreted
as events due to the study drug. However, if there is a similar
degree of misinterpretation between new users of study drug,
the effects may be offset.

5. Conclusions
No new serious safety concerns were found regarding theuse of mirogabalin or pregabalin. However, the crude RR
for any adverse drug reaction was higher among miroga­
balin users than among pregabalin users. In addition, therisk of common events, such as somnolence, dizziness,
nausea, edema, addition of acetaminophen, and additionof antidepressants, was higher with mirogabalin use thanwith pregabalin use. In patients with neuropathic pain who
are newly administered mirogabalin, monitoring of such
events by medical staff will contribute to the enhancementof clinical care in real-world clinical settings.

Acknowledgments
The authors sincerely thank the participating pharmacists for providing
data. We would also like to express our gratitude to the staff of the Japan
Pharmaceutical Association for data collection and management.

Funding
This work was supported by the Japan Pharmaceutical Association.

EXPERT OPINION ON DRUG SAFETY

Abbreviations
DEM, drug event monitoring; CI, confidence interval; HR, hazard ratio; JPA,
Japan Pharmaceutical Association; MedDRA, Medical Dictionary forRegulatory Activities; OTC, over-the-counter; PS, propensity score; RMP,
risk management plan; RR, risk ratio

Declaration of interest
The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in this manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, and royalties.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or otherrelationships to disclose.

Author contributions
All authors were involved in the conception and design of this study.
Nakajima and Ooba analyzed and interpreted the data. All authors criti­
cally reviewed the manuscript, revised the paper for intellectual content,
provided detailed feedback, read and approved the final manuscript, andagreed to be accountable for all aspects of this work.

Data availability
The data used to support the findings of this study have not been madepublicly available due to patient privacy or ethical restrictions by theJapan Pharmaceutical Association Ethics Committee.

ORCID
Rie Nakajima
http://orcid.org/0000-0002-1986-9086
Nobuhiro Ooba
http://orcid.org/0000-0003-0579-3946

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