Association of nefopam use with postoperative nausea and vomiting in gynecological patients receiving prophylactic ramosetron: A retrospective study
Association of nefopam use with postoperative nausea and vomiting in gynecological patients receiving prophylactic ramosetron: A retrospective study
Sun-Kyung Park 0 1
Seokha Yoo 0 1
Won Ho Kim 0 1
Young-Jin Lim 0 1
Jae-Hyon Bahk 0 1
Jin-Tae Kim 0 1
0 Editor: Wataru Nishimura, International University of Health and Welfare School of Medicine , JAPAN
1 Department of Anesthesiology and Pain Medicine, Seoul National University Hospital , Seoul , Republic of Korea
The combined use of nefopam with fentanyl in IV PCA was not associated with the higher
incidence of PONV compared with the use of ketorolac and fentanyl combination in patients
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
who received ramosetron as PONV prophylactic agent. However, prospective trials are
required for a confirmative conclusion.
Postoperative analgesia is important to achieve patient rehabilitation and satisfaction.[
Intravenous patient-controlled analgesia (IV PCA) is widely used in patients undergoing surgery
with moderate to severe postoperative pain.[
] Opioids play a pivotal role in the management
of postoperative pain with IV PCA,[
] and fentanyl is a commonly used opioid in IV PCA,
providing potent analgesia. However, fentanyl is associated with a high incidence of
postoperative nausea and vomiting (PONV), which varies from 20% to 60% according to the literature.
 PONV is related to undesirable consequences, such as pulmonary aspiration, dehiscence of
surgical wounds, dissatisfaction of patients, and delayed recovery.[
] As opioids alone
require a high dose to achieve sufficient analgesia and can cause undesirable side effects,
multimodal or balanced analgesia has been suggested. The basic concept for multimodal
analgesia is that by using analgesic agents with different mechanisms of action in combination,
dosage and side effects of each medicine can be minimized.[
Nefopam, a centrally acting non-opioid analgesic drug, has emerged as a good candidate
for inclusion in multimodal analgesia.[
] Nefopam exerts anti-nociceptive effects by inhibiting
the synaptosomal reuptake of serotonin, dopamine, and norepinephrine.[4,9±11] Nefopam
has been reported to be effective in postoperative pain control with an opioid-sparing effect.
] However, nefopam itself can induce PONV according to some studies,[
] and there
is relatively little information on the effect of nefopam on PONV when used in combination
Ramosetron, a selective 5-HT3 receptor antagonist, is widely used for the prevention and
treatment of PONV. A previous trial showed that ramosetron was more effective than
ondansetron in preventing vomiting and decreasing nausea related to fentanyl-based IV PCA. [
However, no study has reported the use of ramosetron with nefopam-containing IV PCA.
Considering that the antinociceptive effect of nefopam involves the inhibition of the
synaptosomal reuptake of serotonin, the combination of ramosetron and nefopam can theoretically
manifest in a mutually contrasting effect on 5-HT3 receptors. In that scenario, the antagonistic
interaction between nefopam and ramosetron might attenuate the analgesic effects of nefopam
or antiemetic effect of ramosetron. Although a previous study revealed that concomitant use
of ondansetron and nefopam had no antagonistic interaction, [
] no study has evaluated the
clinical consequence when ramosetron and nefopam are used concurrently.
Therefore, the aim of our study was to examine whether nefopam was associated with the
higher incidence of PONV in gynecological patients who received ramosetron for PONV
prophylaxis. To achieve this aim, we conducted a retrospective cohort study of the patients who
used IV PCA containing fentanyl either with or without nefopam after gynecological surgery.
Materials and methods
Ethical approval for this study [IRB No. H-1610-056-798] was obtained from the Institutional
Review Board of Seoul National University Hospital, Seoul, Korea. Written informed consent
was waived because of the retrospective nature of the study. Because all data in the present
study were obtained retrospectively from electronic medical records, the study was not
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publicly registered before collecting data. Our retrospective observational study is compliant
to STROBE checklist (S1 Checklist). We reviewed the electronic medical records of 296
patients undergoing gynecological surgery between April 25, 2016 and July 4, 2016. We
enrolled all patients who met the eligible criteria during the study period. Inclusion criteria
were adult patients (age 18 years) who had used IV PCA after gynecological surgery under
general anesthesia during the study period. Gynecological surgeries included laparoscopic
ovarian cystectomy, laparoscopic salpingo-oophorectomy, laparoscopic hysterectomy,
laparoscopic myomectomy, total abdominal hysterectomy, abdominal myomectomy, and vaginal
hysterectomy. The exclusion criteria were patients with inadequate medical records, those
who had maintained their use of IV PCA for less than 2 days, and those with a hospital stay of
less than 2 days.
The regimen of IV PCA in the present study was not determined for research purposes and
the analysis was performed retrospectively. Before May 29, 2016, IV PCA in our institution
consisted of fentanyl and ketorolac. On May 30, 2016, the IV PCA regime was changed to
nefopam and fentanyl. As the potency of nefopam 20mg lies in the range of morphine 6±12
mg according to previous literature,[10,18±21] we assumed that nefopam 20mg was
equipotent with morphine 9 mg. Because ketorolac 30 mg was reported to equipotent with morphine
12 mg, [
] and the regimen was determined based on the assumption that the analgesic
potency of nefopam 80 mg was equipotent to that of ketorolac 90 mg. The regimen of IV PCA
before and after the change is described in Table 1. Patients who used IV PCA, including
nefopam were labeled as Group N (nefopam group), and those who used IV PCA without nefopam
were labeled as Group K (ketorolac group). The dosage of fentanyl was same in both groups.
For all patients, the IV PCA was set to provide a continuous infusion of 1 mL/h, 1 mL bolus,
and 15 minutes of lockout time. Every patient received 0.3 mg IV of ramosetron at the end of
surgery for PONV prophylaxis according to the PONV guideline.[
] Rescue antiemetic
treatment (ondansetron 4 mg IV) was additionally provided at the discretion of the attending
physicians in response to vomiting or severe nausea or patient's request. Ketorolac 30 mg IV or
tramadol 100 mg IV was provided as rescue analgesics at the discretion of the attending
The primary endpoint was the incidence of PONV during the 3-day postoperative period.
Secondary outcomes included the incidences of PONV on the operation day, postoperative day
(POD) 1, and POD 2, and pain scores assessed by a numeric rating scale (NRS; 0 = no pain,
10 = maximum pain imaginable) at the same time points, the median NRS score during the
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3-day postoperative period, the occurrence of clamping of IV PCA during the 3-day
postoperative period, the number of patients who received antiemetic agents during the 3-day
postoperative period, and the timing of antiemetic agents were administered. Data on the
administration of rescue analgesic agents were also collected. All outcome measures were
routinely checked by ward nurses. The ward nurses performed the regular assessments on whether
the patient suffered from nausea or not every 6 hours, and assessed the severity degree of
nausea using 3-point scale (mild, moderate, or severe). If the patient complained of nausea before
the nurse's regular assessment, it was also recorded. Demographic data, length of hospital stay,
and baseline clinical parameters which were previously identified as risk factors for PONV,
were included in our study. The factors included a history of PONV, nonsmoking status,
history of motion sickness, history of migraine, duration of surgery, use of volatile anesthetics,
laparoscopic surgery, and intraoperative opioid use. Digestive diseases before surgery were
Sample size determination
A clinically significant difference was considered to be a difference of 15% in the incidence of
PONV. The sample size calculation was based on a preliminary survey conducted in our
institution. The preliminary survey reported that the incidence of PONV during the 3-day
postoperative period in gynecological patients was 30%. Thus, for α risk of 0.05 and β risk of 0.20, we
needed to enroll at least 242 patients (121 patients per group) for testing two-sided equality
(PASS software 2008 ver. 8.0.16; NCSS statistical software, Kaysville, UT, USA). We decided to
include 290 patients to account for exclusions because of insufficient documentations. The
calculated sample size was also validated for the multivariable logistic regression analysis
according to the rule that outcome events should be ten per each independent predictor.[
] For this
study, it was estimated that 266 patients or more are necessary to permit unbiased
accommodation of eight or fewer predictive variables in a multivariable logistic regression model (under
the estimated 30% incidence of PONV). In addition, under the observed 26.0% incidence of
PONV in 296 patients (i.e., 77 cases of outcome events), it allowed us to include up to 7
variables in our multivariate model based on the rule of requiring 10 cases with the outcome of
interest for every variable in the model.
Categorical variables were reported as absolute number (n) and relative frequencies (%), and
compared using the χ2 test or Fisher's exact test according to their expected counts.
Continuous variables were reported as mean (standard deviation) or median [interquartile range] and
tested for their normal distribution by the Kolmogorov±Smirnov test. After the normality was
verified, Student's t-test was performed for the analysis. If the data did not follow a normal
distribution, they were analyzed by the Mann±Whitney U test. The incidences of PONV, PCA
clamping, and the request of antiemetics were analyzed using χ2 test or Fisher's exact test. Pain
scores were analyzed using two-way repeated measures ANOVA. Data were analyzed using
the SPSS software version 23.0 (IBM Corp., Armonk, NY, USA).
We conducted the logistic regression analyses according to our aims described in the
introduction section. Logistic regression models were used to identify risk factors for PONV within
3 days of surgery. Univariate logistic regression analysis was performed first to identify
potential risk factors for PONV from clinical and demographic variables. Multivariable logistic
regression with the backward Wald stepwise variable selection process was then performed to
identify independent predictors for PONV using initial inclusion criteria of P<0.3 on the
univariate analysis. We also included possible risk factors (age, use of volatile agents, operation
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time, and nonsmoking status) as variables for multivariable logistic regression. We selected
these variables as potential predictors of PONV based on clinical knowledge and previous
] All results with a P value<0.05 with 2-tailed analyses were considered significant.
A total of 301 patients who underwent gynecological surgery under general anesthesia during
the study period were initially identified by screening of the electronic medical records. Three
patients were excluded because of early discharge (postoperative hospital stay less than 2 days),
and 2 patients were excluded because they were pediatric (aged 13 and 15 respectively). As a
result, 296 patients were included in final analysis. No differences were observed in baseline
patient characteristics between group N and group K (Table 2). Length of hospital stay was
similar between the groups. One patient in group K had previous history of migraine before
surgery. No patient had previous history of motion sickness before surgery. One patient in
group K had previous history of gastroesophageal reflux disease before surgery. Three patients
(2 in group K, 1 in group N) had previous history of chronic gastritis before surgery.
The overall incidence of PONV was 26.0% (n = 77). The incidence of PONV was not
significantly different between group N (30.6%) and group K (21.5%, P = 0.073) (Table 3). However,
the incidence of nausea on POD 2 was significantly higher in group N (10.3%) than in group K
(2.8%, P = 0.016). There were no significant differences in the number of patients received
rescue antiemetic agents between group N and group K on the operative day (16 patients (10.9%)
vs. 11 patients (7.4%), respectively; P = 0.295), on POD 1 (11 patients (7.5%) vs. 7 patients
(4.7%), respectively; P = 0.342), and on POD 2 (6 patients (4.1%) vs. 2 patients (1.3%),
respectively; P = 0.172). There was no difference in severity of nausea between Group N and Group
K at each day. Pain scores showed no differences between the two groups (Fig 1).
Baseline patient characteristics according to the occurrence of PONV within 3 days of
surgery are shown in Table 4. Although the patients who experienced PONV were slightly more
likely to have used nefopam (58.4%) than those who did not experience PONV (46.6%), the
difference was not significantly different (P = 0.073).
(n = 149)
Our retrospective study demonstrated that the combined use of nefopam with fentanyl in IV
PCA did not increase the incidence of PONV after gynecological surgery in patients who
received ramosetron. The incidence of PONV during the 3-day postoperative period after
gynecological surgery was not significantly different between patients who received the
nefopam±fentanyl combination and those who received the ketorolac±fentanyl combination. The
use of nefopam was not a significant predictor for PONV after multivariable adjustment.
Moreover, this is the first report showing that nefopam and ramosetron can be used in
combination without any undesirable interaction.
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Fig 1. Numeric rating scale pain score assessed at different times during the 3-day postoperative follow-up period.
Data are expressed as mean (SD). NRS, numeric rating scale; Group N, nefopam group; Group K, ketorolac group;
POD 1, postoperative day 1; POD 2, postoperative day 2.
Previous clinical trials with nefopam have reported inconsistent results on the incidence of
PONV. Only a few previous randomized trials have found that nefopam reduced the incidence
] However, the incidence of PONV was often not reduced by opioid-sparing
Total (n = 296)
Patients without PONV (n = 219)
Patients with PONV (n = 77)
Values are expressed as mean (SD), median [interquartile range] or number (%). PONV: postoperative nausea and vomiting.
PLOS ONE | https://doi.org/10.1371/journal.pone.0199930
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strategies with nefopam, as reported in several randomized trials.[
] Furthermore, a few
studies have even showed a relatively frequent PONV incidence in patients treated with
] suggesting that nefopam is emetic. A previous systematic review showed nefopam
was not significantly associated with PONV. The present findings also suggested that
nefopam is not significantly associated with PONV. However, our results should be cautiously
interpreted considering the retrospective design.
A recent randomized clinical trial comparing nefopam and ketorolac as adjuvant analgesics
for IV PCA reported that the incidence of PONV was higher in the nefopam group than in the
] However, the investigators did not use prophylactic antiemetics, which
did not conform to the PONV guidelines since most patients included in the study had two or
three major PONV risk factors. Considering the unusually high incidence of PONV (59%) in
nefopam group in the study,[
] the results should be cautiously interpreted.
Although a large number of clinical trials have explored the use of nefopam in various
] the efficacy of nefopam in PCA remains unclear.[
] Only a few studies have
reported the efficacy and side effects of using nefopam combined with fentanyl in PCA,[13±
15,27] as in the present study. Kim et al. compared three PCA groups after cardiac surgery:
nefopam alone, fentanyl alone, or nefopam and fentanyl.[
] They found that pain scores were
comparable between the groups and that the fentanyl-alone group had a significantly higher
incidence of nausea. Moon et al. found that the combined use of nefopam and fentanyl in IV
PCA significantly reduced fentanyl consumption after laparoscopic hysterectomy, but pain
scores and the incidence of PONV was not significantly decreased in the nefopam group.[
Jin et al. also showed that total PCA fentanyl consumption was reduced by the combined use
of nefopam in PCA after laparotomy; however, the incidence of PONV showed no significant
difference between the fentanyl and nefopam-fentanyl combination groups.[
] Our cohort
study also showed that the combined use of nefopam with fentanyl in IV PCA after
gynecological surgery resulted in comparable pain scores and no increase in the incidence of PONV
compared with the ketorolac-fentanyl combination. Thus, the use of nefopam in combination
with fentanyl in IV PCA may be a reasonable option for the management of moderate to
severe postoperative pain. However, further research with these combining methods is
required for a confirmative conclusion.
It is theoretically possible that the combination of nefopam and ramosetron leads to
mutually contrasting modifications of serotonergic transmission mediated by 5-HT3 receptors,
8 / 11
because ramosetron is a selective 5-HT3 receptor antagonist[
] and nefopam involves the
inhibition of serotonin reuptake.[
] Although Lu et al. demonstrated that ondansetron did
not attenuate the analgesic efficacy of nefopam, there is no evidence that the combination
of ramosetron and nefopam can be safely used without any undesirable interaction. To our
knowledge, our study is the first to report the efficacy and safety of the co-administration of
ramosetron and nefopam. Our findings may indicate that there is no antagonistic interaction
between ramosetron and nefopam, suggesting that ramosetron can be used as antiemetics with
nefopam, without compromising the analgesic efficacy of nefopam. However, prospective
trials are required to validate our results.
The present study has several limitations. First, as our study had a retrospective design,
there might have been an effect of unmeasured confounding variables. In particular, the
administration of rescue antiemetic agents might cause potential bias in the incidence of
PONV and it could not be completely controlled in the present study. However, to control
potential confounding factors, we included only gynecological patients in our analysis, which
was a relatively homogenous population in terms of PONV risk factors, and we also performed
the multivariable logistic regression analysis. Second, our study data were derived from
electronic medical records, which may have resulted in an underestimation of the true incidence
of adverse events. In addition, potential risk factors for PONV, for example, the history of
motion sickness, migraine, and digestive diseases, in patients included in our study might be
possibly underestimated because of insufficient documentation. Third, we could not measure
the cumulative consumption of IV PCA drugs because of retrospective design. Thus, we could
not estimate the amount of each PCA drug consumed by each patient. Fourth, we could not
obtain sufficient data about duration of PONV from our electronic medical records. Fifth, we
could not blind all the participants to the kinds of used drug and could not exclude the
possibility of unrecognized differences between the two groups as the present study retrospectively
compared the PCA drugs before and after the selected time point. Lastly, considering the wide
range of the confidence interval for the adjusted odds ratio, we could not eliminate the
possibility that nefopam increases the risk of PONV.
In conclusion, our study demonstrates that the combined use of nefopam with fentanyl in
IV PCA was not associated with a higher incidence of PONV compared to a ketorolac-fentanyl
combination in gynecological patients receiving prophylactic ramosetron. Our findings
suggest that nefopam in combination with ramosetron can be safely used via fentanyl-based IV
PCA. However, prospective trials are required to validate our results.
S1 Checklist. A STROBE checklist for the present study.
S1 File. A dataset for the present study.
Conceptualization: Jin-Tae Kim.
Data curation: Seokha Yoo.
Formal analysis: Sun-Kyung Park.
Investigation: Young-Jin Lim.
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Methodology: Won Ho Kim.
Validation: Jae-Hyon Bahk.
Visualization: Seokha Yoo.
Writing ± original draft: Sun-Kyung Park, Jin-Tae Kim.
Writing ± review & editing: Seokha Yoo, Won Ho Kim, Young-Jin Lim, Jae-Hyon Bahk.
10 / 11
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