Anesth Pain Med 2014; 9: 110-114
Postoperative pain and side effects after thyroidectomy:
randomized double blind study comparing nefopam and
ketorolac
Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
Bora Yoo, Jae-Young Kwon, Boo-Young Hwang, Jung-Min Hong, Tae-Kyun Kim, and Hae-Kyu Kim
Background: Nefopam is a centrally acting, non-opioid analgesic
drug used to reduce opioid consumption and so reduce the
prevalence of postoperative nausea and vomiting (PONV). This
study compared and assessed the effects of nefopam and ketorolac
on postoperative pain and PONV after thyroid surgery.
Methods: Two hundred patients underwent total thyroidectomy
with central compartment neck dissection in our hospital during a
5 month enrollment period. Group N and Group T was administered
nefopam 20 mg and ketorolac 30 mg, respectively, during the last
30 minutes of surgery. Pain was measured using a 10-point
numerical rating scale. Pain scores and PONV were assessed 30
min, 1, 6, and 24 h postoperatively.
Results: Pain scores and episodes of vomiting and shivering did
not differ significantly between the two groups. Group N patients
experienced fewer episodes of nausea at 30 min, 1 h and 6 h after
the operation.
Conclusions: Nefopam and ketorolac are similarly effective in
reducing postoperative pain after thyroid surgery. Postoperative
nausea was less in Group N patients within 6 h postoperatively,
especially 1 h. Nefopam is favored for pain management after
thyroidectomy. (Anesth Pain Med 2014; 9: 110-114)
Key Words: Ketorolac, Nausea, Nefopam, Postoperative pain,
Vomiting.
INTRODUCTION
Most patients who undergo total thyroidectomy may suffer
from postoperative pain, nausea, and vomiting (PONV) [1,2].
Thyroid surgery induces brief postoperative pain caused by
several mechanisms [1]. The management of postoperative pain
is a critical component of patient care and is associated with
Received: January 9, 2014.
Revised: 1st, January 24, 2014; 2nd, February 19, 2014.
Accepted: March 11, 2014.
Corresponding author: Jae-Young Kwon, M.D., Ph.D., Department of
Anesthesia and Pain Medicine, Pusan National University Hospital, 10,
Ami-dong 1-ga, Seo-gu, Busan 602-739, Korea. Tel: 82-51-240-7398, Fax:
82-51-242-7466, E-mail: jykwon@pusan.ac.kr
110
￭Clinical Research￭
patient satisfaction and postoperative outcomes in thyroid
surgery [3,4]. Non-steroidal anti-inflammatory drugs (NSAIDs)
and opioids are typically administrated to reduce postoperative
pain. The use of NSAIDs does not increase cervical bleeding
after thyroid and parathyroid surgery [1]. PONV are common
problems following general anesthesia, occurring in 20–30% in
all patients and in up to 80% of high-risk patients including
those undergoing thyroid surgery [5]. The incidence of PONV
is an important cause of delayed discharge from the recovery
room and decreased patient satisfaction [6,7].
Nefopam is a centrally acting non-opioid analgesic benzo-
xazocine [8,9]. The action mechanism of nefopam is not well
understood, although inhibition of serotonin, dopamine, and
norepinephrine re-uptake is thought to be involved in its
analgesic effects; other modes of action may involve histamine
H3 receptors and glutamate [10,11]. In clinical practice, the
administration of nefopam has been reported to reduce the use
of opioid analgesics, which reduces the prevalence of PONV
[12].
A comparison between nefopam and ketorolac has not been
reported. This study compared and assessed the effects of
nefopam and ketorolac on the postoperative pain and
side-effects, such as nausea, vomiting, shivering, and cervical
bleeding, after thyroid surgery.
MATERIALS AND METHODS
Patients
This study was approved by the Institutional Review Board
of our hospital, and written informed consent for participation
was obtained from all patients. Two hundred patients between
18 and 70 years of age with American Society of
 Bora Yoo, et al：Nefopam and ketorolac after thyroidectomy 111
󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Anesthesiologists physical status classification I–II who were the NRS and patient recounted type, location, and intensity of
scheduled for elective total thyroidectomy were enrolled. The the pain at 30 min, 1, 6, and 24 h after surgery. Pain rated
exclusion criteria were gastrointestinal bleeding disorders; as above 8 points on NRS prompted intravenous admini-
allergy or sensitivity to ketorolac, aspirin, or other NSAIDs; stration of ketorolac 30 mg as a rescue analgesic. Secondary
severe cardiac disease; renal or hepatic insufficiency; outcomes were the incidence of side effects including
coagulopathy; severe bronchial asthma; administration of shivering, nausea, vomiting, and postoperative bleeding. The
monoamine oxidase inhibitor; glaucoma; seizure; and epilepsy. incidence of nausea and the number of vomiting episodes were
Patients who did not provide informed consent or who could estimated at 1, 6, and 24 h after the operation. Severe nausea
not use the numerical rating scale (NRS) were excluded. and episodes of vomiting prompted intravenous administration
of ramosetron 0.3 mg as a rescue antiemetic. Patient
Treatments
satisfaction was gauged in an interview (1: very dissatisfied, 2:
Premedication, induction, and maintenance of general dissatisfied, 3: mildly satisfied, 4: moderately satisfied, 5: very
anesthesia were standardized. Patients were fasted from satisfied) at 24 h postoperatively. Adverse events, such as
midnight prior to the surgery. During the preoperative sedation, shivering, and postoperative bleeding were recorded
anesthetic examination, the NRS was explained to the patients. for the first 24 h postoperatively.
The NRS ranged from 0 (no pain) to 10 (worst pain imagin-
Statistical analyses
able). All drugs were discontinued except for antihypertensive
drugs. The demographic data of patients and anesthetic
Patients were randomly assigned to two groups. Group N characteristics were compared using the Student’s t-test and
(n = 100) received nefopam 20 mg mixed with 100 ml normal chi-square test. BIS was compared using two-way repeated
saline and group T (n = 100) received ketorolac 30 mg mixed measures ANOVA. Pain scores were compared using two-way
with 100 ml normal saline. Both drugs were infused for the repeated measures ANOVA at each time point. Side effects
last 30 min of surgery. All patients were premedicated with a and the type and location of the pain were compared between
intramuscular injection of glycopyrrolate 0.2 mg. Anesthesia two groups using chi-square test or Fisher’s exact test. Fisher's
was induced with a combination of propofol 2 mg/kg, exact test was used to compare the satisfaction scores of two
rocuronium 0.8 mg/kg, and remifentanil 0.2 mg/h. After groups.
tracheal intubation, anesthesia was maintained using desflurane,
which was managed with Bispectral index (BIS, XP version
RESULTS
4.1; Aspect Medical Systems, Newton, MA, USA) targeting a
value of 40 to 50. The BIS was measured every 5 min from There was no significant difference in patients’ characteri-
beginning to infusion of nefopam 20 mg or ketorolac 30 mg. stics between two groups (Table 1). No significant difference
Desflurane concentration was unchanged after the start of was found in BIS scores after the administration of nefopam
nefopam or ketorolac infusion. After the end of surgery, all and ketorolac between both groups. Emergence profiles
patients were injected intravenously with pyridostigmine 10 mg between two groups showed no significant difference between
and glycopyrrolate 0.4 mg. The remifentanil infusion was
stopped at the end of surgery. After desflurane and remifen-
Table 1. Demographic Data
tanil were discontinued, the elapsed time to eye opening,
recovery of tidal volume above 6 ml/kg, and extubation were Group N Group T
P value
measured. No preventive antiemetics were administered. All (n = 100) (n = 100)

patients were extubated when BIS value was above 80 and Age (yr) 52.1 ± 9.8 52.0 ± 10.0 0.736
tidal volume was recovered above 6 ml/kg in the operating Sex (F/M) 87/13 89/11 0.663
Height (cm) 159.3 ± 6.6 158.8 ± 6.7 0.556
room.
Weight (kg) 59.8 ± 9.4 59.3 ± 9.7 0.534
Outcomes
Data are expressed as mean ± SD or number (%). Group N (n =
100) was infused 20 mg of nefopam, and Group T was infused 30
The primary outcome of this study was the effects of
mg of ketorolac during the 30 minutes before the end of surgery.
nefopam and ketorolac on postoperative pain measured using There was no significant difference between two groups.
112 Anesth Pain Med Vol. 9, No. 2, 2014
󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Table 2. Emergence Profiles of Each Group Table 3. Type and Location of the Pain after Total Thyroidectomy
with Central Compartment Neck Dissection in Each Group
Group N Group T
P value
(n = 100) (n = 100) Group N Group T
P value
(n = 100) (n = 100)
TV recovery time (sec) 408.9 ± 123.4 416.7 ± 133.1 0.763
Eye opening time (sec) 434.5 ± 127.2 434.1 ± 131.5 0.854 Type
Extubation time (sec) 454.7 ± 126.6 451.7 ± 137.8 0.926 Dullness 68 (68) 69 (69) 0.879
Sharp 11 (11) 15 (15) 0.4
Data are expressed as mean ± SD. Group N (n = 100) was Tearing 3 (3) 6 (6) 0.498
infused 20 mg of nefopam, and Group T was infused with 30 mg Tingling 23 (23) 21 (21) 0.733
of ketorolac during the 30 minutes before the end of surgery. There Location
was no significant difference between two groups. TV: Tidal Volume. Incision lesion 96 (96) 98 (98) 0.543
Shoulder pain 4 (4) 7 (7) 0.352
Headache 15 (15) 12 (12) 0.535
Rescue drug
Ketorolac 24 (24) 25 (25) 0.869

Data are expressed as number (%). Group N (n = 100) was

infused with 20 mg of nefopam, and Group T was infused with 30
mg of ketorolac during 30 minutes before the end of surgery. There
was no significant difference in the type and location of pain and
rescue drug between two groups.

Table 4. Incidence of Post-operative Side Effects

Group N Group T
P value
(n = 100) (n = 100)

Nausea
Fig. 1. Numerical rating scale at 30 min, 1, 6, and 24 h after the end ＜1 h 10 (10) 32 (32) ＜0.001
of the surgery. Data are expressed as mean ± SD. Group N (n = 100) 1–6 h 3 (3) 12 (12) 0.016
was infused with 20 mg of nefopam, and Group T was infused with 30 ＜6 h 1 (1) 3 (3) 0.312
mg of ketorolac during the 30 minutes before the end of surgery. There Rescue antiemetics
was no significant difference between two groups. Both groups showed
Ramosetron 0 (0) 3 (3) 0.013
decrease in pain with time.
Vomiting 2 (2) 1 (1) 0.561
Shivering 5 (5) 7 (7) 0.552
Bleeding 0 (0) 1 (1) 0.316
two groups (Table 2).
There was no significant difference in NRS at 30 min, 1, 6, Data are expressed as number (%). Group N (n = 100) was
and 24 h after the operation between both groups, and NRS infused with 20 mg of nefopam, and Group T was infused with 30
mg of ketorolac during 30 minutes before the end of surgery. The
scores decreased with time (Fig. 1). There was no significant
incidence of nausea within 6 h after the end of surgery was less in
difference in the type and location of pain and numbers of nefopam group, compared to that of ketorolac group. The number of
rescue analgesics prescription between both groups (Table 3). rescue antiemetics (ramosetron 0.3 mg) use of Group T was
No significant difference was found in the incidences of side significantly greater than that of Group N.

effects including shivering, vomiting, and postoperative bleeding

between both groups. One patient had postoperative bleeding in
Group T, and underwent emergency surgery for hemostasis.
The incidence of nausea of group N within 1 h (10%) and 1 h
to 6 h (3%) after operation was significantly lower than those
in group T (32 and 12%, respectively; P ＜ 0.001 and P =
0.016, respectively) (Table 4). However, there was no signi-
ficant difference in the incidence of nausea from 6 h after
operation between two groups. The incidence of rescue
antiemetics (ramosetron 0.3 mg) use of group T (3%) was
significantly greater than that (0%) of group N (P = 0.013,
Table 4). Group N patients reported greater satisfaction (P =
0.041, Table 5).
DISCUSSION
After thyroid surgery, most patients suffer from minor
 Bora Yoo, et al：Nefopam and ketorolac after thyroidectomy 113
󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏
Table 5. Patient Satisfaction
Satisfaction level Group N (n = 100) Group T (n = 100)
1 0 (0) 0 (0)
2 4 (4) 2 (2)
3 20 (20) 38 (38)
4 50 (50) 39 (39)
5 26 (26) 21 (21)
Data are expressed as number (%). Group N (n = 100) was
infused with 20 mg of nefopam, and Group T was infused with 30
mg of ketorolac during 30 minutes before the end of surgery.
Satisfaction level was divided into five levels (1: very dissatisfied, 2:
dissatisfied 3: mildly satisfied, 4: moderately satisfied, 5: very
satisfied). The patients in Group N showed higher satisfaction level
than the patients in Group T at 24 hours after operation (P =
0.041).
postoperative discomforts from complex mechanisms. Cervico-
tomy itself, orotracheal intubation, and the cervical hyperex-
tension position can induce postoperative discomfort, neck pain,
and shoulder pain. Most patients who undergo thyroidectomy
do not use patient-controlled analgesia, because the postopera-
tive pain does not usually last for a long time. Basto et al.
[1] showed that the pain scores fell markedly between 24 and
36 h after an operation. In this study, the pain intensity was
also decreased at 24 h after operation. However, the mean
NRS exceeded 5 at 30 min after operation, and about 25% of
patients needed rescue analgesics. This result suggests that the
increased dose of analgesics may be needed during the early
postoperative period. Ketorolac was used as a rescue analgesic
in both groups. The use of ketorolac as a rescue analgesic
after nefopam or ketorolac treatment might have affected the
results. Combination therapy of nefopam and ketorolac may be
needed in the future.
The incidence of PONV in group T patients was similar to
that of a recently reported study [13] that investigated the
incidence of PONV in endoscopic thyroidectomy. That study
reported rates of nausea of 35.9 and 23.5% at ‘0–2 hour’ and
‘2–6 hour’ after surgery, respectively. The present and prior
study differed concerning the endoscopic procedure and the use
of meperidine as first choice of postoperative pain control,
which seemed to be attributable to a marginally higher
incidence of nausea in the previous study [13].
Ketorolac is a heterocyclic acetic acid derivative NSAID that
is used as an analgesic. It acts by inhibiting the bodily
synthesis of prostaglandins. The primary mechanism of action
responsible for ketorolac's anti-inflammatory, antipyretic, and
analgesic effects is the inhibition of prostaglandin synthesis by
competitive blocking of the enzyme cyclooxygenase. NSAIDs
are not usually recommended for coadministration with other
NSAIDs, because of the potential side effects. NSAIDs carry
the risk of systemic side effects such as bleeding, gastroduo-
denal bleeding, and kidney damage [14]. One report described
inhibited spinal fusion [15]. NSAIDs also inhibit platelet
aggregation and may be associated with an increased risk of
bleeding [16]. In thyroid surgery, ketorolac might have a risk
for postoperative bleeding, and postoperative bleeding after
thyroidectomy can induce dyspnea and decreased saturation.
Patients who undergo cervicofacial surgery are at high risk
of nausea and vomiting due to edema and inflammation on the
neck tissue and parasympathetic impact through vagus,
recurrent laryngeal, and glossopharyngeal nerves to the
vomiting center [17,18]. In particular, women have a high
incidence of nausea and vomiting [2]. Postoperative nausea and
vomiting in patients with thyroid surgery are very important,
because they lead to cough or movement inducing postope-
rative bleeding. Therefore, we seldom used an opioid after
thyroidectomy, and had to find other medications to reduce
postoperative pain and emesis [2].
The action mechanism of nefopam has not been discovered
completely yet. Serotonin reuptake inhibition involves nefo-
pam's analgesic action. Serotonin reuptake inhibition can
induce nausea and vomiting by 5HT3 receptor involvement. Lu
et al. [19] used ondansetron as an antiemetic with nefopam;
ondansetron did not inhibit nefopam's analgesic effect. The
authors suggested that nefopam involves specific serotonin
receptor subtypes.
The action mechanism of nefopam on decreased nausea is
unclear. Nefopam has previously been associated with a 15–
30% incidence of minor side‐effects, especially nausea,
dizziness, and sweating [9]. However, the incidences of the
minor adverse events of nefopam and placebo groups with
morphine PCA were similar [20]. In another study, the
incidence of postoperative nausea was lower in the nefopam
20 mg group than the placebo and nefopam 40 mg group
[12]. We did not evaluate the dose-dependent effect of
nefopam on the incidence of nausea. A small dose change of
nefopam may lead to an altered incidence or severity of
nausea. In this study, nefopam 20 mg infusion significantly
reduced the incidence of nausea compared to ketorolac within
6 h after thyroidectomy. We checked the incidence of nausea
divided into “within 1 h”, “within 6 h”, and “after 6 h”,
because the nausea within 6 h might be influenced by the
114 Anesth Pain Med Vol. 9, No. 2, 2014
󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏
anesthesia or surgical factors, such as inhalation agents and the
operation itself. In this study, most of nausea symptoms
subsided quickly after intravenous administration of ramosetron
0.3 mg, although the severity of nausea was not evaluated.
As the knowledge of the effect of nefopam on PONV is
still limited, it should be further investigated in terms of
benefit and side effects according to the dose, interaction
between other analgesics or opioids, and the influence of
anesthetics (inhalation vs intravenous).
In conclusion, nefopam showed similar analgesic effects
compared to ketorolac. Since nefopam more effectively reduced
the incidence of postoperative nausea within 6 h after the
operation, it is suggested as another effective choice to reduce
pain and nausea after total thyroidectomy.
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