The effects of paracetamol, ketorolac, and paracetamol plus morphine on pain control after thyroidectomy.

Abstract

The aim of this study was to compare the efficacy of ketorolac, paracetamol, and paracetamol plus morphine on pain relief after thyroidectomy.
Eighty patients were randomly allocated to one of the 4 groups: normal saline (group C), ketorolac 30 mg (group K), paracetamol 1 g (group P), and paracetamol 700 mg plus morphine 3 mg (group PM). Each regimen was administered intravenously (IV) 30 min. before the end of surgery. If pain was not relieved, patients received an IV bolus of pethidine hydrochloride 25 mg. Pain intensity using a visual analogue scale (VAS) was recorded at 0.5, 1, 2, 4, and 6 hr after the end of surgery.
VAS at 0.5 and 1 hr after the end of surgery were significantly lower in group K, group P, and group PM than in group C (P < 0.05). The number of patients receiving pethidine hydrochloride at 0.5 and 1 hr after the end of surgery was significantly lower in group K, group P, and group PM than in group C (P < 0.05). There was no significant difference among the groups in the incidences of adverse events associated with study medications and patient satisfaction (P > 0.05).
Paracetamol 1 g IV possesses a similar analgesic efficacy to ketorolac 30 mg IV after thyroidectomy. Paracetamol may represent an alternative to ketorolac for pain prevention after mildly to moderately painful surgery in situations where the use of NSAIDs is unsuitable.

Full text

Page 1

Received March 21, 2010. Revised April 16, 2010. Accepted April 27, 2010.
Correspondence to: Won Hyung Lee, MD
Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam National University, 640, Daesa-dong, Jung-gu, Daejeon
301-721, Korea
Tel: ＋82-42-280-7840, Fax: ＋82-42-280-7968, E-mail: whlee@cnu.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Copyright ⓒ The Korean Pain Society, 2010
Korean J Pain 2010 June; Vol. 23, No. 2: 124-130
pISSN 2005-9159eISSN 2093-0569
DOI：10.3344/kjp.2010.23.2.124
| Original Article |
The Effects of Paracetamol, Ketorolac, and Paracetamol
Plus Morphine on Pain Control after Thyroidectomy
Department of Anesthesiology and Pain Medicine, Chungnam National University School of Medicine, Daejeon, Korea
Sun Yeul Lee, MD, Won Hyung Lee, MD, Eun Ha Lee, MD,
Kyu Cheol Han, MD, and Young Kwon Ko, MD
Background:
The aim of this study was to compare the efficacy of ketorolac, paracetamol, and paracetamol plus morphine
on pain relief after thyroidectomy.
Methods:
Eighty patients were randomly allocated to one of the 4 groups: normal saline (group C), ketorolac 30 mg
(group K), paracetamol 1 g (group P), and paracetamol 700 mg plus morphine 3 mg (group PM). Each regimen
was administered intravenously (IV) 30 min. before the end of surgery. If pain was not relieved, patients received
an IV bolus of pethidine hydrochloride 25 mg. Pain intensity using a visual analogue scale (VAS) was recorded
at 0.5, 1, 2, 4, and 6 hr after the end of surgery.
Results:
VAS at 0.5 and 1 hr after the end of surgery were significantly lower in group K, group P , and group PM
than in group C (P ＜ 0.05). The number of patients receiving pethidine hydrochloride at 0.5 and 1 hr after
the end of surgery was significantly lower in group K, group P , and group PM than in group C (P ＜ 0.05).
There was no significant difference among the groups in the incidences of adverse events associated with study
medications and patient satisfaction (P ＞ 0.05).
Conclusions:
Paracetamol 1 g IV possesses a similar analgesic efficacy to ketorolac 30 mg IV after thyroidectomy.
Paracetamol may represent an alternative to ketorolac for pain prevention after mildly to moderately painful
surgery in situations where the use of NSAIDs is unsuitable. (Korean J Pain 2010; 23: 124-130)
Key Words:
analgesics, ketorolac, paracetamol, thyroidectomy.

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SY Lee, et al / Analgesic Efficacy of Paracetamol
125
Table 1. Demographic Data
　
Group C
(n = 20)
Group K
(n = 20)
Group P
(n = 20)
Group PM
(n = 20)
Age (yr)
Height (cm)
Weight (kg)
Duration of operation (min)
Duration of anesthesia (min)
46.3 ± 9.5
157.1 ± 3.9
58.8 ± 7.5
71.3 ± 16.8
105.5 ± 14.1
46.1 ± 9.9
158.1 ± 3.9
59.0 ± 7.6
72.5 ± 15.4
108.5 ± 15.2
44.7 ± 7.3
158.6 ± 3.9
57.0 ± 7.9
74.5 ± 18.9
109.0 ± 21.4
45.2 ± 9.4
159.5 ± 3.1
56.2 ± 6.1
72.8 ± 14.6
108.8 ± 15.2
Value are mean ± SD. There was no significant difference among the groups (P ＞ 0.05). Group C: normal saline, Group K: ketorolac
30 mg, Group P: paracetamol 1 g, Group PM: paracetamol 700 mg + morphine 3 mg.
INTRODUCTION
Postoperative pain hinders the recovery from an op-
eration and causes various stress reactions [1]: it can neg-
atively affect the cardiovascular system and the respira-
tory system by stimulating the sympathetic nervous sys-
tem and causing hypoxia in body organs, as well as pneu-
monia and other pulmonary complications resulting from
respiratory failure. The reactions in the cardiovascular
system include an increase of heart rate, stroke volume,
myocardial oxygen consumption, and peripheral vascular
resistance [2]. In addition, it can bring about complications
such as phlebothrombosis, pulmonary embolism, respira-
tory failure, and myocardial infarction [3].
In addition to opioids, non-steroidal anti-inflammatory
drugs (NSAIDs) are frequently used in postoperative pain
control [4,5]. NSAIDs such as ketorola are able to effec-
tively control mild and moderate postoperative pain [6,7],
but long-term administration of them may cause hemor-
rhaging at the operated part, gastrointestinal bleeding,
and renal insufficiency [8]. Recently, paracetamol, an
acetaminophen venous drug, was developed (PerfalganⓇ,
BMS Pharmaceutical Korea), and it has a similar analgesic
effect as that of NSAIDs, but with less side effects [9,10].
Paracetamol is a useful pharmaceutical that can be applied
for the treatment when immediate venous injection is re-
quired due to the pain or high fever, or when the side ef-
fects of NSAIDs concerned, and when venous injection is
the only possible treatment for mild and moderate pain,
especially for postoperative pain and fever. In addition,
since paracetamol has an opioid-sparing effect when it is
used together with a small quantity of opioid, it can show
good analgesic effect while minimizing the side effects of
opioid, such as respiratory depression, bradycardia, and
hypoxia.
Therefore, to study the effects of paracetamol, which
might be substituted for NSAIDs or opiods but with less
side effects, we compared the postoperative analgesic ef-
fects and the side effects by medicating paracetamol 1 g
or ketorolac 30 mg, each of the drugs independently, or
by medicating paracetamol 700 mg and morphine 3 mg
together for thyroidectomy patients.
MATERIALS AND METHODS
Conforming to the ethics regulations of the hospital
ethics committee, this study was conducted after giving an
explanation to the patients and obtaining their consent.
The subjects of this study were the 80 female patients,
aged between 20 and 60, who were scheduled to undertake
regular surgery under general anesthesia, had already un-
dergone a total thyroidectomy without endoscopy and ro-
bot-aided procedure, and were at the Class 1 and 2 of the
American Society of Anesthesiologists Physical Status
classification. Those who had a history of drug abuse, hy-
persensitivity to drugs, diseases in the cardiovascular sys-
tem, respiratory system, kidneys or liver, those who had
been medicated with drugs that could affect the analgesic
effect before the operation, and those who were regarded
inappropriate for the clinical test for other reasons were
excluded from the subjects. There was no significant dif-
ference among the subjects in the 4 groups of age, height,
weight, and the duration of anesthesia (Table 1).
The subject patients were divided into 4 groups, 20
patients in each. An intravenous injection of paracetamol
1 g was performed for 15 minutes, 30 minutes before the
end of the operation to P Group (n = 20), ketorolac 30 mg
to K Group (n = 20), paracetamol 700 mg and morphine

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Korean J Pain Vol. 23, No. 2, 2010
Table 2. Pain Scores (VAS)
Group C
(n = 20)
Group K
(n = 20)
Group P
(n = 20)
Group PM
(n = 20)
30 min
1 h
2 h
4 h
6 h
6.2 ± 1.2
5.9 ± 1.0
3.8 ± 1.1
3.5 ± 1.3
3.4 ± 1.0
4.0 ± 1.2*
3.8 ± 1.2*
3.3 ± 0.9
3.2 ± 1.1
3.3 ± 1.3
4.1 ± 1.1*
3.9 ± 1.3*
3.3 ± 1.1
3.2 ± 1.0
3.4 ± 1.2
4.1 ± 1.2*
3.9 ± 1.1*
3.4 ± 1.1
3.3 ± 1.0
3.3 ± 1.1
Value are mean ± SD. Group C: normal saline, Group K: ketorolac
30 mg, Group P: paracetamol 1 g, Group PM: paracetamol 700
mg ＋ morphine 3 mg. *P ＜ 0.05 compared with group C.
Fig. 1. Comparison of postoperative VAS for pain. VAS at
0.5 and 1 hr after the end of surgery were significantly
lower in group K, group P , and group PM than in group C.
Value are mean ± SD. Group C: normal saline, Group K:
ketorolac 30 mg, Group P: paracetamol 1 g, Group PM:
paracetamol 700 mg ＋ morphine 3 mg. *P ＜ 0.05 com-
pared with group C.
3 mg to PM Group (n = 20), and normal saline to C Group
(n = 20).
All the patients underwent alimentary abstinence for
8 hours before the operation, and midazolam 2 mg and
glycopyrrolate 0.2 mg were injected through the muscle 30
minutes before the operation as the preanesthetic
medication. The induction was performed by the intra-
venous injection of propofol 2 mg/kg. After loss of con-
sciousness and sufficient muscle relaxation with rocuro-
nium 0.8 mg/kg, the endotracheal intubation followed. The
anesthesia was maintained with 2 L/min of O2 and N2O,
as well as sevoflurane 1.5-3.0 vol%. The tidal volume and
respiratory rate were regulated to keep the positive end
expiratory carbon dioxide pressure at 30-35 mmHg.
Opiods that could affect the postoperative analgesic effect
were not used. Ramosetron (NaseaⓇ, Astellas Pharma
Korea) 0.3 mg was intravenously injected just before fin-
ishing the operation to prevent nausea and vomiting. The
effect of muscle relaxant was reversed by using pyr-
idostigmine 15 mg, glycopyrrolate 0.2 mg, and atropine 0.5
mg after the end of the operation.
The duration of the anesthesia was recorded as the
time from the induction to the removal of the endotracheal
tube, and the duration of the operation was recorded as
the time from the initiation of the skin incision to the end
of the skin suture. The anesthesiologists, who were blinded
to the patients' groupings, visited the patients after 30
minutes and 1 hour in the postoperative recovery room,
and after 2, 4, and 6 hours at the ward; they surveyed
the degree of pain (VAS, visual analogue scale: 10 cm), side
effects, such as nausea, vomiting, headache, sedation,
dizziness, and respiratory depression, and the patients'
overall degree of satisfaction regarding the pain control.
The patients' overall degree of satisfaction regarding the
pain control was evaluated for a comparison among the
groups on a 4-point scale: 1 point for poor, 2 points for
fair, 3 points for good, and 4 points for excellent. When
the patients wanted treatment because the pain was not
regulated and the patient could not endure the pain, an
intravenous injection of pethidine hydrochloride 25 mg was
performed and a repeated injection was allowed for the
same patient who wanted more pain control.
The statistical process was conducted with SPSS ver-
sion 13.0 (SPSS Inc. Chicago, IL, USA) and the comparison
among the groups were analyzed by an ANOVA test and
a Pearson chi-square test. All the measurements were ex-
pressed as ''mean ± standard deviation'' and the cases
with the P value less than 0.05 were judged to be statisti-
cally significant.
RESULTS
The VASs of C Group were 6.2 ± 1.2 and 5.9 ± 1.0
at 30 minutes and 1 hour after the operation, respectively.
The VASs of K Group, P Group, and PM Group were 4.0
± 1.2, 4.1 ± 1.1, and 4.1 ± 1.2, respectively, at 30 minutes
after the operation, and 3.8 ± 1.2, 3.9 ± 1.3, and 3.9 ±
1.1, respectively, at 1 hour after the operation. The VASs
of C Group were significantly higher than those of K Group,

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SY Lee, et al / Analgesic Efficacy of Paracetamol
127
Table 3. Incidences of Uses of Rescue Drugs During Each Period
　
Group C
(n = 20)
Group K
(n = 20)
Group P
(n = 20)
Group PM
(n = 20)
0-0.5 h
0.5-1 h
1-2 h
2-4 h
4-6 h
6 (30)
8 (40)
2 (10)
1 (5)
2 (10)
1 (5)*
2 (10)*
1 (5)
0 (0)
2 (10)
1 (5)*
1 (5)*
1 (5)
1 (5)
2 (10)
2 (10)*
1 (5)*
2 (10)
0 (0)
1 (5)
Data are numbers (%) of patients. Group C: normal saline, Group
K: ketorolac 30 mg, Group P: paracetamol 1 g, Group PM:
paracetamol 700 mg ＋ morphine 3 mg. *P ＜ 0.05 compared with
group C.
Table 4. Patient Satisfaction at Six Hours after Surgery Using a
Verbal Rating Scale
　
Group C
(n = 20)
Group K
(n = 20)
Group P
(n = 20)
Group PM
(n = 20)
Poor
Fair
Good
Excellent
4 (20)
7 (35)
8 (40)
1 (5)
1 (5)
5 (25)
11 (55)
3 (15)
2 (10)
6 (30)
9 (45)
3 (15)
2 (10)
6 (30)
10 (50)
2 (10)
Data are numbers (%) of patients. There was no significant
difference among the groups (P ＞ 0.05). Group C: normal saline,
Group K: ketorolac 30 mg, Group P: paracetamol 1 g, Group PM:
paracetamol 700 mg ＋ morphine 3 mg.
Table 5. Incidences of Adverse Events
　
Group C
(n = 20)
Group K
(n = 20)
Group P
(n = 20)
Group PM
(n = 20)
Nausea & Vomiting
Dizziness
Sedation
Headache
1
0
0
3
1
0
1
4
2
1
1
3
2
1
1
4
Data are numbers of patients. There was no significant difference
among the groups (P ＞ 0.05). Group C: normal saline, Group K:
ketorolac 30 mg, Group P: paracetamol 1 g, Group PM: para-
cetamol 700 mg ＋ morphine 3 mg.
P Group, and PM Group (P ＜ 0.05). There was no sig-
nificant difference among the groups in the VAS at 2 hours,
4 hours, and 6 hours after the operation. The VAS tended
to decrease in all the 4 groups as the time passed after
the operation (Table 2, Fig. 1).
The number of cases where pethidine hydrochloride,
the additional analgesic, was used was 6 (30%) and 8 (40%)
at 30 minutes and 1 hour after the operation, respectively,
in C Group. The number of additional analgesic injection
in K Group, P Group, and PM Group was 1 (5%), 1 (5%),
and 2 (10%) at 30 minutes, and 2 (10%), 1 (5%), and 1 (5%),
respectively, at 2 hours after the operation. Thus, the use
of pethidine hydrochloride was significantly (P ＜ 0.05)
more in C Group than K Group, P Group, and PM Group
(Table 3).
The patients' overall degree of satisfaction in C Group,
K Group, P Group, and PM Group was evaluated as ''poor
(1 point)'' by 4 (20%), 1 (5%), 2 (10%), and 2 (10%), re-
spectively, “fair (2 points)'' by 7 (35%), 5 (25%), 6 (30%),
and 6 (30%), respectively, ''good (3 points)'' by 8 (40%), 11
(55%), 9 (45%), and 10 (50%), respectively, and ''excellent
(4 points)'' by 1 (5%), 3 (15%), 3 (15%) and 2 (10%),
respectively. Although the overall degree of satisfaction
was lower in C group than in K Group, P Group, and PM
Group, it was not significantly different among the 4
groups (Table 4).
The overall occurrence of nausea and vomiting was
not significantly different among the 4 groups. No sig-
nificant difference was found among the 4 groups in the
occurrence of side effects related to the medication, such
as dizziness, sedation, respiratory depression, and head-
ache (Table 5).
DISCUSSION
Postoperative pain causes not only physical suffering
but also mental fear and anxiety, affecting the recovery
procedure of the patients by bringing about limited ex-
ercise, declined respiratory capability, and pulmonary com-
plications [11]. Hence, effective control of postoperative
pain can provide a lot of advantages, including a reduction
of the complications and early discharge from the hospital.
Thyroidectomy is now an operation that is frequently per-
formed thanks to the development of diagnosis technology,
but it makes the patients uncomfortable, like other oper-
ations, due to the pain and the sequela caused by the pain.
The analgesics that are now used for postoperative
pain control include opioids and NSAIDs. Ketorola, a
NSAID, shows a powerful analgesic, anti-inflammatory,
and antipyretic effect by inhibiting cyclooxygenase I and
cyclooxygenase II. Since ketorola can be administrated in
a parenteral manner, and it does not seriously suppress

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Korean J Pain Vol. 23, No. 2, 2010
the respiratory and cardiovascular systems, it has been
used for the purpose of postoperative pain control, in-
dependently or by mixing it with opioids through the pa-
tient- controlled analgesia equipment [12,13]. However,
there have reports that intermittent intravenous injection
or intramuscular injection of ketorolac elongated the
bleeding time and reduced the platelet aggregation capa-
bility [14,15]. Thus, the effect of ketorolac on the intra-
operative and postoperative hemorrhage is still a
controversy. Splinter et al. [16] reported that preoperative
administration of ketorolac 1 mg/kg to the children under-
going tonsillectomy significantly increased the amount of
intraoperative bleeding compared with the group to which
codeine was administrated. In contrast, Power et al. [17]
reported that an intramuscular injection of ketorolac 30
mg during the induction of a patient undergoing chol-
ecystectomy increased the duration of bleeding and the
platelet aggregation capability, but not the quantity of
bleeding. The potential risk of side effects by ketorolac is
increased when it is medicated in a high dose, used for
5 days or longer, or when it is used on patients who are
vulnerable to drugs, such as elderly patients [18]. Thus, to
prevent side effects, it should be used in an appropriate
dose for a short period of time, or after checking whether
the patients have a contraindication or not.
On the other hand, though acetaminophen has been
universally used for pain treatment by oral administration,
it could not be applied to patients who had to undergo
postoperative alimentary abstinence. However, the re-
cently-developed paracetamol is an acetaminophen for in-
travenous injection, and its use for postoperative pain
control is gradually increasing. The modus operandi of
paracetamol has not yet been clearly revealed, but it has
been reported that paracetamol shows a powerful anti-
pyretic and analgesic effect by inhibiting cyclooxygenase
I and cyclooxygenase II, like NSAIDs, and inhibiting pros-
taglandin synthesis; additionally, it has weak anti-in-
flammatory effect and does not cause platelet function de-
clination or gastric mucosal damage, and in such ways is
different from NSAIDs [19-21]. Based on the functions of
paracetamol that are different from those of NSAIDs, 1 hy-
pothesis assumes that it might act on cyclooxygenase III
and other mechanisms. Also, suppression of nitric oxide
synthesis and supraspinal serotonin-dependent anti-
nociceptive mechanism are studied at present [22,23].
Propacetamol, N-acetyl-paramino-phenol diethyl ami-
noacetic ester, the prodrug of paracetamol, is produced by
the esterification of paracetamol and hydrolyzed by non-
specific plasma esterase. Thus, 2 g of propacetamol is
pharmacokinetically equivalent to 1 g of paracetamol. Many
studies regarding the effect of propacetamol on post-
operative pain control have been reported: Varrassi et al.
[24] reported that 2 g of propacetamol showed a similar
analgesic effect to that of 30 mg of ketorolac in a gyneco-
logical operation. Zhou et al. [10] reported that 2 g of
propacetamol and 30 mg of ketorolac showed an almost
identical effect in acute pain control after a total hip re-
placement or total knee replacement. Van Aken et al. [25]
claimed that propacetamol 2 g and morphine 10 mg showed
a similar analgesic effect after a dental operation, just as
paracetamol 1 g, ketorolac 30 mg, and paracetamol 700
mg ＋ morphine 3 mg showed a similar analgesic effect
in this study.
According to Moller et al. [26], the onset time of prop-
acetamol for intravenous injection was 3 to 5 minutes, and
the maximum analgesic effect was found 15 to 45 minutes
after the injection. They also reported that, since the drug
action duration was 4 to 6 hours, the analgesic effect could
be maintained up to 6 hours after the operation, showing
a similar pharmacodynamic property with that of
ketorolac. In this study, considering time of the maximum
analgesic effect of the drug, the analgesics were injected
30 minutes before the end of the operation to maximize
the analgesic effect. Moderate analgesic effect was shown
similarly for 6 hours after the operation in the K Group,
P Group, and PM Group.
The postoperative pain evaluation, VAS, in this study
was higher in C Group than in K Group, P Group, and PM
Group at 30 minutes and 1 hour after the operation, but
there was no significant difference in VAS at 2 hours, 4
hours, and 6 hours. This is assumed to be the results of
an additional administration of the analgesic carried out to
significantly more patients, 6 (30%) and 8 (40%) in C
Group, than those in K Group, P Group, and PM Group,
within 30 minutes and 1 hour after the operation,
respectively. Thus, no significant difference was found
among the groups at the times after 1 hour.
For an evaluation of the patients' overall degree of
satisfaction regarding the pain control, the 4-point scale
created by Zhou et al. [10] was employed. A measure of
dissatisfaction was found in C Group at the times 30 mi-
nutes and 1 hour after the operation, as the significantly