Received July 19, 2011. Revised August 5, 2011. Accepted August 8, 2011.
Correspondence to: Mehrdad Hosseinpour
Trauma Research Center, Kashan University of Medical Sciences, Gotbe Ravandi Blvd., Kashan, Iran
Tel: ＋983116255368, Fax: ＋983116255368, E-mail: email@example.com
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Copyright ⓒ The Korean Pain Society, 2011
Korean J Pain 2011 September; Vol. 24, No. 3: 137-140
pISSN 2005-9159 eISSN 2093-0569
| Original Article |
Preemptive Use of Ketamine on Post
Operative Pain of Appendectomy
Medical University of Isfahan, Trauma Research Center, Kashan University of Medical Sciences
Akbar Behdad, Mehrdad Hosseinpour, and Parastoo Khorasani
Although early reviews of clinical findings were mostly negative, there is still a widespread belief for the
efficacy of preemptive analgesia among clinicians. In this study, we evaluated whether the preemptive use of
ketamine decreases post operative pain in patients undergoing appendectomy.
In double-blind, randomized clinical trials, 80 adult male patients undergoing an operation for acute
appendicitis were studied. Patients were randomly assigned to two groups. In the operating room, patients in
the ketamine group received 0.5 mg/kg of ketamine IV 10 minutes before the surgical incision. In the control
group, 0.5 mg/kg of normal saline was injected. The pain intensity was assessed at time 0 (immediately after
arousal) and 4, 12, and 24 hours postoperatively using the 10 points visual analogue scale (VAS).
Eighty patients (40 for both groups) were enrolled in this study. For all of the evaluated times, the VAS score
was significantly lower in the ketamine group compared to the control. The interval time for the first analgesic
request was 23.1 ± 6.7 minutes for the case group and 18.1 ± 7.3 minutes for the control (P = 0.02). The
total number of pethidine injections in the first 24 hours postoperatively was 0.6 ± 0.6 for the case group
and 2.0 ± 0.8 for the controls (P = 0.032). There were no drug side effects for the case group.
A low dose of intravenously administered ketamine had a preemptive effect in reducing pain after
appendectomy. (Korean J Pain 2011; 24: 137-140)
appendectomy, ketamine, pre-emptive analgesia.
Korean J Pain Vol. 24, No. 3, 2011
The concept of preemptive analgesia to reduce the
magnitude and duration of postoperative pain was first in-
troduced in 1983 by Woolf  who showed evidence for a
central component of post-injury pain hypersensitivity in
experimental studies. Subsequently, several experimented
studies demonstrated that various anti-nociceptive techni-
ques applied before injuries were more effective in reducing
the post-injury central sensitization phenomena compared
to administration after injury.
Although early reviews of clinical findings were mostly
negative [2,3] there is still a widespread belief in the effi-
cacy of preemptive analgesia among clinicians.
Since ketamine is a well known general anesthetic and
short acting intra operative analgesic that acts on nicotinic
and muscarinic receptors , in this study, we evaluated
whether preemptive use of ketamine decreases post oper-
ative pain in patients undergoing appendectomies.
MATERIALS AND METHODS
In a double blind, randomized clinical trial, 80 adult
male patients who were undergoing an operation for acute
appendicitis were included in this study. The study was ap-
proved by the local ethical committee. After obtaining in-
formed written consent, patients were randomly assigned
to two groups (ketamine and control). Patients were ex-
cluded if they had a history of cardiovascular disease, hy-
pertension (as evaluated by cardiovascular internist), in-
creased intracranial pressure, epilepsy, cerebrovascular
accident (as evaluated by one neurologist), psychiatric dis-
orders, and drug abuse.
To examine the preemptive effect of ketamine, a
randomized controlled trial was done from April 2010 to
March 2011. A double - blind technique was used in which
the surgeon and research physician who was responsible
for data collection were unaware of the allocation of the
study participants. The authors randomly assigned pa-
tients into a case group and a control group (patients with
an even identical number were assigned to the ketamine
group and those with an odd number to the control group).
In operating room, patients in ketamine group, re-
ceived 0.5 mg/kg of ketamine IV, 10 minutes before surgi-
cal incision by specialist nurse. In the control group, 0.5
mg/kg of normal saline was injected. All patients were
premedicated with midazolam 0.05 mg/kg IV before anes-
thesia to avoid the probable side effects of ketamine.
Patients were operated on under general anesthesia with
a Mcburney incision and the appendectomy was done.
General anesthesia was induced with thiopental (6 mg/kg)
and atracurium (0.5 mg/kg). For maintenance, isoflurane
(0.5-1%), 50% N2O, and 50% O2 were used.
Postoperatively, if patients asked for analgesia, 1
mg/kg of pethidine was administered intravenously for ad-
equate analgesia. Pain intensity was assessed at time 0
(immediately after arousal) and 4, 12, and 24 hours post-
operatively by a physician who was unaware of the alloca-
tion of the study’s participants. Time 0 was the time of
complete consciousness. Pain was scored using the 10
point visual analogue scale (VAS; 0 = no pain, 10 = worst
Other than the VAS score, the interval time for the
first request of analgesia and the number of times pethi-
dine was injected in the first 24 hours was recorded.
Patients also were checked for side effects such as delu-
sions and delirium. Data were presented as the mean ±
SD for quantitative variables. The Mann Whitney test was
used to compare VAS scores, interval time of the first re-
quest of analgesia, and total amount of analgesia in the
first 24 hours. Statistical analysis was done with SPSS 11.5
(Chicago, SPSS Inc). A P less than 0.05 was considered
Eighty patients (40 in the ketamine group and 40 in
the control group) were enrolled in this study. The mean
age of the patients was 25.3 ± 11.4 years (rang 16-24
years). The duration of the surgery was 33.2 ± 10.3
minutes. The duration of the anesthesia was 47.2 ± 11.2
minutes. Table 1 shows the comparison of the basic data
in the two groups. There were no significant differences
in these variables between the groups. VAS scores are
presented in Table 2. For all of the evaluated times, the
VAS score was significantly lower in the ketamine group
than that of the control group. The interval time for the
first analgesic request was 23.1 ± 6.7 minutes in the ket-
amine group and 18.1 ± 7.3 minutes in the control group
(P = 0.02). In the ketamine group, 42.5% of the patients
did not need analgesics postoperatively. The total number
of pethidine injections in first 24 hours postoperatively was
A Behdad, et al / Preemptive Use of Ketamine on Post Operative Pain of Appendectomy
Table 1. Basic Variables of Patients
Number of cases
Duration of surgery (min)
Duration of anesthesia (min)
28.0 ± 10.4
35.3 ± 11.0
45.1 ± 10.0
24.5 ± 10.4
31.4 ± 9.5
49.1 ± 13.1
Values are mean ± SD.
Table 2. Changes of VAS Score During 24 Hours after Appendec-
Time (hrs)04 1224
4.5 ± 1.0
6.6 ± 1.1
4.7 ± 0.1
4.7 ± 1.0
2.2 ± 1.1
3.5 ± 0.9
1.3 ± 0.5
1.8 ± 0.6
Values are mean ± SD.
0.6 ± 0.6 in the ketamine group and 2.0 ± 0.8 in the
control group (P = 0.032). There were no drug side effects
in the ketamine group.
Surgical procedures almost invariably cause tissue
damage resulting in pain. The impact of inadequate pain
relief is well known and it can result in delayed mobilization
and related complications as well as psychological distress
and anxiety. The main finding of this study shows that
preemptive intravenous low dose ketamine decreased post-
operative pain in patients undergoing appendectomies.
Ketamine is a well known general anesthetics and short
acting intraoperative analgesic in use for almost 4 decades
. It is well-known that high doses of ketamine act as
an intravenous anesthetic, and low doses of ketamine act
as an analgesic agent [6,7].
Some studies have reported the recent discovery of
the N-methyl-D-aspartate (NMDA) receptor , which
seems to play a role in pain transmission, and according
to other studies , ketamine binds to these receptors with
a nonselective antagonism reducing hyperalgesia. Keta-
mine acts on nicotinic [10,11] and muscarinic receptors; it
blocks sodium channels in the peripheral and human cen-
tral nervous system and interacts with opioid receptors, μ,
δ, and κ, and with calcium channels . Ketamine also
acts as a non-competitive antagonist at the phencyclidine
receptor site in the NMDA receptor complex channel
[13,14]. The role of NMDA receptors in the processing of
nociceptive input is antagonized by low-doses of ketamine,
which induces a noncompetitive blockade [15-18]; this rais-
es the possibility that ketamine can become "trapped" in
the receptor channel until the channel reopens after ago-
nist activation. Many clinical trials have been done to eval-
uate ketamine administration for postoperative pain man-
agement; the oral , rectal , and intranasal 
routes of administration for ketamine have been evaluated
to provide premedication for general anesthesia  or se-
dation , but the analgesic effects of these routes of
administration during the postoperative period have not
been well determined. Some authors [21,22] evaluated the
subcutaneous administration of this general intravenous
anesthetic; it has been shown that low doses (1.7 μg/kg
per min) subcutaneous.
Ketamine administered after major abdominal surgery
did not produce adverse effects and provided postoperative
analgesia equivalent to a subcutaneous morphine infusion
of 2 mg/h. The rationale for preemptive analgesia in the
management of postoperative pain has been reported by
many authors [23,24]; since ketamine is an NMDA-re-
ceptor (involved in the mechanisms of hyperalgesia) an-
tagonist, it is hypothesized to prevent or reverse central
sensitization and thus, to reduce postoperative pain. In
carrying out our study and analyzing the literature, we had
to answer some clinical questions, and the first was “Can
ketamine be administered as a postoperative analgesic?”
According to the literature and to the results of this study,
we can answer this question as “yes.” Preemptive ket-
amine for the control of postoperative pain is currently in
use even if its use is controversial; it use has consensus
and dissension; different doses and routes of admin-
istration (intravenous or epidural) are suggested, as well
as different adequate perioperative times of administration
(at the induction of anesthesia or at the awakening). In this
study, VAS measurements showed that ketamine provided
good analgesia. Moreover, some patients who received
preemptive ketamine did not require any postoperative an-
algesia within the first 24 hours of the operation. In our
investigation, there was a statistical difference between
the two groups in the total dose of analgesic consumption
postoperatively and in the time interval to request the first
In conclusion, a low dose of intravenously administered
Korean J Pain Vol. 24, No. 3, 2011
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