Pain Medicine 2018; 19: 561–568

doi: 10.1093/pm/pnx105

Original Research Article

Effect of Intrathecally Administered Ketamine,
Morphine, and Their Combination Added to
Bupivacaine in Patients Undergoing Major

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Abdominal Cancer Surgery a Randomized,
Double-Blind Study

Ahmad M. Abd El-Rahman, MD, Ashraf A.
Mohamed, MD, Sahar A. Mohamed, MD, and
Mohamed A. M. Mostafa, MD
Department of anesthesia, South Egypt Cancer
Institute, Assiut University, Assiut, Egypt.
Correspondence to: Ahmad Mohammad Abd El-
Rahman, MD, South Egypt Cancer Institute, Assiut
University, Assiut 171516, Egypt. Tel:
þ201000525368; Fax: þ20882348609; E-mail:
ahmad23679@gmail.com.
Conflicts of interest: The authors have no conflict of
interests.
Abstract
Objective. Effective postoperative pain control re-
duces postoperative morbidity. In this study, we in-
vestigated the effects of intrathecal morphine,
ketamine, and their combination with bupivacaine
for postoperative analgesia in major abdominal can-
cer surgery.
Study Design. Prospective, randomized, double-
blind.
K 1 M) received both 0.3 mg morphine and 0.1 mg/kg
ketamine in 1 mL volume intrathecally. Postoperative
total morphine consumption, first request of analge-
sia, visual analog score (VAS), and side effects were
recorded.
Results. Total PCA morphine was significantly de-
creased in group M 1 K compared with groups M
and K. Time to first request of analgesia was pro-
longed in groups M and M 1 K compared with group
K (P < 0.001). VAS in group M 1 K was reduced from
two to 24 hours, and in group M from 12 and
18 hours postoperation compared with group K,
with an overall good analgesia in the three groups.
Sedation was significantly higher in group M 1 K
compared with group M until six hours postopera-
tion. No other side effects were observed.
Conclusions. Adding intrathecal ketamine 0.1 mg/kg
to morphine 0.3 mg in patients who underwent major
abdominal cancer surgery reduced the total postoper-
ative morphine consumption in comparison with ei-
ther drug alone, with an overall good postoperative
analgesia in all groups, with no side effects apart
from sedation.
Key Words. Intrathecal; Ketamine; Morphine;
Lower Abdominal Cancer Surgery

Setting. Academic medical center. Introduction

Patients and Methods. Ninety ASA I–III patients age
30 to 50 years were divided randomly into three
groups: the morphine group (group M) received
10 mg of hyperbaric bupivacaine 0.5% in 2 mL vol-
ume and 0.3 mg morphine in 1 mL volume intrathe-
cally. The ketamine group (group K) received
0.1 mg/kg ketamine in 1 mL volume instead of mor-
phine. The morphine 1 ketamine group (group
Effective postoperative pain control is an essential com-
ponent of the care of surgical patients. Inadequate pain
control, apart from being inhumane, may result in in-
creased morbidity or mortality [1,2].
The advantages of effective postoperative pain manage-
ment include patient comfort and therefore satisfaction,
earlier mobilization, fewer pulmonary and cardiac

C 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
V 561
Abd El-Rahman et al.
complications, a reduced risk of deep vein thrombosis,
faster recovery with less likelihood of the development
of neuropathic pain, and reduced cost of care [3].
Despite extensive discourse, there is still controversy in
the literature as to the safety and analgesic efficacy of
ketamine through the intrathecal route [4–9].
Preservative-free racemic ketamine was shown to be
devoid of neurotoxic effects after both single and re-
peated administration in animals [4–6].
Ketamine, a phencyclidine derivative, has recently been
found to be effective by epidural and intrathecal routes.
It possesses some definite advantages over the conven-
tional local anesthetic agents as it stimulates the cardio-
vascular system [10,11] and respiratory system [12].The
onset of anesthesia (sensory block) and motor paralysis
is found to be earlier than the conventional local anes-
thetics [11]. The intensity of the sensory block is 100%
as it is described to be due to the potent analgesic ef-
fect of ketamine [13].
Intrathecal opioid administration is an attractive analge-
sic technique as the opioid is injected directly into the
cerebrospinal fluid, close to the structures of the central
nervous system where the opioid acts. The procedure is
simple, quick, and with a relatively low risk of technical
complications or failure [14].
However, it is known that intrathecal morphine, alone or
as an adjuvant to a local anesthetic, increases the risk
of respiratory depression. Respiratory depression is a
major risk [15].
The objective of this study was to investigate the effects
of intrathecal morphine, ketamine, and their combination
when added to bupivacaine for postoperative analgesia
in major abdominal cancer surgery.
Methods
This randomized, double-blind study was approved by
the ethics committee of South Egypt Cancer Institute,
Assiut University, Assiut, Egypt (registered at www.
ClinicalTrials.gov with identifier No. NCT02726828).
After obtaining written informed consent, 90 American
Society of Anesthesia (ASA) I–III patients age 30 to
50 years scheduled for major abdominal cancer surgery
were included in the study. Patients with a known al-
lergy to the study drugs, significant cardiac, respiratory,
renal or hepatic disease, coagulation disorder, infection
at or near the site of intrathecal injection, drug or alco-
hol abuse, body mass index (BMI) greater than 30, or
psychiatric illnesses with the potential to interfere with
perception and assessment of pain were excluded from
the study.
Preoperatively, patients were taught how to evaluate
their own pain intensity using the visual analogue scale
(VAS), scored from 0 to 10 (where 0 ¼ no pain and
10 ¼ the worst pain imaginable).
562
Oral diazepam (5 mg) was given the night before sur-
gery. Upon arrival at the operative theater, a 16-gauge
catheter was introduced intravenously at the dorsum of
the hand; lactated Ringer’s solution 10 mg/kg was in-
fused intravenously over 10 minutes before initiation of
spinal anesthesia. Basic monitoring probes (electrocardi-
ography, noninvasive blood pressure, O2 saturation, and
temperature) were applied. Patients were placed in the
sitting position, and a 25-gauge Quincke needle was
placed in the L2-3 or L3-4 interspaces.
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Patients were randomly divided, by selecting sealed en-
velopes, into one of three groups (30 patients each):
• The morphine group (group M) patients received
10 mg of hyperbaric bupivacaine 0.5% in 2 mL volume
and 0.3 mg morphine in 1 mL volume intrathecally.
• The ketamine group (group K) patients received
10 mg of hyperbaric bupivacaine 0.5% in 2 mL volume
and 0.1 mg/kg ketamine in 1mL volume intrathecally.
• The morphine þ ketamine group (group M þ K) pa-
tients received 10 mg of hyperbaric bupivacaine 0.5%
in 2 mL volume and 0.3 mg morphine plus 0.1 mg/kg
of ketamine in 1 mL volume intrathecally.
Immediately after successful spinal anesthesia, the pa-
tients were placed in the supine position, general anes-
thesia was induced with fentanyl 1.5 to 2 mg/kg,
propofol 2 to 3 mg/kg, and lidocaine 1.5 mg/kg.
Endotracheal intubation was facilitated by cis-atracurium
0.15 mg/kg. Heart rate, systolic, and diastolic blood
pressure were recorded at five, 10, 20, 30, 60, 120,
180 minutes. Anesthesia and muscle relaxation were
maintained by isoflurane 1 to 1.5 MAC in 50% oxygen/
air mixture, and cis-atracurium 0.03 mg/kg bolus was
given every 30 minutes.
At the end of surgery, muscle relaxation was reversed
by neostigmine 50 mg/kg and atropine 10 mg/kg.
Patients were extubated and transferred to a postanes-
thesia care unit (PACU) and monitored for vital signs
(heart rate, noninvasive blood pressure, respiratory rate,
and O2 saturation) immediately postoperation and at
two, four, six, 12, 18, and 24 hours postoperation.
Total analgesic consumption in the first 24 hours post-
operation and the time of first request of analgesia were
recorded. VAS scores were assessed at the same time
intervals. Rescue analgesia was represented by patient-
controlled analgesia (PCA) with intravenous morphine,
with an initial bolus of 0.1 mg/kg once pain was ex-
pressed by the patient or if VAS is 3 or more (VAS  3),
followed by 1 mg boluses with a lockout period of five
minutes. The patient’s level of sedation was assessed
at the same time points with scores from 0 to 4, where
0 ¼ awake, 1 ¼ easily aroused, 2 ¼ awakens after tactile
stimulation, 3 ¼ awakens after verbal stimulation, and
4 ¼ not arousable.
The attendant anesthesiologist was blinded to patient
assignment to a specific group. Postoperative adverse
 Intrathecal Ketamine and Morphine in Abdominal Cancer Surgery
effects such as nausea, vomiting, hypotension, brady-
cardia, and itching were recorded and treated.
Hypotension is defined as a 15% decrease in systolic
blood pressure from baseline. Bradycardia is defined as
a heart rate slower than 50 beats per minute or a de-
crease in heart rate of 20% or more from baseline,
whichever is lowest. Hypoxia is defined as an oxygen
saturation of less than 90%. Hypotension was treated
with intravenous bolus of ephidrine 0.1 mg/kg and nor-
mal saline 5 mL/kg; the same doses were repeated as
required. Bradycardia was treated with intravenous atro-
pine 0.01 mg/kg.
Statistical Analysis
Power of the Study
The primary end point was the total dose of intravenous
PCA morphine consumption in the first 24 hours post-
operation. Secondary end points were the safety profile
of the study drugs in terms of predefined adverse ef-
fects, nausea, vomiting, and level of sedation during the
study period. To detect a difference of one SD [16] be-
tween the mean of the total amount of postoperative
morphine consumption between the study groups in the
24 hours, we estimated that 28 patients in each group
would be required to have a power of 90% and an al-
pha error not exceeding 0.05. We included 30 patients
in each group to compensate for possible patient
dropouts.
Data Analysis
Analysis was performed using the Statistical Package
for Social Sciences software, version 20 (SPSS Inc.,
Chicago, IL, USA). Data were presented as mean 6 SD,
numbers, and percentages. Analysis of variance, fol-
lowed by post hoc tests, was used for comparison of
parametric data. The Kruskal Wallis test was used to
compare nonparametric data while Mann-Whitney was
used to compare between the two groups. The chi-
square test was used for comparison between percent-
ages and frequencies. A P value of less than 0.05 was
considered significant.
Table 1 Demographic data in different groups
Item Group “M” (N ¼ 30) Group “K” (N ¼ 30)
1) Age, year 41.50 6 3.90
2) Weight, Kg 69.73 6 8.48
3) Height, cm 163.03 6 11.85
4) BMI, Kg/m2 26.93 6 7.95
5) Duration of surgery, hours 2.68 6 0.30
BMI ¼ body mass index; K ¼ ketamine group; M ¼ morphine group; M þ K ¼ morphine þ ketamine group.
Results
There were no significant differences between groups in
demographic data regarding age, weight, height, BMI,
and duration of surgery (P > 0.05) (Table 1). There was
no significant difference among groups regarding post-
operative pulse rate and mean blood pressure (P >
0.05) (Figures 1 and 2). There was a significant increase
in sedation score in group M þ K compared with group
M, which started from 0 line until six hours postop-
eration, with no significant differences in sedation score
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between group K and group M þ K (P > 0.05) (Figure
3). There was a significant reduction in mean VAS score
in group M þ K compared with group K, starting two
hours until 24 hours postoperation and in group M com-
pared with group K at 12 and 18 hours postoperation
(Figure 4). The time to first request of rescue analgesia
was significantly prolonged in group MþK
(12.00 6 2.29 hours) and group M (11.94 6 1.46 hours)
compared with group K (6.42 6 1.43 hours) (P > 0.001)
(Table 2). The mean total consumption of PCA morphine
in the PACU was significantly decreased in group M þ K
(6.00 6 2.10 mg) compared with groups M and K
(9.23 6 3.50 mg and 12.67 6 3.49 mg, respectively) in
the first 24 hours postoperation (P > 0.04) (Table 2).
Only five patients (16.6%) in group M þ K requested res-
cue analgesia, while in groups M and K 14 (46.6%) and
22 (73.3%) patients needed rescue analgesia, respec-
tively (Table 2). There was significantly higher sedation
(P > 0.01) in groups K and M þ K compared with group
M. Apart from sedation, there was no significant differ-
ence in the incidence of other side effects between the
three studied groups (Figure 5).
Discussion
In this study, adding intrathecal ketamine 0.1 mg/kg to
intrathecal morphine 0.3 mg had the advantage of re-
ducing the total postoperative morphine consumption in
comparison with using either drug alone. The three
study groups had an overall good analgesia with the
use of postoperative PCA morphine. Sedation scores
were higher in the combination group and in the intra-
thecal ketamine group than in the morphine group.
Ketamine is a noncompetitive antagonist of the N-
methyl-D-aspartate (NMDA) receptors. It is used for
Group “MþK” (N ¼ 30) P
41.23 6 4.12 41.70 6 3.80 P ¼ 0.903n.s
69.43 6 8.58 70.10 6 8.33 P ¼ 0.954n.s
162.20 6 12.04 162.83 6 11.35 P ¼ 0.960n.s
27.28 6 9.83 27.04 6 7.30 P ¼ 0.987n.s
3.67 6 1.01 2.71 6 0.33 P ¼ 0.483n.s
563
Abd El-Rahman et al.

94

92

90

88

86
G"M"
HR

84
G"K"
82 G"M+K"

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80

78

76

74
HR0 HR2 HR4 HR6 HR12 HR18 HR24

Figure 1 Heart rate in different groups. HR ¼ heart rate; K ¼ ketamine group; M ¼ morphine group; M þ K ¼ mor-
phine þ ketamine group.

96
94
92
90
88
86 G"M"
MBP

84 G"K"

82 G"M+K"

80
78
76
74
MBP0 MBP2 MBP4 MBP6 MBP12 MBP18 MBP24

Figure 2 Mean blood pressure in different groups. K ¼ ketamine group; M ¼ morphine group; M þ K ¼ mor-
phine þ ketamine group; MBP ¼ mean blood pressure.

premedication, sedation, induction, and maintenance of
general anesthesia. Central, regional, and local anes-
thetic and analgesic properties have been reported for
ketamine [17].
Other possible peripheral mechanisms of action of keta-
mine include binding to multiple opioid receptors (ORs)
[18], binding to monoamine transporters [19], binding to
muscarinic and nicotinic cholinergic receptors and inhi-
bition of function [20], binding to D2 and 5-HT2 recep-
tors [21], inhibition of ion channels (Naþ, Ca2þ, Kþ)
[22,23], decreased activation and migration of microglia
[23], and finally, inhibition of production of inflammatory
mediators [24].
Despite extensive discourse, there is still controversy in
the literature as to the safety and analgesic efficacy of
ketamine through the intrathecal route [4–6,8,9]. When
intrathecal ketamine was evaluated as a sole anesthetic
agent [25,26], its psychomimetic disturbances and inad-
equate analgesia precluded its use for this purpose.
Intrathecal ketamine has been studied extensively in ani-
mals. Borgbjerg and Svenssson [6] administered

564
 Intrathecal Ketamine and Morphine in Abdominal Cancer Surgery

1.8

1.6

1.4

1.2

1 G"M"
SS

0.8 G"K"
G"M+K"

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0.6

0.4

0.2

0
SS0 SS2 SS4 SS6 SS12 SS18 SS24

Figure 3 Sedation score in different groups. K ¼ ketamine group; M ¼ morphine group; M þ K ¼ morphine þ keta-
mine group; SS ¼ sedation score.

2.5

G"M"
VAS

1.5
G"K"
G"M+K"
1

0.5

0
VAS0 VAS2 VAS4 VAS6 VAS12 VAS18 VAS24

Figure 4 Visual analog score in different groups. K ¼ ketamine group; M ¼ morphine group; M þ K ¼ mor-
phine þ ketamine group; VAS ¼ visual analog score.

preservative-free ketamine 5 mg intrathecally to rabbits
for a period of 14 days and concluded that it has no
harmful neurotoxic effects, even after repeated injec-
tions. On the contrary, Vranken et al. [8] found that re-
peated administration of preservative-free S(þ)-ketamine
for seven days resulted in histopathologic spinal cord
changes. However, they argued that there was no sig-
nificant difference in neurologic status between the two
groups after seven days of intrathecal treatment and
that not all animals given intrathecal preservative-free
S(þ)-ketamine developed neurologic deterioration de-
spite histologic evidence of neurotoxicity. They also
postulated that the spinal cords of rabbits may be more
sensitive than those of humans. In our opinion, it is the
dose of intrathecal ketamine used and the repetition of
exposure to ketamine that might play the major role in
the resulting neurotoxic changes as the authors used a
dose of 0.7 mg/kg of ketamine given daily for successive
seven days.
Data from the above and similar studies led to the con-
cept that multiple factors, like preservatives (chlorobuta-
nol and benzethonium chloride), the use of multiple
drugs for a long period, and the use of intrathecal

565
Abd El-Rahman et al.

30

25

20
% of cases

15
G "M"

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G "K"
10
G"M+K"

0
ea ng

m
s
us

ain

n
gs

es
ct

us iti

tio
ea
gm

in
fe

in

tp
Na

da
m

Dr
el
ef

o zz
sta

es
fe

Se
V
Di
ive

Ch
Ny

le
iat

ng
oc

ra
St
ss
Di

Figure 5 Side effects in different groups. K ¼ ketamine group; M ¼ morphine group; M þ K ¼ morphine þ ketamine
group.

Table 2 Time to first request of rescue analgesia, total morphine consumption in different groups

Item Group “M” Group “K” Group “MþK” P

Time to first request, h 11.94 6 1.46 6.42 6 1.43 12.00 6 2.29 P < 0.001**
No. of patients who requested rescue analgesia (%) 14 (46.6) 22 (73.3) 5 (16.6) —
Total morphine dose, mg 9.23 6 3.50 12.67 6 3.49 6.00 6 2.10 P < 0.04*
Range of total morphine dose, mg 7–13 9–16 6–9 —

**highly significant difference.

*significant difference.

catheters may be responsible, in part, for neurological
complications [4–6,8], in addition to the doses and con-
centrations used. By contrast, Yu et al. [9] reported that
ketamine provided potent protective effects against the
ischemic reperfusion in spinal cord injuries.
Khezri et al. [27] have reported that using ketamine in-
trathecally at a concentration of 0.1 mg/kg could be a
proper alternative to achieve postoperative analgesia as
it resulted in no side effects.
A major mechanism of spinal opioid analgesia is inhibi-
tion of transmitter release from C-fiber primary afferent
terminals. The presynaptic action of opioids, along with
the postsynaptic location of NMDA receptors, is the ra-
tionale for the combination of these two drugs. The ke-
tamine acts as the agonist with opiate receptors [28,29]
by producing a synergistic effect to achieve the desired
level of postoperative analgesia, with concomitant
reduction of side effects. This was the rationale for
choosing morphine and ketamine in this study.
Sandler et al. [30] suggested that epidural ketamine may
have an additive effect on opioids and local anesthetics.
Long after that, this was studied by Arati and colleagues,
and they concluded that combining ketamine with mor-
phine epidurally provided a synergistic effect with good an-
algesia and facilitated early mobilization. Side effects like
nausea, vomiting, and sedation were minimal in the group
of patients who were administered morphine 0.3 mg/kg
with ketamine 0.25 mg/kg [31].
Combining intrathecal morphine with other drugs might
not give similar results. Abdel-Ghaffar et al. [32] studied
the combination of 0.5 mg morphine and 5 mg dexme-
detomidine, and their results didn’t support improved
analgesia despite the absence of significant adverse
effects.

566
 Intrathecal Ketamine and Morphine in Abdominal Cancer Surgery
The selection of an intrathecal ketamine dose of 0.1 mg/
kg was based on the fact that several previous studies
showed that the use of such dose could prolong the du-
ration of analgesia without additional side effects [33–35].
In our study, VAS scores in the three groups were kept
within a narrow range. Thus, we can say that the three
groups experienced an overall equal analgesic effect,
but at the expense of the total amount of rescue PCA
morphine.
Our findings support the hypothesis of improved analge-
sia when giving these two drugs intrathecally in combi-
nation. But we think that further work on this specific
drug combination is needed with trying different doses
of both drugs in different surgical situations and, of
course, with larger sample size if possible to reach opti-
mal analgesia with the fewest possible untoward effects.
In conclusion, adding intrathecal ketamine 0.1 mg/kg to
morphine 0.3 mg in patients who underwent major ab-
dominal cancer surgery reduced the total postoperative
morphine consumption in comparison with either drug
alone, with an overall good postoperative analgesia in all
groups, with no side effects apart from sedation.
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