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EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS

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 Banode S.V. et al EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS

EFFECT OF KETOROLAC ON OPIOID INDUCED

ANTINOCICEPTION IN RATS
IJMPS
Vol 03 issue 03 Banode S.V.1, Borkar A.S.2, Badwaik R.T.2
Section: Medicine
Category: Research 1
Department of Pharmacology, RD Gardi Medical College, Ujjain (MP), India
2
Received on:10/09/12 NKP Salve Institute of Medical Sciences, Nagpur, (MS), India
Revised on:22/09/12
Accepted on:03/10/12 E-mail of Corresponding Author: sbanode@yahoo.co.in

ABSTRACT
Objective: To explore the antinociceptive effects of combination of ketorolac with different opioids in
central and visceral nociception. Methods: Tail flick method and writhing method were used as animal
models of central and visceral nociception, respectively. Results: Coadministration of subeffective doses
of combination of ketorolac (10mg/kg) with different opioids (morphine 1.5mg/kg, pethidine 10mg/kg,
fentanyl 20µg/kg, buprenorphine 0.05mg/kg, and tramadol 10mg/kg) increased pain threshold (percentage
analgesia) in tail flick method and decreased the number of writhes (increased percentage inhibition) in
writhing method significantly. Ketorolac fentanyl combination in subeffective doses was more effective
in enhancing the pain threshold, producing highly significant antinociceptive effect (93.33% analgesia) in
tail flick method whereas the combination of subeffective doses of ketorolac and tramadol produced
highly significant effect (88.99% inhibition) in writhing method. Conclusion: The present study suggests
that coadministration of ketorolac with fentanyl produces the maximum analgesia in central pain model
whereas ketorolac tramadol combination is more effective in visceral pain. In clinical practice this would
allow use of combination for effective analgesia according to the type of pain.
Keywords: ketorolac, opioid, tail flick, writhing

INTRODUCTION greater patient satisfaction. (5) However the

Ketorolac is a nonsteroidal anti inflammatory
drug with potent analgesic and modest anti
inflammatory activity. Ketorolac in common
with other NSAIDs is an inhibitor of
prostaglandin synthesis. (1) The pharmacological
target of ketorolac is cyclo oxygenase enzyme
(COX) which is responsible for synthesis of
prostaglandins. Two isoforms of COX enzyme
i.e.COX-1 and COX-2 are known. Ketorolac is a
nonselective COX enzyme inhibitor. (2) The
widespread use is limited due to possibility of
gastrointestinal and renal bleeding. (1)
Opioid analgesics are thought to produce
analgesia through their actions in the CNS. (3, 4)
Improved knowledge about opioid
pharmacology has provided better analgesia and
problems of adverse opioid effects remain.
Administration of opioid in the perioperative
setting may contribute to early or delayed
respiratory depression, confusion, nausea and
vomiting, decreased gastrointestinal motility and
pruritus.(6)
In response to this issue, ketorolac is commonly
administered in the perioperative setting.(7,8)
There is evidence in humans that the analgesia
provided by 30 mg parenteral ketorolac may be
as effective as 12 mg parenteral morphine in the
post operative period. (9,10,11) Nevertheless, if
pain persists or breaks through the initial dose of
NSAID, extended use of parenteral NSAID
increases the risk of hepatic or renal impairment,
bleeding complications, gastrointestinal erosions

Int J Med Pharm Sci, Nov 2012 / Vol 03 (03)

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 Banode S.V. et al EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS

and ulcerations.(7,12,13) Many, if not all, of these Drugs: Following drugs were used; ketorolac
adverse effects are dose dependent. Therefore (Dr Reddy’s Lab), morphine (Troikaa
using combinations of medications that offer Pharmaceuticals), pethidine (Verve Health Care
synergy should allow reduction in required Ltd), fentanyl (Troikaa Pharmaceuticals),
dosage and decrease the incidence of adverse buprenorphine (Neon Laboratories), tramadol
effects. (Piramal Health Care) and 4% NaCl (prepared
Recently, combined use of NSAID and opioid is freshly).
advocated in clinical practice to reduce the dose Assessment of central nociception
related side effects of both drugs.(14,15,16) Further Tail flick test (radiant heat induced
some clinical studies also suggest that NSAIDs nociception)
potentiate the analgesic effects of opioid.(17)
Present study was mainly aimed to explore the The hyperalgesic response in the tail withdrawal
interaction between ketorolac and different test (analgesiometer) is generally attributed to
opioids in animal models of central and visceral central mechanism. Tail withdrawal latency
nociception. from the radiant heat source was taken as
endpoint. The intensity of the radiant heat was
MATERIALS AND METHODS adjusted so that the baseline latency for tail
Animals: Albino rats (150-250 gms) of either withdrawal of rat was 4-5 seconds. A cut off
sex were used. Animals were housed under time of 15 seconds was imposed to prevent any
standard laboratory conditions with free access injury to tail. Analgesic response was expressed
to food and water ad libitum. The rats were as percentage analgesia and was calculated as
fasted from 8 am on the day of experimentation. follows:
The experimental protocol was approved by
institutional animal ethics committee.
after drug – before drug
% analgesia = ----------------------------------------------------- X 100
15(cut of time in sec) – before drug

Assessment of visceral nociception of abdomen with extension of hind limbs. The

Writhing method number of writhes before and after drug
The rats were given 0.4ml/100gm of freshly administration was counted for a period of 10
prepared 4% NaCl solution by intraperitoneal minutes. Based on the number of writhes
route. Within few seconds the rats showed percentage inhibition was calculated by using
characteristics writhes which was the contraction the following formula:
writhes with NaCl - writhes with NaCl after giving drug
% inhibition = ---------------------------------------------------------------------- x 100
writhes with NaCl

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 Banode S.V. et al EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS
Drugs administration
All the drugs were administered by
intraperitoneal route (i.p.) and subsequent
subeffective doses (producing 20-30% response)
were determined. In tail flick method,
combination of ketorolac with different opioids
in subeffective doses was coadministered at one
time and reaction time was observed before and
20-30 minutes after administration while in
writhing method, number of writhes induced by
4% NaCl was calculated before and after
injecting the drug combinations. All these drugs
were diluted in distilled water to prepare
solutions of desired strengths.
STATISTICAL ANALYSIS
Results were expressed as mean ± SEM. Paired t
test was used to compare reaction time before
and after injecting the drugs. Percentage
analgesia and percentage inhibition in ketorolac
group (group I), different opioids group (group
II) and combinations of ketorolac with
respective opioids (group III) were compared by
one way analysis of variance (ANOVA).
Bonferroni test was used for multiple
comparisons whereas comparison of analgesia of
addition of ketorolac and different opioids
administered alone (group I and group II) with
respective ketorolac opioid coadministration
group (group III) was done by proportion test.
The value of p<0.05 was considered as
statistically significant and p<0.01 as highly
significant.
RESULTS
Effect of ketorolac on opioid antinociception
in tail flick method in rats:
Coadministration of subeffective doses of
ketorolac (10mg/kg) with different opioids
(morphine 1.5mg/kg, pethidine 10mg/kg,
fentanyl 20µg/kg, buprenorphine 0.05mg/kg,
and tramadol 10mg/kg) enhanced the
antinociceptive effect which was maximally
seen with ketorolac and fentanyl combination
producing 93.33% analgesia which was highly
Int J Med Pharm Sci, Nov 2012 / Vol 03 (03)
Page 9
significant as compared to per se effects of both
drugs and was significant compared with
addition of the per se of ketorolac and fentanyl.
Effect of ketorolac on opioid antinociception
in writhing method in rats:
Coadministration of subeffective doses of
ketorolac (10mg/kg) with different opioids
(morphine 1.5mg/kg, pethidine 10mg/kg,
fentanyl 20µg/kg, buprenorphine 0.05mg/kg,
and tramadol 10mg/kg) enhanced the
antinociceptive effect which was maximally
seen with ketorolac and tramadol combination
producing 88.99% inhibition which was highly
significant as compared to per se effects of both
drugs and was to the significant level when
compared with addition of the per se of
ketorolac and tramadol.
Figure 1. Effect of ketorolac (10 mg/kg),
morphine (1.5 mg/kg), pethidine (10 mg/kg),
fentanyl (20 µg/kg), buprenorphine (0.05 mg/kg)
and tramadol (10 mg/kg) against tail flick
method (A) and writhing method (B) in rats.
Figure 2. Effect of ketorolac (10 mg/kg), in
combination with different opioids, morphine
(1.5 mg /kg), pethidine (10 mg/kg), fentanyl (20
µg/kg), buprenorphine (0.05 mg/kg) and
tramadol (10 mg/kg) against tail flick method
(A) and writhing method (B) in rats.
DISCUSSION
An important technique for decreasing side
effects in pharmacology is the use of low doses
of several agents that produce the same
therapeutic effects. A potential advantage of
using combination therapy is that analgesic
effects can be maximized while the incidence of
adverse effects is minimized. (18) Therefore using
combinations of medications that offer analgesic
synergism should allow a reduction in required
dosage and decrease the incidence of adverse
effects. (19)
 Banode S.V. et al EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS
Radiant heat method and 4% NaCl induced
writhing method are recognized screening tests
for potential antinociceptive properties of central
and visceral nociception, respectively. Used
together these two complimentary tests detect
antinociceptive actions of all major analgesic
drugs in clinical use.
The type of interaction between drugs according
to theory of drug interaction can be expressed as
antagonism, addition or synergism when the
combined effect of two drugs are lower, equal or
greater than the sum of effect of each agent
given alone, respectively.(20) Synergism requires
that drugs have different mechanisms of
actions.(21) The synergistic interaction usually
occurs between two drugs with different
mechanisms of actions which additively takes
place when two agents potentiate each other’s
activity profile at their target sites.
Consequently, ketorolac and opioid seem to be
consistent with therapeutic consideration.
However the combinations of ketorolac fentanyl
and ketorolac tramadol were more effective in
tail flick method and writhing method,
respectively. These findings may offer
advantages while using combination of ketorolac
with opioid drugs in selecting different opioid in
different types of pain.
The reason behind such type of interaction might
be related to the potency of the drugs used such
as fentanyl which is more potent among the
drugs used or to their additional mechanisms of
actions such as inhibition of norepinephrine and
serotonin uptake in case of tramadol in addition
to its opioid mechanism of action. The reason
behind this kind of difference in interaction
remains unclear.
It has been proposed that this synergistic
interaction between NSAIDs and opioids occur
at intracellular sites of convergence between
prostanoid and opioid receptor transduction
mechanisms. (22) Vaughan et al 1997(23) proposed
a novel cellular mechanism underlying the
synergism between opioids and NSAIDs in the
Int J Med Pharm Sci, Nov 2012 / Vol 03 (03)
Page 10
midbrain periacqueductal gray, a brain region
critical for analgesic action of both opioids and
NSAIDs.
CONCLUSION
These findings suggest that ketorolac exhibits
synergistic action with opioid when used in
combination even at subeffective doses. In
clinical practice this would allow use of
combination for effective analgesia according to
the type of pain. Such combination would have
reduced incidence of adverse effects.
ACKNOWLEDGEMENT
We acknowledge the immense help received
from the scholars whose articles are cited and
included in reference in the manuscript. We are
also grateful to the authors /editors/publishers of
all those articles, journals and books from where
the literature of this article has been reviewed
and discussed.
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Banode S.V. et al EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS

Figure 1(A)

Figure 1(B)

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 Banode S.V. et al EFFECT OF KETOROLAC ON OPIOID INDUCED ANTINOCICEPTION IN RATS

Figure 2(A)

Figure 2(B)

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