Regional Anesthesia and Pain Medicine 24(3): 225-230, 1999

Postoperative Pain Following Knee

Arthroscopy: The Effects of Intra-articular
Ketorolac and/or Morphine
Anil Gupta, M.D., F.R.C.A., Ph.D., Kjell Axelsson, M.D., Ph.D.,
Renne Allvin, R.N., Jan Liszka-Hackzell, M.D.,
Narinder Rawal, M.D., Ph.D., Bo Althoff, M.D., Ph.D., and
Bengt G6ran Augustini, M.D.
Background and Objectives. Morphine and nonsteroidal antiinflammatory drugs (NSAID)
have been found to be effective in relieving postoperative pain. The goal of this study was
to determine whether ketorolac alone or in combination with morphine provides
superior pain relief following arthroscopy performed with local anesthesia (LA). Methods.
This was a randomized, double-blind, prospective, study in 100 healthy patients from 15
to 60 years of age. Knee arthroscopy was performed with LA using 40 mL prilocaine (5
mg/mL) with adrenaline (4/xg/mL). At the end of the operation, a catheter was inserted
intra-articularly, and one of the following solutions diluted to a total volume of 40 mL
was injected: group P (40 mL normal saline), group M (3 mg morphine), group K30 (30
mg ketorolac), group K60 (60 mg ketorolac), and group KM (3 mg morphine + 30 mg
ketorolac). Visual analog scale (VAS) pain scores (0-100 mm) were measured preoperative and at 30, 60, 90, 120 minutes postoperative and thereafter 4, 8, 24, and 48 hours
at rest and on movement of the levee. The total number of distalgesic tablets (325 mg
paracetamol + 32.5 mg dextropropoxyphene) consumed during the 48 hours postoperative was recorded. Results. Significant differences in VAS pain scores were seen
between group P and group IGM at 4, 8, and 24 hours (P < .05) and between group M
and group KM at 4, 8, 24, and 48 hours (P < .01) after the operation at rest. During
mobilization of the knee, a significant difference in VAS pain score was found between
group P and group I_Mat 8, 24, and 48 hours (P < .05) and between group P and group
K60 at 24 and 48 hours (P < .05). The total consumption of distalgesic tablets did not
differ among the groups. Conclusions. The combination of 3 mg morphine plus 30 mg
ketorolac provided significantly better analgesia than either placebo alone or morphine
alone. This result could be a synergistic effect. Reg Anesth Pain Med 1999: 24: 225-230.
K e y w o r d s : morphine, ketorolac, postoperative pain.

I n t r a - a r t i c u l a r i n j e c t i o n of m o r p h i n e h a s b e e n
f o u n d to b e effective in p r o v i d i n g a n a l g e s i a b y s o m e
( 1 - 3 ) b u t n o t o t h e r s ( 4 - 6 ) . It is b e l i e v e d t h a t t h e

i n t r a - a r t i c u l a r a n a l g e s i c effects of m o r p h i n e a r e o p t i m a l l y f o u n d in t h e p r e s e n c e of p r e - e x i s t i n g in~
f l a m m a t i o n w h i c h m a y p a r t l y a c c o u n t for t h e disc r e p a n c y i n t h e r e s u l t s b e t w e e n t h e studies.
Ketorolac, a nonsteroidal antinflammatory drug
(NSAID), h a s b e e n s h o w n to p r o v i d e s a t i s f a c t o r y
a n a l g e s i a i n t h e early p o s t o p e r a t i v e p e r i o d w h e n
i n j e c t e d i n t r a m u s c u l a r l y (7), d u r i n g i n t r a v e n o u s reg i o n a l a n a e s t h e s i a (8), as w e l l as w h e n i n j e c t e d
i n t r a - a r t i c u l a r l y (9). A l t h o u g h t h e m e c h a n i s m of
a c t i o n of NSAIDs is u n k n o w n , it i s h y p o t h e t i z e d
t h a t t h e y act v i a d i r e c t m o d u l a t i o n of p e r i p h e r a l l y

From the Departments of Anesthesiology and Orthopedic Surgery, Orebro Hospital Medical Center, 701 85 Orebro, Sweden.
This study was presented in part at the European Society of
Regional Anesthesia Meeting in London, 1997.
Accepted for publication October 17, 1998.
Reprint requests: Anti Gupta, M.D., F.R.C.A., Ph.D., Departmerit of Anesthesiology, 0rebro Hospital Medical Center, 701 85
Orebro, Sweden.
Copyright 1999 by the American Society of Regional
Anesthesia.
0146-521X/99/2403-000855.00/0

225

226

RegionalAnesthesia and Pain Medicine Vol. 24 No. 3 May-June 1999

acting pain mediators or via the central nervous

system (10). Nonsteroidal anti-inflammatory drugs
could also act locally via inhibition of prostaglandin
synthesis which is responsible in part for inflammatory changes following surgical trauma. The goal of
this study was to determine whether ketorolac
alone or in combination with morphine is superior
for pain relief following arthroscopy performed
with local anesthesia (LA).

Methods
This was a prospective, randomized, double-blind
study. All patients were ASA physical status I and II
and underwent ambulatory arthroscopic knee surgery with LA (diagnostic arthroscopy, debridement,
shaving, and meniscus repair). Any patient with a
significant cardiac, respiratory, metabolic, or neurologic condition was excluded. The study was approved by the Hospital Ethics Committee. Verbal
informed consent was obtained from 100 patients
prior to entry into the study. The procedure was
carefully explained to the patients who were admitted directly from the outpatient clinic and were not
premedicated. An intravenous catheter was placed
on the nondominant hand so as to administer drugs
and fluids if necessary. Standard monitoring techniques were used, including electrocardiography,
blood pressure, and pulse oximetry. Preoperative
visual analog scale (VAS) scores were obtained from
all patients on a 100-mm VAS scale by asking the
average intensity of pain during rest. The scale had
markings where 0 corresponds to no pain and 100
corresponds to "worst imaginable" pain. Arthroscopy was performed approximately 30 minutes after injecting LA (40 mL of prilocaine 5 mg/mL with
adrenaline 4 /xg/mL). The local anesthetic was injected partly at the site of insertion of the arthroscope and other instruments (10 mL), and the rest
intra-articularly. No sedatives or analgesics were
given to any of the patients, and the tourniquet was
not used during the procedure. One patient complained of severe pain (VAS > 70 mm) during the
procedure which was relieved by supplemental injection of local anesthetic intra-articularly. At the
end of the operation, a catheter was inserted intraarticularly into the knee joint under direct vision
and the knee bandaged after closing all portals.
Ten minutes after the end of the operation, one
of the following solutions was injected intra-articularly via the catheter by a person who was blinded
to the injectate, and randomization was performed
by a computer in such a way that the 100 patients
were divided equally among the 5 groups.

Group M: Morphine special (preservative-free) 3

mg (3.5 mL) diluted in 36.5 mL 0.9% saline
(total volume 40 mL)
Group P: 40 mL 0.9% saline (Placebo)
Group K30: Ketorolac 30 mg (1 mL) + 39 mL
0.9% saline (total volume 40 mL)
Group K60: Ketorolac 60 mg (2 mL) + 38 mL
0.9% saline (total volume 40 mL)
Group KM: Ketorolac 30 mg (1 mL) + 3 mg morphine special (3.5 mL) + 35.5 mL 0.9% saline
Visual analog scale pain scores were obtained
from all patients at 30, 60, 90, and 120 minutes
after the end of the operation. Distalgesic tablets
(325 mg paracetamol + 32.5 mg dextropropoxyphene) were offered to the patients for pain requiring intervention. If the intensity of pain exceeded
50 ram, the patients were offered morphine intravenously in incremental doses of 1 mg until the
pain decreased below 30 ram. The total dose of
distalgesic tablets and morphine consumed and the
time to administration of the first dose were recorded. The patients were discharged home after 2
hours if no side effects were recorded and there was
minimal pain and no vomiting. Standard written
instructions regarding activity, mobilization, and
positioning were given to all patients. The patients
were asked to assess the severity of pain at home 4,
8, 24, and 48 hours after the operation with the
help of a VAS both at rest and on maximum tolerable flexion of the knee joint. If the pain was moderate to severe, they were advised to take a distalgesic tablet. The total number of tablets consumed
0-2 hours, 2-24 hours, and 24-48 hours postoperative was noted by the patients at home. All patients
were interviewed by telephone 24 hours after the
operation and were reminded to fill in the VAS pain
scores as well as a questionnaire about the intensity of
pain during the operation and any side effects experienced during the 48-hour observation period.

Statistics
Demographic data were analyzed using the oneway analysis of variance. The changes in the intensity of pain from preoperative values were analyzed
using the Kruskal-Wallis test. When a significant
result was obtained, the Mann-Whitney U test was
performed to determine which groups differed significantly from each other. A post hoc modified
Bonferroni correction was used to correct for multiple comparisons with a significance level at P less
than .01. For comparison of analgesic drugs consumed postoperative, the chi-square test was used.

Postoperative Pain Following Knee Arthroscopy

Gupta et al. 227

Table 1. Demographic Characteristics and Severity of Pain During the Operation

Group P
Age
44.3 _+ 16.4
Sex (M:F)
17:3
Severity of pain during the operation
Mild
18
Moderate
2
Severe
0

Group M

Group K30

Group K60

Group KM

36.3 -+ 11.3
14:6

43.5 _+ 15.0
10:10

36.6 _+ 15.1
14:6

44.3 -- 11.6
11:9

16
4
0

15
4
1

17
3
0

14
6
0

Age is expressed as mean _+ SD. Group P, placebo; group M, morphine; group K30, 30 mg ketorolac; group K60, 60 mg ketorolac;
group KM, 30 mg ketorolac + 3 mg morphine.

Results
The groups were comparable with respect to demographic data and the severity of pain during the
operation (Table 1).
The n u m b e r of patients w h o experienced moderate
to severe pain (VAS > 30 mm) during the operation
was similar a m o n g the groups. No differences were
found among the groups in the VAS pain scores during the first 2 hours after the operation (Fig. 1). The
changes in VAS pain scores 4 - 4 8 hours after the
operation are s h o w n in Fig. 2 (at rest) and Fig. 3 (on
movement). In general, patients in group K60 and
group KM had less pain postoperative compared with
preoperative values. Significant differences were seen
between group P and group IgAMat 4, 8, and 24 hours
(P < .05) and between group M and group IA4 at 4,
8, 24, and 48 hours (P < .01) after the operation at
rest. A significant difference was also found between
group P and group KM at 8, 24, and 48 hours (P <
.05) and between group P and group K60 at 24 and 48
hours (P < .05) after the operation during knee flex-

ion. No other differences were seen among the groups

at rest or during flexion.
The average n u m b e r of distalgesic tablets cons u m e d was similar a m o n g the groups at different
time periods (<2 hours, 2 - 2 4 hours, and 2 4 - 4 8
hours) at h o m e (Table 2). One patient each in
group P and group KM required m o r p h i n e during
the first 2 hours postoperative for pain relief. The
side effects reported by the patients at h o m e are
summarized in Table 2. No significant differences
were f o u n d a m o n g the groups. One patient in
group K60 had itching a r o u n d the knee joint during
the postoperative period, but this subsided spontaneously w i t h o u t treatment.

Discussion
In this study, we f o u n d that the combination of
30 mg ketorolac and 3 mg m o r p h i n e injected intraarticularly resulted in excellent analgesia up to 48

10-

1o1
o -El

=:?0 e

: =;Loto

;>
-lO

Placebo

Placebo

Morphine
[] Keto 30
I~ Keto 60
[] Morph + keto
-20
24O

30

60

90

1213

Time after injection of study drug (rain)

Fig. 1. Changes in postoperative VAS pain score (ram)

from preoperative values during the first 2-hour observation period in the day care surgical unit, Results are
expressed as changes in median values. Absence of a bar
indicates "no change" from preoperative value.

48O

1440

2880

Time after injection of study drug (min)

Fig. 2. Changes in VAS pain score (mm) from preoperative values at rest during the observation period at home
(4-48 hours). Results are expressed as changes in median
values. Absence of a bar indicates "no change" from
preoperative value. *, P < .01 compared with morphine
group, t, P < .01 compared with placebo group.

RegionalAnesthesiaand Pain Medicine Vol. 24 No. 3 May-June 1999

228

than that in a control group (3). In the former

study, patients had general anesthesia with opioids,
whereas in the latter study, opioids were excluded
from the anesthetic. It is thus possible that the
administration of opioids intraoperative may reduce early postoperative pain, and therefore beneficial effects of bupivacaine administered postoperatively may be masked. This was also the finding by
Bj/Srnsson et al. who found no benefit of bupivacaine injected postoperative after anesthesia with
intraoperative opioids (4). One confounding factor
could, however, be the use of epinephrine. Heard et
al. found beneficial effects of bupivacaine when
epinephrine was injected (3), whereas Henderson
et al. (5) and Bj6rnsson et al. (4) found no effect of
bupivacaine in the absence of epinephrine. In the
present study, prilocaine with epinephrine was injected preoperative during opioid-free analgesia,
and excellent effects were obtained in all five
groups during the first 2 hours. Thus, the following
factors could influence early postoperative pain
when using local anesthetics intra-articularly: epinephrine, opioids, and preoperative (as opposed to
postoperative) injection of local anesthetics. More
studies are needed in the literature to analyze these
factors.

i Morphine
Placebo
Keto30

20

Morph+ keto

=
r~

j
#

240

480

1440

2880

Time after injection of study drug (rain)

Fig. 3. Changes in VAS pain score (mm) from preoperative values on flexion of the knee joint during the observation period at home (4-48 hours). Results are expressed as changes in median values. Absence of a bar
indicates "no change" from preoperative value. *, P < .01
compared with morphine group. J-, P < .01 compared
with placebo group.

hours after the operation. Significantly better analgesia was also provided by 60 mg ketorolac compared with placebo or morphine alone and better
than that obtained by 30 mg ketorolac injected
intra-articularly. The internal validity of this study
can be confirmed by the fact that all groups were
comparable in the pain intensity during the first 2
hours which is consistent with the known duration
of action of prilocaine when combined with adrenaline.

Effects of Morphine
Although morphine has also been administered
intra-articularly for postoperative analgesia, the results have been equally conflicting (1,4,6,11). Likar
et al. found that morphine had good analgesic effects when injected locally in patients with chronic
knee inflammation (12), but only mild analgesia
was seen after acute postoperative pain (13). Although some studies suggest that morphine has a
prolonged effect for up to 48 hours after the operation (2), the mechanism for this remains unclear,
In the present study, we did not find any beneficial
effects of 3 mg morphine alone when compared
with another group without morphine during at-

Effects of Local Anesthetics

Local anesthetics injected into the articular space
have been found to provide variable results (3,5).
Henderson et al. found no benefit after injecting 30
mL 0.25% bupivacaine at the end of surgery in 275
patients undergoing arthroscopic surgery (5). Heard
et al., however, found that 20 mL 0.25% bupivacaine with adrenaline provided better analgesia

Table 2. Analgesic Consumption and Postoperative Side Effects

Analgesic tablets c o n s u m e d (mean)

<2 h
2-24 h
24-48 h
Side effects
Tiredness
Nausea
Giddiness

Group P

Group M

G r o u p K30

G r o u p K60

Group KM

0
2.7
1.7

0.3
2.8
0.9

0.4
2.2
1.5

0.4
2.0
0.6

0.8
2.0
1.2

3
5
0

3
4
4

5
1
2

1
2
0

7
4
3

Group P, placebo; group M, morphine; K30, 30 mg ketoroIac; group K60, 60 mg ketorolac; group KM, 30 mg ketorolac + 3 mg
morphine. Some patients had more t h a n one side effect.

Postoperative Pain Following Knee Arthroscopy

throscopy performed with LA. Morphine was injected postoperative via a catheter placed intraarticularly and following the closure of all portals
thus minimizing leakage of drug into the tissues.
Effects of Ketorolac
Reuben et al. found that the injection of 60 mg
ketorolac intra-articularly provided better analgesia
than if ketorolac was injected intravenously during
the first 2 hours after surgery. They also found that
the combination of bupivacaine and ketorolac injected intra-articularly offered significantly better
pain relief when compared with either bupivacaine
or ketorolac alone. This could be an additive effect
of local anesthetic when combined with an NSAID.
However, Reuben et al. had no control group, and
their study was confounded by the administration
of fentanyl intraoperative to all patients which
may have interacted with ketorolac. Besides, the
difference in pain intensity among the groups was
somewhat surprising considering that the local
anesthetic effects of bupivacaine injected intraarticularly should have persisted in all groups during the 2-hour observation period. In our study,
arthroscopy was performed with LA, and therefore
almost all patients had only mild pain during the
first 2 hours because of the effects of the local
anesthetic into the postoperative period. It was consequently impossible to detect the effects of ketorolac during this period. After returning home and
during the first 48 hours, the local anesthetic would
be unlikely to have any carry-over effect. Therefore, any differences among the groups should be
the result of the drug injected. Ketorolac 60 mg
offered some degree of analgesia during the 4-48hour period, particularly during flexion of the knee.
Although the duration of action of ketorolac is
about 4 - 6 hours after intramuscular administration
(7), Ben-David et al. also found a longer analgesia
(24 hours) after intra-articular administration of
ketorolac (14). Although 30 mg ketorolac also offered some analgesic effect, it did not reach statistical significance when compared with placebo, and
the intensity of pain in the 60 mg ketorolac group
was always less than that in the 30 mg ketorolac
group at home, suggesting that there could be a
dose-dependent analgesic effect of ketorolac when
injected locally and that the plateau effect may not
have been reached even after 60 my.
Effects of Morphine, Ketorolac,
and Local Anesthetic
Because the effect of local anesthetics is usually
rather short lasting, one could anticipate pain after

Gupta et al. 229

a few hours. Ketorolac has been shown to have a

duration of effect of up to 24 hours after intraarticular administration (14). In at least one study,
morphine has shown to have an effect of up to 48
hours when injected locally. We postulated, therefore, that the combination of these three drugs may
reduce postoperative pain over a long period. We
found that when 3 mg morphine was combined
with 30 mg ketorolac and local anesthetic, excellent
pain relief was obtained during the 48-hour observation period. The analgesic effect persisted for up
to 48 hours and was seen at rest and on flexion of
the knee joint. Consequently, there could be an
interaction between ketorolac and morphine when
injected locally. The onset of action of ketorolac
when given intramuscularly (ketorolac is not registered for intra-articular use) is about 30 minutes,
and peak effect is reached after about 50 minutes.
The pain relief observed in our patients during the
first 1-2 hours is probably the result of the local
anesthetic used during surgery. However, the pain
relief registered during the next few hours in the
ketorolac-morphine group could be the anti-inflammatory effect of ketorolac injected locally. The
subsequent prolonged effect for up to 48 hours is
difficult to explain but could be either the effect of
morphine or a combination of ketorolac and morphine. Patients in the 30 mg ketorolac group also
had some degree of pain relief up to 48 hours
postoperative at rest (which, however, did not
reach statistical significance), but not those in the
morphine group. Thus, although 3 mg morphine
and 30 mg ketorolac alone do not provide any
significant pain relief, the combination of these
drugs provided excellent analgesia. Our hypothesis
is that this could be a synergistic effect. We have
observed clinically that many patients who do not
respond to large doses of morphine intravenously
feel remarkably better after receiving 15-30 mg
ketorolac intravenously. The morphine-sparing effects of ketorolac are well known in the postoperative period. However, it is u n k n o w n if this is a
synergistic or additive effect. Reuben et al. found no
beneficial effect of the combination of ketorolac and
morphine injected intra-articularly during the
2-hour observation period. In our study, all groups
were comparable with respect to pain intensity during the first 2 hours which, we believe, is a result of
the effect of local anesthetic persisting into the postoperative period. The mean intensity of postoperative pain as seen by Reuben et al. during this period
was about 5-40 mm on the VAS, which is rather
mild pain. Once again, no control group was available for comparison of pain intensity. More studies
are needed to confirm or deny our findings.

230

RegionalAnesthesia and Pain Medicine Vol. 24 No, 3 May-June 1999

The c o m b i n a t i o n of 30 m g k e t o r o l a c a n d 3 m g
m o r p h i n e injected i n t r a - a r t i c u l a r l y after a r t h r o scopic k n e e s u r g e r y p e r f o r m e d w i t h LA p r o v i d e d
excellent p a i n relief w i t h o u t a n y m a j o r side effects a n d offers a g o o d a l t e r n a t i v e to the m e t h o d s
a l r e a d y available. M o r p h i n e a l o n e injected intraarticularly p r o v i d e d no p a i n relief. K e t o r o l a c int r a - a r t i c u l a r l y offered s o m e degree of p a i n relief
w h i c h was dose d e p e n d e n t . M o r e studies are
n e e d e d to d e t e r m i n e the o p t i m u m dose of k e t o r o lac t h a t can be a d m i n i s t e r e d to obtain the m a x i m u m effect.

5.

6.

7.

8.

Acknowledgment
9.
The authors t h a n k the operating theatre personnel at the D e p a r t m e n t of Orthopedic Surgery and
the postoperative p e r s o n n e l at the D e p a r t m e n t of
Anesthesia a n d Intensive Care for their assistance
during various phases of the study.

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