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How Readily Does Ketorolac Penetrate Cerebrospinal Fluid in Children?

Elina Kumpulainen, Hannu Kokki, Merja Laisalmi, Marja Heikkinen, Jouko Savolainen, Jarkko Rautio and Marko
Lehtonen
J. Clin. Pharmacol. 2008; 48; 495 originally published online Feb 13, 2008;
DOI: 10.1177/0091270007313389

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 How Readily Does Ketorolac Penetrate
Cerebrospinal Fluid in Children?
Elina Kumpulainen, BM, Hannu Kokki, MD, PhD, Merja Laisalmi, MD, PhD, Marja
Heikkinen, MD, Jouko Savolainen, PhD, Jarkko Rautio, PhD, and Marko Lehtonen, MSc
Ketorolac is a potent nonsteroidal anti-inflammatory anal-
gesic used in postoperative pain management. Ketorolac
elicits its analgesic action by inhibiting the cyclo-oxyge-
nase enzyme in peripheral tissues and in the spinal cord.
Central nervous system penetration of parenteral ketorolac
has been evaluated in adults but not in children. In the pre-
sent study we investigated ketorolac cerebrospinal fluid
penetration via spinal anesthesia in 30 healthy children
undergoing surgery in the lower part of the body. A single
cerebrospinal fluid and blood sample was obtained
between 11 minutes and 6 hours after receiving ketorolac
0.5 mg⋅kg–1 IV. Ketorolac concentrations were determined
by gas chromatography with mass spectrometric detection.
K etorolac is the only parenteral nonsteroidal anti-
inflammatory drug (NSAID) approved by the US
Food and Drug Administration for pediatric use. In
children, ketorolac tromethamine injection is indi-
cated as a single intravenous (IV) dose for the man-
agement of moderate to severe acute postoperative
pain. A single dose of ketorolac provides comparable
analgesia to that of morphine; the onset of analgesic
action is slower after ketorolac than that with mor-
phine, but once pain relief is established, it lasts
From the Department of Pharmacology and Toxicology, University of
Kuopio (Ms Kumpulainen, Dr Kokki); the Department of Anesthesiology
and Intensive Care, Kuopio University Hospital (Ms Kumpulainen, Dr
Kokki, Dr Laisalmi); the Department of Surgery, Kuopio University
Hospital (Dr Heikkinen); Oy Fennopharma Ltd (Dr Savolainen); and the
Department of Pharmaceutical Chemistry (Dr Rautio, Mr Lehtonen),
University of Kuopio, Kuopio, Finland. Some of the results were pre-
sented as an abstract at the FEAPA European Conference on Paediatric
Anaesthesia, Amsterdam, September 27-29, 2007. Submitted for publi-
cation June 19, 2007; revised version accepted December 7, 2007.
Address for correspondence: Hannu Kokki, MD, PhD, Department of
Anesthesiology and Intensive Care, PO Box 1777, FI-70211 Kuopio,
Finland; e-mail: hannu.kokki@kuh.fi.
DOI: 10.1177/0091270007313389
J Clin Pharmacol 2008;48:495-501
Ketorolac was detected from 22 of the 30 cerebrospinal
fluid samples, and the concentrations ranged between 0.2
and 7.6 μg⋅L-1 (median, 0.6 μg⋅L-1). The cerebrospinal fluid
to unbound plasma concentration–ratio ranged between
0.01 and 0.69 (median, 0.08). These low concentrations
indicate that ketorolac does not readily penetrate cere-
brospinal fluid in children.
Keywords: Ketorolac; cerebrospinal fluid; pharmacoki-
netics; child; infant
Journal of Clinical Pharmacology, 2008;48:495-501
© 2008 the American College of Clinical Pharmacology
longer with ketorolac.1,2 Becauce ketorolac causes
less sedation and emesis than morphine and does not
cause respiratory depression, it is a commonly used
analgesic for pediatric surgery in some countries.3
Ketorolac is a racemic agent, a pyrrole acetic acid
derivative structurally related to indomethacin, with
potent analgesic properties and moderate anti-
inflammatory and antipyretic effects. Ketorolac is
selective for cyclo-oxygenase-1 (COX-1), and inter-
rupts prostaglandin synthesis by inhibiting COX-1
in lower concentrations than COX-2.4 In addition to
peripheral adverse effects, ketorolac may cause
some neurological adverse effects. Headache, dizzi-
ness, somnolence, nervousness, and paresthesias
have been reported, and very rare cases of serious
adverse effects such as seizures, hearing loss, and
psychotic disorders have also been reported.5
Both animal and human data indicate that COX
inhibitors suppress primary hyperalgesia both at
peripheral tissues and in the central nervous system
(CNS). At the spinal cord, ketorolac and other NSAIDs
suppress prostaglandin (PG), especially PGE2-produc-
tion, which elicits nociceptive behavior and is an
important mediator in different pain states.6 Animal
495
 KUMPULAINEN ET AL
data shows that intrathecal NSAIDs are 100-fold more
potent than systemic NSAIDs in reducing postopera-
tive pain and inflammatory hyperalgesia.7 Recent
human data has shown that ketorolac and other COX
inhibitors exert a potent antihyperalgesic action fol-
lowing spinal delivery by suppressing PGE2 produc-
tion.8 However, it should be noted that the commercial
ketorolac tromethamine injection should not be given
intrathecally because it contains alcohol.
In order to have CNS effects, whether beneficial or
harmful, the drug would penetrate the blood–brain
barrier (BBB) at sufficient concentrations. There
seems to be significant differences in the rate and
extent of BBB penetration between different nonopi-
oid analgesics.9-12 The physical and chemical charac-
teristics of NSAIDs would suggest that their CNS
penetration is low, and the data from adults indicates
that ketorolac may be one of the compounds with rel-
atively poor cerebrospinal fluid (CSF)-penetration.13
To our knowledge, the BBB penetration of ketorolac
has not been described in children. Therefore, we
designed the present study to evaluate the lumbar
CSF penetration of ketorolac via spinal anesthesia in
healthy children undergoing surgery in the lower
part of the body.
METHODS
This open, prospective study was conducted in the
Kuopio University Hospital, Kuopio, Finland. The
protocol was approved by the Research Ethics
Committee of the Hospital District of Northern Savo,
Kuopio, Finland (No. 120/2004), the Finnish National
Agency for Medicines was notified (No. 161/2004),
and the trial was recorded in the EudraCT database
(No. 2004-001702-27) and conducted in accordance
with the Declaration of Helsinki.
This report is a part of our “Nonopioid analgesics
in CSF in children” study, and the protocol has been
described earlier.9-12 Briefly, 33 children were asked to
participate in the study, and parents of 30 generally
healthy children, aged 3 months to 12 years, who had
surgery in the lower part of the body under spinal
anesthesia, gave written informed consent, and
children old enough to understand gave their assent.
Children who had contraindications to ketorolac or
lumbar puncture were excluded. The children under-
went inguinal (n = 10), urological (n = 11), or lower
limb orthopedic (n = 9) surgery.
The children received a single 5-minute IV injec-
tion of ketorolac 0.5 mg⋅kg–1 (Toradol 30 mg⋅mL–1,
Roche Oy, Espoo, Finland, lot No. B1889), diluted
496 • J Clin Pharmacol 2008;48:495-501
in 20 mL of normal saline in a dorsal hand vein.
Midazolam-ketamine premedication and midazo-
lam, thiopental, and/or propofol sedation was used
to facilitate lumbar puncture. During lumbar punc-
ture, between 11 minutes and 6 hours and 23 min-
utes after ketorolac injection, a 1 mL CSF sample
was collected, and thereafter levobupivacaine was
injected intrathecally. Within 2 minutes, an indwelling
catheter was inserted in a dorsal foot vein, and a
3-mL blood sample was obtained.
In the postanesthesia care unit (PACU), vital signs,
adverse effects, and pain were monitored. Six children
had an epidural catheter for postoperative pain man-
agement. Before discharge in the PACU, the children
received acetaminophen 15 mg⋅kg–1 IV or 30 mg⋅kg–1
per rectum (n = 29) and ketoprofen 1 mg⋅kg–1 IV (n =
20), or ibuprofen 10 mg⋅kg–1 by mouth (n = 2). Ten
children had significant pain in the PACU (pain
score >3 at rest and/or >5 with light pressure [20 N]
on wound area on a scale of 0-10), and they were
given a single dose of fentanyl 1 μg⋅kg–1 IV (n = 8) or oxy-
codone 0.05 mg⋅kg–1 IV (n = 2) for rescue analgesia.
Ketorolac Assay
Ketorolac concentrations were measured in CSF,
plasma, and protein-free plasma samples by gas chro-
matography with mass spectrometric detection. Briefly,
blood samples were collected into heparinized tubes,
plasma was obtained by centrifugation at 3000 g
at 20°C for 10 minutes, and the samples were stored
for 5 to 7 months at –80°C in polypropylene tubes
and protected from light. Protein-free plasma was
obtained by ultrafiltration at 25°C using the
Centrifree Micropartition Devices (Centrifree YM-30;
Millipore Corporation, Bedford, Mass). Ketorolac was
isolated from CSF (500 μL), plasma (100 μL), and pro-
tein-free plasma (200 μL) by solid phase extraction.
Analytes were quantified with selected ion monitoring
at mass-to-charge ratio 254 and 294 for pentafluo-
robenzyl derivative of ketorolac and diclofenac (inter-
nal standard), respectively. The range of the method
was 0.1 to 14 μg⋅L–1, 340 to 17 000 μg⋅L–1, and 0.7 to
34 μg⋅L–1 for CSF, plasma, and protein-free plasma
samples, respectively. Accuracy, recovery, and intra-
day precision of the method was studied at 3 different
concentration levels in each range of the method. The
accuracy and recovery of the methods ranged between
80% to 120% and 80% to 95%, respectively. The
intraday precision at the lowest level of quantification
was less than 20% (percentage of the coefficient of
variation [%CV]).
 KETOROLAC IN CSF
Figure 1. Cerebrospinal fluid (CSF) and plasma concentrations
of ketorolac after an IV injection of 0.5 mg⋅kg–1. One patient was
administered ketorolac 0.35 mg⋅kg–1 subcutaneously.
Figure 2. The ratio of ketorolac cerebrospinal fluid (CSF) to
unbound plasma concentrations. Open squares ( ) represent
children who received IV ketorolac 0.5 mg⋅kg–1. Dark squares („)
represent children who received IV ketorolac 0.5 mg⋅kg–1 where no
ketorolac was detected in the CSF. Dark triangle (S) represents the
one patient who received ketorolac 0.35 mg⋅kg–1 subcutaneously.
Asterisk (*) represents the one blood-stained CSF sample.
Statistics
No formal sample size calculation was performed, but
a sample of 30 children was considered to provide suf-
ficient information on CSF penetration of ketorolac.
Data was entered and analyzed with the Statistical
Package for Social Sciences (SPSS software version
14.0 for Windows; SPSS Inc, Chicago, Ill). Correlations
between ketorolac concentrations and patient charac-
teristics were tested with the Pearson correlation test
and independent samples t test. Cerebrospinal fluid
concentrations below the limit of detection (0.1 μg⋅L–1)
PEDIATRICS
were included in the analysis with the value 0.05 μg⋅L–1
(ie, the value between 0 and 0.1 μg⋅L–1). A P value of .05
was considered as the limit of statistical significance.
Data are expressed as number of cases or minimum,
median, and maximum.
RESULTS
Thirty-three patients were asked to participate, parents
of 3 refused the consent and therefore the study group
consisted of 30 generally healthy children: 17 boys
and 13 girls aged 3 months to 11 years and 2 months
(median, 3 y, 10 mo). Their weight ranged between 6
and 49 kg (median, 15 kg) and height between 59 and
159 cm (median, 100 cm). There was one minor pro-
tocol deviation: one child (patient No. 14) had ketoro-
lac 0.35 mg⋅kg–1 subcutaneously due to extravasation
of the infusion. One CSF sample (patient No. 19) was
yellowish in color indicating that it may have been
contaminated with blood. His sample contained the
highest CSF concentration of ketorolac. Neither of the
results was excluded. All the remaining children
received the study medication as defined in the proto-
col, and all CSF and plasma samples were collected as
defined in the protocol.
The patients’ characteristics, individual sampling
times, and ketorolac concentrations are presented in
Table I and Figure 1. Ketorolac was detected from
22 of the 30 CSF samples, and concentrations ranged
between 0.2 and 7.6 μg⋅L–1 (median, 0.6 μg⋅L–1). There
was no statistically significant correlation between
the CSF ketorolac concentration and the sampling
time or gender of the children, but the CSF ketorolac
concentration had a negative correlation with the
children’s age (Pearson r = –0.52; P = .005), height
(Pearson r = –0.57; P = .002), weight (Pearson r = –0.50;
P = .007), and body surface area (Pearson r = –0.53;
P = .003); that is, younger and smaller children had
higher CSF ketorolac concentrations.
Ketorolac was detected in all 30 plasma samples at
similar concentrations reported earlier.14,15 Ketorolac
total plasma concentrations ranged between 449 μg⋅L–1
and 4831 μg⋅L–1 (median, 2603 μg⋅L–1), and unbound
ketorolac plasma concentrations ranged between 2.0
μg⋅L–1 and 31.9 μg⋅L–1 (median, 9.1 μg⋅L–1).
The CSF to unbound plasma concentration ratio
ranged between 0.01 and 0.69 (median, 0.08) (Figure 2).
The CSF to total plasma concentration ratio ranged
between 0.00007 and 0.002 (median, 0.0002). Ketorolac
was 99.2% to 99.9% (median, 99.7%) bound to
plasma proteins. Nine children developed 9 nonseri-
ous, expected adverse effects: agitation (n = 4), anxiety
(n = 3), vomiting (n = 1), and urticaria (n = 1).
497
 KUMPULAINEN ET AL

Table I Cerebrospinal Fluid (CSF), Unbound Plasma, and Total Plasma Ketorolac
Concentrations in Each Patient
Patient Sampling CSF Concentration, Unbound Plasma Total Plasma
Number Gender Age, mo Height, cm Weight, kg Time, min μg⋅⋅L–1 Concentration, μg⋅⋅L–1 Concentration, μg⋅⋅L–1

24 Male 61 121 22 11 ND 14.9 2160

17 Female 47 103 17 13 0.3 15.6 579
22 Female 16 80 11 18 1.6 15.4 4496
29 Female 122 141 33 18 ND 13.9 3889
3 Male 25 96 18 19 ND 31.9 1265
13 Male 24 89 12 21 0.4 29.7 1522
21 Male 26 93 15 22 0.5 12.1 1883
23 Male 13 76 10 25 0.7 8.3 1680
30 Male 10 75 11 25 3.0 25.8 1560
26 Male 6 67 8 31 0.9 7.7 2622
19 Male 3 59 6 32 7.6a 11.0 2623
14 Male 31 85 13 50 0.2b 5.5b 2603b
20 Male 6 65 6 50 2.9 9.8 3617
4 Female 55 110 18 62 2.0 10.8 1553
11 Female 11 76 12 65 0.6 3.3 1922
25 Male 114 143 35 71 0.6 13.7 623
27 Male 37 94 13 76 1.6 9.1 3521
1 Female 67 120 20 77 0.3 4.1 449
28 Male 80 123 24 77 0.3 9.1 3245
5 Male 70 115 22 78 ND 6.9 3851
10 Male 46 101 15 80 0.4 7.5 3953
12 Female 53 98 14 80 0.4 11.2 4386
8 Female 113 136 29 87 0.3 5.0 4352
15 Female 88 119 24 95 0.2 3.8 3093
6 Male 74 120 24 109 ND 4.3 1738
7 Female 54 110 15 136 ND 5.8 2618
9 Female 134 159 49 205 ND 3.3 1985
2 Male 35 94 13 246 0.4 2.0 1463
16 Female 4 63 7 325 0.9 2.6 2431
18 Female 122 138 33 383 ND 2.0 4831
Minimum 3 59 6 11 0.2 2.0 449
Maximum 134 159 49 383 7.6 31.9 4831
Median 47 101 15 71 0.6 9.1 2603
ND, none detected.
a. Blood-stained sample.
b. Received ketorolac 0.35 mg⋅kg–1 subcutaneously.

DISCUSSION the ketorolac plasma concentration was found in the

To our knowledge this is the first study describing the
CSF penetration of ketorolac in children. The present
study indicates that ketorolac does not readily pene-
trate the BBB, because ketorolac was detected in only
two thirds of the CSF samples, and these were at low
concentration (less than 3 μg⋅L–1 except for the one
blood-stained sample). While the CSF ketorolac con-
centrations ranged between 0.2 μg⋅L–1 and 3.0 μg⋅L–1,
the plasma concentrations ranged between 450 μg⋅L–1
and 4800 μg⋅mL–1. In other words, less than 0.05% of
CSF. In the present study the BBB penetration of
ketorolac was negligible, especially in older children.
The highest CSF concentrations were measured in the
youngest children aged 3, 6, and 10 months, and in all
9 children ≤2 years old, ketorolac could be quantified
from the CSF samples. On the contrary, in 8 of 21
children >2 years of age, the CSF ketorolac concentra-
tions were below the quantification limit of 0.1 μg⋅L–1.
In the present study, ketorolac was dosed according
to body weight. However, in pediatric pharmacother-
apy, drugs are commonly dosed according to the body

498 • J Clin Pharmacol 2008;48:495-501

 KETOROLAC IN CSF
Figure 3. Ketorolac concentrations in cerebrospinal fluid (CSF).
Open squares ( ) represent children who received IV ketorolac
0.5 mg⋅kg–1 in the present study (n = 30). Asterisk (*) represents
the one blood-stained CSF sample in the present study. Dark dia-
monds (‹) represent adults who received intramuscular ketoro-
lac 90 mg in a previous study (n = 29, Rice et al, 1993).13
surface area (BSA), which results in higher doses in
small children. Therefore, if we had used BSA-based
dosing, small children would have had probably
higher CSF concentrations. Moreover, the sampling
times were not evenly distributed in the different age
groups, and further studies are warranted to confirm
this finding.
Rice et al13 administered ketorolac intramuscu-
larly in adults at a dose of 1.3 mg⋅kg–1, ie, a 2.6-fold
higher dose than that in the present study. They
found the highest CSF concentration of ketorolac of
5.7 μg⋅L–1 (vs 3.0 μg⋅L–1 after ketorolac 0.5 mg⋅kg–1 IV
in the present study), and an average concentration
of 2.1 μg⋅L–1 (vs 0.5 μg⋅L–1 in the present study). After
intramuscular injection, the highest CSF concentra-
tions were obtained later, at 100 to 150 minutes
(compared with 25-50 minutes in the present study
after IV administration). However, the retention time
of ketorolac in CSF seems to be short after IV injec-
tion, because in the present study ketorolac could be
detected from only 2 of the 6 CSF samples obtained
later than 95 minutes after injection, while after
intramuscular administration, significant concentra-
tions were detected up to 5 hours later (Figure 3).
The determination of the CSF penetration of
ketorolac and other nonopioid analgesics may clar-
ify differences in their analgesic efficacy and CNS
adverse effects. It is assumed that the analgesic
effects of ketorolac, as well as other nonopioid anal-
gesics, are partly due to central effects of these
drugs,7,8,16,17 which are possible only if a sufficient
amount of the drug enters the CNS and reaches the
PEDIATRICS
receptor site. Drugs can permeate the BBB by passive
diffusion and by active transport. Ketorolac is a
small, lipophilic molecule, suggesting ready diffu-
sion. However, in plasma ketorolac is ionized and
extensively bound to proteins (>99%), which sug-
gests poor diffusion. Moreover, there is evidence
that NSAIDs such as indomethacin and ibuprofen
interact with efflux-proteins, which are present also
at the BBB (organic anion transporter [OAT], mul-
tidrug resistance protein [MRP]).18,19 However, the
role of transporters with ketorolac is not known.
There seems to be significant differences between
different nonopioid analgesics in their CSF penetration
in children. The BBB penetration of indomethacin,
which is another acetic acid derivative and structurally
related to ketorolac, also seems to be negligible.10 After
indomethacin 0.35 mg⋅kg-1 IV, CSF concentrations
ranged between 0.2 μg⋅L–1and 5.0 μg⋅L–1, and the aver-
age CSF concentration was 1.9 μg⋅L–1 (vs 0.5 μg⋅L–1 after
ketorolac 0.5 mg⋅kg–1 IV in the present study). As with
ketorolac, the BBB penetration of indomethacin was
less in older children but contrary to the present study,
most children developed significant CSF concentra-
tions, and the clearance of indomethacin from the CSF
was slower than that of ketorolac.
The propionic acid derivatives ibuprofen and
ketoprofen seem to penetrate the BBB more readily
than the acetic acid derivatives. After ibuprofen 10
mg⋅kg–1 IV, the average CSF concentration was 184
μg⋅L–1, which is 400 times higher than that in the pre-
sent study after IV ketorolac, although the dose was
only 20 times higher. Moreover, the CSF ibuprofen
concentration equaled the unbound plasma concen-
tration quickly, and up to 2% of the total plasma con-
centration could be detected in the CSF.11 The data
on ketoprofen indicates that not only the extent but
also the rate of BBB permeation may vary between
the different compounds. After ketoprofen 1 mg⋅kg–1
IV, the average CSF concentration was 8 μg⋅L–1 and
the CSF concentration increased with increasing time,
which is a unique phenomenon among the com-
pounds tested in our studies so far and which we
believe could explain the excellent analgesic efficacy
of ketoprofen in acute pain management in children.9
Acetaminophen penetrates the BBB much more
readily than NSAIDs and remains in the CSF in
appreciable concentrations significantly longer. One
hour after acetaminophen 15 mg⋅kg–1 IV, the CSF
concentrations are similar or higher to those in
plasma, ie, up to 200% of that in plasma could be
detected in the CSF, and the CSF acetaminophen
concentrations are above 5 mg⋅L–1 for up to 4 hours
after injection.12
499
 KUMPULAINEN ET AL
The time course of the CSF penetration of ketoro-
lac in the present study was similar to the onset of
analgesia reported following IV ketorolac. Ketorolac
was detected in only 3 of the first 5 samples collected
at 11 to 19 minutes. The first significant CSF concen-
tration of ketorolac was measured at 18 minutes and
the highest CSF concentrations at 25 and at 32 min-
utes after the injection, which is consistent with the
onset of pain relief after IV ketorolac within 15 to 20
minutes both in children1 and in adults.2 This sup-
ports the assumption that the COX inhibition at the
spinal cord has an important role in the analgesic
action of NSAIDs in acute pain. It has been suggested
that spinal COX-1 inhibition plays an important role
in suppression of the nociceptive component of acute
pain and later when the COX-2 expression has
occurred, spinal COX-2 inhibition suppresses inflam-
matory pain.16 In animal studies it has been shown
that ipsilateral spinal COX-1 increases significantly
after surgery16 and that COX-1-inhibition at the spinal
cord restores spontaneous behavior after surgery.20
Since animal data shows that intrathecal administra-
tion of ketorolac is 200 times more potent than
systemic administration,7 it seems that the CSF con-
centrations achieved after parenteral administration
of ketorolac in children in the present study and in
adults13 could be large enough to counter the initial
nociceptive component of postoperative pain.
Both animal and human data indicates that at the
spinal cord the PGE2 receptor is the key-signaling
element where spinal inflammatory hyperalgesia is
inhibited.17 In the spinal cord, PGE2 stimulates and
enhances evoked release of excitatory neurotrans-
mitters and excites dorsal horn neurons. Recent data
has shown that ketorolac and other COX inhibitors
exert a potent antihyperalgesic action following
spinal delivery by suppressing PGE2 production.8
However, it should be noted that the commercial
ketorolac tromethamine injection contains alcohol
and, thus, should not be given intrathecally. In ani-
mal studies and in phase 1 human experiments,
preservative-free ketorolac has been administered
intrathecally. These studies confirm that ketorolac,
like some other NSAIDs and acetaminophen, has a
powerful spinal antinociceptive action.16,17 The
safety and efficacy of intrathecal ketorolac infusion
has been demonstrated in dogs21 and recently in a
phase I study in human volunteers.8
In conclusion, the present study indicates that the
CSF penetration of ketorolac in children is relatively
slow in rate and low in extent, and that ketorolac is
cleared from the CSF relatively rapidly when admin-
istered as an IV bolus. However, because the peak
concentration in CSF is achieved at the same time as
500 • J Clin Pharmacol 2008;48:495-501
the onset of meaningful analgesic action is seen, this
supports the assumption that COX-1 inhibition is
important for reducing the first nociceptive compo-
nent after surgery.
Financial disclosure: None declared.
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