Current Medical Research and Opinion Vol. 28, No.

12, 2012, 1873–1880

0300-7995 Article ST-0208.R1/744302

doi:10.1185/03007995.2012.744302 All rights reserved: reproduction in whole or part not permitted

Brief review
A review of intranasal ketorolac tromethamine
for the short-term management of moderate
to moderately severe pain that requires
analgesia at the opioid level

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Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14

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Abstract
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Andy He

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Post-Doctoral Fellow, College of Pharmacy and Health

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Background:

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Sciences, St. John’s University, Queens, New York;
American Regent, Inc., Shirley, New York, USA An intranasal (IN) formulation of ketorolac was recently FDA approved in adult patients for the short-term
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le is al management of moderate to moderately severe pain that requires analgesia at the opioid level.
Elliot V. Hersh
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For personal use only.

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Department of Pharmacology, University of

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Scope:
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Pennsylvania School of Dental Medicine, Philadelphia,

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PA, USA The aim of this paper is to provide an overview of the clinical pharmacology, pharmacokinetics, efficacy, and
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tolerability of IN ketorolac. Databases used for this literature search include PubMed, International
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Pharmaceutical Abstracts, Cochrane Library and ClinicalTrials.gov from January 1980 to January 2012.
Address for correspondence:
All primary papers on IN ketorolac were eligible, including pharmacologic, pharmacokinetic, clinical,
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Andy He, PharmD, St. John’s University, St. Albert Hall

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outcomes, and meta-analyses. The approved product labeling was a source of information, as well as
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Room 114, 8000 Utopia Parkway, Queens,

the bibliographies of published articles which were reviewed for additional pertinent literature.
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NY 11439, USA.
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Tel.: þ1 631 924-4000 x228;

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Fax: þ1 631 924-1731; Findings:

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hea@stjohns.edu
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The search yielded six relevant studies all of which were selected for this review and included efficacy and
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safety trials, one pharmacokinetics study, and one preclinical study. IN ketorolac is a non-steroidal
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Keywords: inflammatory drug that exhibits its effect mainly by inhibiting cyclo-oxygenase (COX) 1 and 2 with high
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Acute pain – Intranasal analgesic – Intranasal affinity for COX-1. Absorption of IN ketorolac displays a median tmax of 0.50–0.75 hours and has a t½ of
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ketorolac – NSAIDs approximately 5–6 hours. Primary analyses included evaluation of morphine use and summed pain intensity
difference (SPID) which was assessed using a visual analog scale. In one of the two phase III studies, the
Un t

Accepted: 24 October 2012; published online: 9 November 2012

mean SPID6 score was 83.3 in the IN ketorolac group versus 37.2 in the placebo group, p ¼ 0.007. In
th

Citation: Curr Med Res Opin 2012; 28:1873–80

another phase III study, the mean SPID6 score was 117.4 in the IN ketorolac group versus 89.9 in the
placebo group, p ¼ 0.032. IN ketorolac was well-tolerated with most adverse events associated with the
route of administration.

Conclusion:
Based on the clinical trials reviewed, IN ketorolac was associated with significant pain reduction in patients
with various post-operative procedures, with good tolerability.

Introduction
Inadequate pain management is often a problem for the estimated 25 million
Americans experiencing acute pain due to injury or surgery yearly1. The most
common causes of acute pain include surgery, acute illness, trauma, labor/deliv-
ery and medical procedures1. In the majority of the cases, pain management
will rely on pharmacologic treatment, predominantly non-opioid and opioid

! 2012 Informa UK Ltd www.cmrojournal.com He & Hersh 1873

 Current Medical Research and Opinion Volume 28, Number 12
analgesic agents. A new formulation of ketorolac tro-
methamine was recently approved for short-term manage-
ment of moderately to moderately severe pain that requires
analgesia at the opioid level2. Though not a new molecular
entity, ketorolac tromethamine is highly water soluble,
which allows the preparation of a solution for intranasal
use3. Other formulations of ketorolac that are available
include injectable, oral, and ophthalmic formulations,
approved in 1989, 1991, and 1992, respectively4.
The parenteral formulation of ketorolac was the first
injectable non-steroidal inflammatory drug (NSAID)
approved in the United States for use as an analgesic5.
Parenteral ketorolac is distinct from other NSAIDs due
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14
to its strong analgesic activity where it has been shown
to have similar efficacy to injectable opioids6.
Premarketing clinical trials with approximately 5000
patients demonstrated that the analgesic efficacy of paren-
teral ketorolac was similar to that of parenteral opioids in
patients undergoing general and oral surgery5. The anal-
gesic efficacy of intramuscular ketorolac was shown to be
comparable to standard dosages of morphine and meperi-
dine in patients who had various surgical procedures6.
When compared to morphine, the efficacy of intramuscu-
lar ketorolac 30 mg provided relief comparable to intra-
For personal use only.
muscular morphine 6–12 mg7. A recent study in oral
surgery outpatients confirmed its efficacy at a 15 mg intra-
venous dose8. A 10 mg oral formulation is also available,
but is only indicated as continuation therapy after paren-
teral treatment9.
Further supporting of ketorolac’s pronounced analgesic
activity, is its well-described opioid-sparing effect10–12.
Opioid-induced adverse events are a concern as they
may reduce quality of life and further impair it by limiting
the dosage of opioid analgesic due to bothersome to
intolerable side-effects such as sedation, psychomotor
impairment, nausea and constipation13. Opioid-induced
constipation can delay hospital discharge14. A 25–50%
reduction in opioid requirements has been shown
with combination therapy of ketorolac with opioids6.
This benefit of concomitant therapy may decrease
opioid-induced adverse events and accelerate hospital
discharge6.
Ketorolac tromethamine nasal spray is an intranasal
formulation of ketorolac developed for patients who
require pain relief at the opioid level. It was approved by
the US Food and Drug Administration (FDA) in May
2010. This paper reviews the clinical pharmacology,
pharmacokinetic properties, efficacy, and tolerability of
ketorolac tromethamine nasal spray.
Methods
A literature search (from January 1980 to January 2012)
was conducted using the search terms intranasal ketorolac,
1874 He & Hersh
December 2012
O OH
OH HO OH
N
NH2
O
Figure 1. Chemical structure of ketorolac tromethamine2.
nasal ketorolac, SPRIX, and ketorolac from PubMed,
International Pharmaceutical Abstracts, Cochrane
Library, and ClinicalTrials.gov. Data found from various
papers were screened for relevancy for this review. All
primary, original papers on intranasal ketorolac were eli-
gible, including pharmacologic, pharmacokinetic, clinical,
outcomes, as well as any meta-analyses. The approved
product labeling was a source of information, as well as
the bibliographies of published articles which were
reviewed for additional pertinent literature.
Results
Six relevant articles were identified and were included
in this review. Four clinical trials evaluated the efficacy
and safety of intranasal ketorolac. The other two studies
included a pharmacokinetics evaluation in healthy volun-
teers and a preclinical study in rats and rabbits. A numer-
ical discrepancy with regard to doses was found in one of
the articles identified compared with FDA approved doses.
A clarification with the sponsor indicated that the doses
studied were 15.75 mg and 31.5 mg and not 15 mg and
30 mg.
Clinical pharmacology
Ketorolac tromethamine is an NSAID indicated in adult
patients for the short-term (up to 5 days) management of
moderate to moderately severe pain that requires analgesia
at the opioid level2. It is a racemic mixture of [–] S- and [þ]
R-enantiomeric forms, with the S-form having analgesic
activity2. The chemical name for ketorolac tromethamine
is ()-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic
acid, compound with 2-amino-2 -(hydroxymethyl)-1,3-
propanediol (1:1), and the structural formula is shown in
the Figure 12.
Mechanism of action
Behaving like other NSAIDs, ketorolac is a cyclo-oxyge-
nase (COX) inhibitor, inhibiting both COX-1 and COX-
2, although it has higher affinity for COX-1 than other
representative NSAIDS3,16. Cyclo-oxygenase is an
enzyme that metabolizes arachidonic acid to prostaglan-
dins, prostacyclin, and thromboxanes3. Regarding the
www.cmrojournal.com ! 2012 Informa UK Ltd

Table 1. Ketorolac pharmacokinetic parameters after single-dose administration.
Parameter Intranasal
15.75 mg
Cmax, ng/mL 916 (293)
tmax, h* 0.50 (0.25–1.00)
AUC0–t ng h/mL 3723 (1483)
AUC 0–1, ng h/mL 3907 (1569)
t½ , h 4.76 (1.38)
Values are expressed as mean (SD); n ¼ 15.
*Median (range).
activation of peripheral nociceptors, prostaglandin E2
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and prostacyclin (PGI2) appear to be key players17.
Prostaglandins play a function in pain as they are released
from injured tissues3. At the site of injury and inflamma-
tion, prostaglandins are thought to sensitize afferent nerve
endings to other mediators of pain (histamine, bradykinin,
etc.), and thus, diminished prostaglandin concentrations
at these nerve endings should ultimately mitigate the pain
response3,18.
Pharmacokinetics
For personal use only.
McAleer et al.15 conducted a pharmacokinetic and safety
study comparing a single-dose of intranasal (IN) and intra-
muscular (IM) ketorolac in 15 healthy volunteers aged
19–45 years and weighing 49–92 kg who were followed
for up to 24 hours post-dose. In this crossover, randomized
study, 15.75, 31.5, and 47.25 mg of IN ketorolac were com-
pared to 15 and 30 mg of IM ketorolac. Based on this study
and other literature, data have shown that ketorolac exhi-
bits linear pharmacokinetics. Similar to the observed IM
administration, IN ketorolac exhibited rapid absorption
with a median tmax ranging from 0.50 to 0.75 hours, and
a t½ of approximately 5–6 hours. Relative bioavailability of
IN ketorolac was approximately 67–75% as compared to
an absolute bioavailability of 100% in the IM formulation
of ketorolac. Plasma concentrations of 31.5 mg IN
ketorolac fell approximately between that of 15 and
30 mg IM ketorolac. A comparison of the pharmacokinetic
parameters among the treatment groups are displayed
in Table 115.
According to the package insert, the mean apparent
volume of distribution is approximately 13 liters2.
Ketorolac is a highly protein bound drug (approximately
99%). Mainly metabolized by the liver, the metabolic
products are hydroxylated and conjugated forms of the
parent drug. After metabolism, ketorolac and its metabo-
lites are eliminated renally, with around 92% of the given
dose found in the urine and, to a minimal extent, in the
feces (6%).
In a single-dose study (31.5 mg) that was conducted to
explore IN ketorolac’s pharmacokinetics in the elderly, the
! 2012 Informa UK Ltd www.cmrojournal.com
Current Medical Research and Opinion Volume 28, Number 12 December 2012
Intramuscular
31.5 mg 15 mg 30 mg
1806 (883) 1163 (280) 2382 (443)
0.75 (0.50–2.00) 0.75 (0.25–1.50) 0.75 (0.23–1.03)
7141 (3466) 4956 (1921) 10770 (3886)
7477 (3654) 5196 (2077) 11153 (4260)
5.24 (1.33) 5.00 (1.72) 4.80 (1.11)
exposure of IN ketorolac was increased by 23% for adults
65 years as compared to subjects565 years2. Terminal t½
was longer in the elderly population as compared to the
non-elderly, 4.5 vs. 3.3 hours, respectively. From a single-
dose study, the mean t½ of IN ketorolac in renally impaired
patients was found to be between 6 and 19 hours and is also
dependent on the extent of impairment. The AUC1 of
each enantiomer was increased by 100% in patients with
renal disease as compared to healthy volunteers. Reducing
the dose by 50% is recommended in these patient popula-
tions. Hepatic impairment has also been studied; however,
no significant difference in t½, AUC1, and Cmax was
observed.
Efficacy
Four clinical trials have assessed the efficacy of IN ketor-
olac tromethamine using patient populations with moder-
ate-to-severe pain (i.e., abdominal, orthopedic and oral
surgery)19–22. Assessments of pain intensity as measured
on a 100 mm visual analog scale (VAS), pain intensity
difference (PID), summed pain intensity difference
(SPID), morphine dosage use, perceptible and meaningful
relief, quality of pain relief, global assessment of pain con-
trol, and total pain relief scores (TOTPAR) have been
used as outcomes measures. The VAS evaluates pain
intensity from 0 to 100, where 0 represents no pain and
100 is the worst pain imaginable. PID is calculated by sub-
tracting the post-treatment VAS score from the baseline
VAS score. SPID is calculated by adding the weighted PID
score over specific intervals. Therefore, a higher SPID
score indicates greater overall pain relief for that time
period. The use of stopwatch techniques is utilized for mea-
sures of perceptible and meaningful pain relief.
Summarization of the clinical trials is found in Table 2.
Moodie et al.19 reported the results from a randomized,
double-blind, placebo-controlled study that compared the
efficacy of IN ketorolac to placebo in patients (mean age
53 years) who underwent major surgery (i.e., abdominal
and orthopedic). A total of 127 patients were randomized
to receive one of the three intranasal treatments
(i.e., 10 mg, 31.5 mg IN ketorolac, or IN placebo).
He & Hersh 1875
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For personal use only.

1876
He & Hersh
Table 2. Summary of clinical trials of intranasal ketorolac.

Study Study design Patient population Study drug administration Primary efficacy endpoint Efficacy results Tolerability results
Current Medical Research and Opinion

Moodie et al. R, DB, PC 127 patients with 10 mg, 31.5 mg of IN Total morphine use by PCA Mean morphine use (mg) Top 3 adverse events
(2009)19 abdominal or orthope- ketorolac, or IN placebo (from start of dosing (SEM) 0–24 h Placebo: pyrexia (61.9%),
dic surgeries having an Q8H for 40 h through 24 h) Placebo: 56.5 mg (4.8) nausea (47.5%), tachycardia
PI score of 40 mm on Morphine sulfate (1 mg 10 mg IN ketorolac: (40.5%)
a 100 mm VAS of MS each actuation 54.3 mg (6.4) 10 mg IN ketorolac: nausea
with a lockout time of 31.5 mg IN ketorolac: (58.1%), pyrexia (55.8%),
6 min) administered via 37.8 mg (5.0) headache (34.9%)
PCA was available for (p = 0.0013 for 31.5 mg IN ketorolac:
Volume 28, Number 12

pain not relieved by 31.5 mg IN ketorolac nausea (45.2%), pyrexia

study drug vs. placebo) (33.3%), vomiting (28.6%)
Brown et al. R, DB, PC 300 patients with abdom- 31.5 mg of IN ketorolac or 6-h summed pain intensity Mean  SE SPID6 score Top 3 adverse events
(2009)20 Consisted of a inal or orthopedic sur- IN placebo TID for up to difference (SPID6) in 31.5 mg IN ketorolac: Placebo: pyrexia/intermittent
single-dose and geries having an PI 5 days the single-dose phase 83.3  10.6 pyrexia (67%), nausea (60%),
December 2012

a multi-dose score of 40 mm on a Back-up analgesia is Placebo: 37.2  12.9 constipation (36%)
phase 100 mm VAS available with MS as (p = 0.007) 31.5 mg IN ketorolac: nausea
PCA (not available at (58%), pyrexia/intermittent
the single-dose phase) pyrexia (44%), constipation
(29%)
Grant and R, DB, PC 80 patients who had third 31.5 mg of IN ketorolac or 8-h summed pain intensity Mean  SE SPID8 score Adverse events
Mehlisch molar extraction sur- IN placebo difference (SPID8) 31.5 mg IN ketorolac: Placebo: 10 events in 8
(2010)21 gery with bony impac- Rescue analgesic 136.7  33.0 patients
tions having an PI score medication was Placebo: IN ketorolac: 3 events in 3
of 450 on a 100 mm provided for pain not 105.2  29.1 patients
VAS relieved by study drug (p50.001)
Singla et al. R, DB, PC, MC 321 patients who had 31.5 mg of IN ketorolac or 6-h summed pain intensity Least square means  SE Top 3 adverse events
(2010)22 abdominal surgery IN placebo Q6H for the difference (SPID6) SPID6 score Placebo: nausea (62%), pyrexia
having an PI score of first 48 h, then up to 31.5 mg IN ketorolac: (34%) constipation (33%)
40 on a 100 mm VAS 4 times/day for up to 117.4  7.7 31.5 mg IN ketorolac: nausea
5 days Placebo: 89.9  10.6 (57%), constipation (28%),
Access to MS via PCA (p = 0.032) vomiting (24%)
was available for first
48 h. Hydrocodone/
APAP was available
when PCA was no
longer required.

R, randomized; DB, double-blind; PC, placebo controlled; PI, pain intensity; VAS, visual analog scale; IN, intranasal; Q8H, every 8 hours; MS, morphine sulfate; PCA, patient-controlled analgesia; SEM, standard error of the
mean; SPID6, 6-hour summed pain intensity difference; SE, standard error; SPID8, 8-hour summed pain intensity difference; MC, multi-center; Q6H, every 6 hours; h, hours; min, minutes; APAP, acetaminophen.

www.cmrojournal.com ! 2012 Informa UK Ltd


These patients received the study drug if they had a pain
intensity (PI) rating of at least 40 mm on a VAS. Study
drug was administered every 8 hours through 40 hours with
assessment before the study drug, at 30 minutes, and at 1, 2,
3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours
after the first study dose. If completed, the patient would
have received six doses of the study drug. Patients that had
pain despite administration of the study drug had access to
patient-controlled analgesia (PCA), i.e. morphine sulfate.
The primary efficacy endpoint was total morphine use
(mg) by PCA from the start of dosing through 24 hours.
Other endpoints that were examined include morphine
use 24–48 hour, 0–48 hours, PID, and SPID.
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At baseline, PI ratings by VAS were similar among the
three groups in addition to the patient demographics,
except for a trend for older age and a greater proportion
of men in the placebo group. The surgical procedures
included were orthopedic (77/127, 61%) and abdominal
(50/127, 39%). The mean morphine consumption for the
first 24 hours was 56.6 mg in the placebo group, 54.3 mg in
the 10 mg IN ketorolac group, and 37.8 mg in the 31.5 mg
IN ketorolac group, (p ¼ 0.0013 between 31.5 mg IN
ketorolac and placebo and p ¼ 0.0332 between the two
IN ketorolac groups). This study data suggest that IN
For personal use only.
ketorolac in 31.5 mg doses significantly reduced morphine
consumption as compared to the 10 mg IN ketorolac and
placebo groups. There were no statistically significant dif-
ferences between the 10 mg IN ketorolac group and pla-
cebo group and the two IN ketorolac groups at 24–48 hours
and 0–48 hours with regard to morphine use. Mean SPID
scores at 4 and 6 hours were higher in the 31.5 mg IN
ketorolac group compared to placebo. The 4-hour SPID
score was 120.1 in the 31.5 mg IN ketorolac group and 89.6
in placebo group (p ¼ 0.0017). The 6-hour SPID score was
195.5 in the 31.5 mg IN ketorolac group and 130.6 in the
placebo group (p ¼ 0.0015). Higher SPID scores in the
31.5 mg IN ketorolac group indicated better overall pain
relief as compared to the other two groups.
In a randomized, double-blind, placebo-controlled,
phase III clinical trial, by Brown et al.20, patients who
underwent various surgical procedures were randomized
in a 2:1 ratio to either 31.5 mg IN ketorolac or placebo,
respectively. This study consisted of two phases, a single-
dose phase and a multi-dose phase that evaluated the effi-
cacy and tolerability of IN ketorolac. On the day of surgery
(day 0), patients were randomized to IN ketorolac or pla-
cebo when their pain intensity (as assessed via VAS)
reached 40 and began to receive study drug with access
to PCA morphine. The day after surgery (day 1), PCA
was withdrawn and patients entered the single-dose
phase if they had a VAS score 40. These patients
received a single dose of IN ketorolac or placebo with
assessment at 30 minutes and hourly for 6 hours without
access to PCA. Patients in the single-dose phase rejoined
the multi-dose phase when pain returned to baseline or if
! 2012 Informa UK Ltd www.cmrojournal.com
Current Medical Research and Opinion Volume 28, Number 12 December 2012
they requested additional analgesia. Patients whose pain
intensity (as assessed via VAS) never reached 40 after
5 hours of withdrawing PCA on day 1 did not enter the
single-dose phase but returned to the multi-dose phase.
Patients in the multi-dose phase continued to receive
study drug as randomized on day 0 (IN ketorolac or pla-
cebo) given three times a day for up to 5 days with PCA as
an option for pain not relieved by the study drug. The
primary efficacy endpoint was the 6-hour summed pain
intensity difference (SPID6) score for patients in the
single-dose phase. Other endpoints that were examined
include PID scores, duration of analgesia, quality of anal-
gesia, meaningful pain relief, total morphine use and global
assessment of pain control. In addition, a categorical mea-
sure termed quality of analgesia was assessed by patients
on a 5-point scale where 0 ¼ poor and 4 ¼ excellent.
Similarly, global assessments of pain control was defined
by patients on a 5-point scale where 0 ¼ poor and
4 ¼ excellent based on a question regarding overall pain
control.
A total of 300 patients were enrolled in the study with
189 patients in the single-dose phase and 210 patients in
the multi-dose phase. The mean age of the patients was
around 52 years with majority of them being female and
Caucasian. No significant differences in baseline charac-
teristics were found among the two groups. Abdominal
(52%) and orthopedic (46%) surgeries were the most
common types of procedure in this patient population.
Results from the study showed that the mean SPID6
score was significantly higher in the IN ketorolac group
compared with the placebo group (83.3 vs. 37.2,
p ¼ 0.007). With regard to SPID48, a statistically signifi-
cant greater reduction in pain was demonstrated in
patients who received IN ketorolac compared to placebo2.
For the mean PID scores, the IN ketorolac group had sta-
tistically significantly higher scores at 0.5, 1, 2, 3, and 4
hours20. Efficacy analysis of the single-dose phase indi-
cated that patients reported better quality of analgesia
with IN ketorolac at each measurement between 0.5
hours and 5 hours (p50.05). At 6 hours, there was a
trend toward better quality of analgesia with IN ketorolac
(p ¼ 0.068). Duration of analgesia was longer in the IN
ketorolac group (median 3.0 hours) than the placebo
group (1.3 hours, p50.04), which is characterized by the
time to restarting PCA or requesting rescue medication in
the single-dose segment. In assessing acute pain relief, a
greater proportion of patients in the IN ketorolac group
reported meaningful pain relief compared to placebo
within 1 hour, (84 vs. 70%, p50.05). At 2 hours, it still
favored the IN ketorolac group but was not statistically
significant (84 vs. 73%, p ¼ 0.058). Reduced morphine
use was associated with IN ketorolac reduction which
ranged between 20 and 50% for the first 24 hours.
During the multi-dose phase, the quality of analgesia was
significantly higher at 8 hours for IN ketorolac compared
He & Hersh 1877
 Current Medical Research and Opinion Volume 28, Number 12
with placebo, however, it was not statistically significant
at 32, 40, and at 48 hours.
Efficacy of IN ketorolac was also reported by Grant and
Mehlischin in patients who had received third molar bony
impaction surgery21. This was a randomized, double-blind,
placebo-controlled study that compared 31.5 mg IN ketor-
olac to a matching IN placebo. Patients were randomized
to a single dose of IN ketorolac or placebo when their VAS
score was 50 subsequent to the dental procedure for up
to 8 hours. Backup analgesia was permitted for pain not
relieved by the study drug. The primary efficacy endpoint
was SPID8. Assessment of other outcomes included PID,
total pain relief (TOTPAR) scores, global pain control,
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and the time to backup analgesia. Pain relief was assessed
on a 5-point scale where 0 ¼ none and 4 ¼ complete.
TOTPAR is calculated from taking a weighted sum of
pain relief scores.
There were 40 patients in each study arm; patients in
the two arms had similar baseline demographics as well as
pain intensity prior to administration of the study drug.
Mean SPID8 score for the IN ketorolac group was signif-
icantly higher compared with the placebo group (136.7 vs.
–105.2, p50.001). The negative mean SPID score in the
placebo group indicates that during the 8-hour evaluation
For personal use only.
period, mean pain intensity continued to increase com-
pared to baseline. PID scores were also higher at every
time point with statistical significance at 20 minutes
through 8 hours (p50.001). Results from the TOTPAR
score indicated better pain relief from the IN ketorolac
group than the placebo group, reaching statistical signifi-
cance for the 4 -, 6 -, and 8-hour area-under-the-curve
measures. The comparison of IN ketorolac with placebo
indicated a faster median onset of perceptible pain relief
(21.5 vs. 480.0 minutes, p50.001), a faster median onset
of meaningful pain relief (66.0 vs. 480.0 minutes,
p50.001), and a longer median time for rescue analgesic
medication (360.0 vs. 95.5 minutes, p50.001), respec-
tively. As assessed from 20 minutes to 8 hours, a greater
percentage of patients in the IN ketorolac group reported
‘some’ (rating of 2) to ‘complete’ (rating of 4) pain relief
compared to placebo. Global assessment of pain control on
a 0–4 scale also favored IN ketorolac with mean scores of
1.9 for the IN ketorolac group and 0.5 for the placebo
group (p50.001).
Using a multicenter (United States and New Zealand),
randomized, phase III, placebo-controlled design study,
Singla et al.22 studied the efficacy and tolerability of IN
ketorolac in abdominal surgery patients. A total of 321
patients were enrolled in the study to receive 31.5 mg IN
ketorolac or placebo every 6 hours in a 2:1 ratio for up to 5
days. Once the patients reached a VAS score 40, they
received their respective study drug with access to mor-
phine sulfate as PCA if their pain was not alleviated with
the study drug for the first 48 hours. Following the first 48
hours, patients who had pain not controlled by the study
1878 He & Hersh
December 2012
drug were permitted an oral analgesic (e.g., hydrocodone/
acetaminophen). Following an intent-to-treat analysis,
the primary efficacy outcome evaluated was the 6-hour
summed pain intensity difference (SPID6). Other end-
points included morphine usage, SPID4, PID, quality of
pain relief, and global assessment of pain control.
Baseline characteristics of both groups did not show any
apparent disparities (mean age of 46, predominantly
female population of 96%, and mostly white). The major-
ity of the abdominal surgical procedures were hysterecto-
mies (69.5%). IN ketorolac was associated with better pain
relief when compared to placebo, as shown by the SPID6
score (least square means 117.4 vs. 89.9, respectively,
p ¼ 0.032). Efficacy was also demonstrated by SPID48
with a statistically significant greater reduction in pain
associated with IN ketorolac when compared to placebo2.
Mean PID scores were statistically higher at 20 minutes, 1,
2, and 3 hours, but were not statistically significant at 4, 5,
and 6 hours22. Both the IN ketorolac and placebo groups
showed decreased pain intensity (as assessed via mean
VAS scores) at 20 minutes through 30 hours, but the
decreases were statistically significantly greater in the IN
ketorolac group. No statistically significant differences
were found after 30 hours. Patient rating on quality of
analgesia (on a scale of 0–4) were better with IN ketorolac
compared to placebo from 20 minutes to 24 hours with
statistically significant differences, except at 40 minutes
and 6 hours. Global assessment of pain control was signif-
icantly better in the IN ketorolac group compared to the
placebo group on day 1, but was not significantly different
on days 2, 3, and 4. Morphine utilization was evaluated
at several time intervals (i.e., 0–24, 0–48, 24–48 and 0–72
hours). Mean morphine use from 0 to 24 hours was 42 mg
in the IN ketorolac group versus 54 mg in the placebo
group (p ¼ 0.003) representing a 22% decrease in opioid
requirement. Mean morphine use from 24 to 48 hours was
23 mg in the IN ketorolac group versus 31 mg in the pla-
cebo group (p ¼ 0.041), indicating a 26% decrease in
opioid requirement. Statistical significance was not
found between 0 and 72 hours even though a 32% decrease
of morphine use was associated with the IN ketorolac
group compared to the placebo group.
Safety and tolerability
Among the two phase III clinical trials, there were similar
overall rates of adverse events between the study groups,
which were 97.5% in the IN ketorolac group and 98.0% in
the placebo group in one study20 and 93% in the IN ketor-
olac group and 96% in the placebo group in another
study22. Since this product is an intranasal product, it is
not surprising that the most frequent adverse events
reported on the package insert are associated with the
route of administration. Based on the postoperative pain
www.cmrojournal.com ! 2012 Informa UK Ltd

studies conducted with a population of 455 patients who
received IN ketorolac, adverse reactions were observed at a
rate of 2% or more and at least twice the incidence seen
in the placebo group and were as follows: nasal discomfort
(15%), rhinalgia (13%), increased lacrimation (5%),
throat irritation (4%), oliguria (3%), rash (3%), bradycar-
dia (2%), urine output decreased (2%), ALT and/or AST
increased (2%), hypertension (2%), and rhinitis (2%)2.
Local nasal symptoms were reported as mild, transient
and did not increase in severity with repeated
dosing20,22. Conversely, IN ketorolac was associated with
modestly less constipation, pyrexia and pruritus (events
frequently associated with opioids) as compared to
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14
placebo, most likely due to the reduction in morphine
utilization with IN ketorolac administration
(Table 2)19,20,22.
Given that ketorolac is an NSAID that is highly
selective for blocking COX-1, gastrointestinal adverse
events become of greater clinical concern with long-term
use than other NSAIDs16,23. A large epidemiologic study
was conducted and investigated the risk of gastrointestinal
and operative site bleeding associated with the use of
parenteral ketorolac. This study concluded that the risk
For personal use only.
of both gastrointestinal bleeding and operative site
bleeding are small, but the risk is higher when therapy
was in higher doses, in older subjects, and for more than
5 consecutive days5. Currently, the oral, parenteral, and
the nasal formulation of ketorolac have a 5-day limitation
as part of their Black Box Warnings on the product
label2,8,24. All four clinical trials had administered IN
ketorolac with a timeframe of 8 hours to 5 days19–22.
There were no reports of gastrointestinal bleeding
associated with IN ketorolac in the two phase III stud-
ies20,22. From the package insert information, seven
patients (n ¼ 455, 1.5%) treated with IN ketorolac
experienced adverse events of bleeding (four patients) or
hematoma (three patients) at the operative site versus one
patient (n ¼ 245, 0.4%) treated with placebo (hema-
toma)2. Because of its potent antiplatelet effects, IN ketor-
olac (similar to other ketorolac formulations) should not
be used as a pre-emptive analgesic before any major
surgery2.
Within the two phase III trials, there were no
clinically relevant differences among the treatment
groups with reference to vital signs, hematology, or clinical
chemistry measurements20,22. Rates of serious adverse
events were similar in the two phase III trials with
2.5%20 and 6%22 in the IN ketorolac arms and 1.9%20
and 6%22 in the placebo arms. Serious adverse events
that may have been related to IN ketorolac included
wound complication and gastrointestinal events.
Regarding treatment-emergent cardiac adverse events,
Singla et al. reported no differences between the two
groups22.
! 2012 Informa UK Ltd www.cmrojournal.com
Current Medical Research and Opinion Volume 28, Number 12 December 2012
Dosing and administration
Currently, intranasal ketorolac is available as single-day
nasal spray bottles in the US. Each single-day nasal spray
bottle contains a sufficient quantity of solution to admin-
ister 8  100 mL sprays after appropriate priming (instruc-
tions included with package insert). Each spray provides
15.75 mg of ketorolac. For adult patients565 years of age,
the dose is 31.5 mg (one 15.75 mg spray in each nostril)
every 6–8 hours. For patients who are 65 years of age,
renally impaired patients, and patients less than 50 kg,
the dose is 15.75 mg (one 15.75 mg spray in one nostril)
every 6–8 hours2.
Discussion
This review included four studies that reported the efficacy
and safety of intranasal ketorolac in adult patients with
acute postoperative pain. These clinical trials were well-
designed studies with well-defined outcomes and included
an adequate number of patients to provide information
about efficacy and safety. Pain assessments included
summed pain intensity difference scores, summed pain
relief scores, quality of analgesia, global evaluation of
pain control, duration of analgesia, and onset of analgesia.
Measurements were based on VAS and categorical rating
scales. To fully assess acute pain relief, the use of percep-
tible pain relief as well as meaningful pain relief was uti-
lized as outcome measures. Evaluation of an opioid-sparing
effect was investigated by an efficacy measure of morphine
use through various time periods. An additional endpoint
that could have been investigated is the percentage of
subjects who needed a rescue medication.
Results from the two phase III trials, like the phase II
trials, indicated better analgesic efficacy with intranasal
ketorolac as compared to placebo with statistical signifi-
cance20,22. Furthermore, Brown et al. (one of the phase III
trials) reported that patients who were treated with intra-
nasal ketorolac required 34% less morphine than patients
who were treated with placebo over 48 hours20. Likewise,
Singla et al. (the other phase III trial) reported that
patients needed 26% less morphine when treated with
intranasal ketorolac than those with placebo22. These
results support efficacy as well as reduced opioid use.
Intranasal ketorolac proved to be well-tolerated with
local nasal symptoms being the most common adverse
reactions among post-operative patients. Among the four
clinical trials, there were no gastrointestinal bleeding
events reported with intranasal ketorolac use.
Major advantages of intranasal ketorolac are the con-
venience afforded by its route of administration relative
to injectable forms and the ability to provide a level of
analgesia similar to that of opioids without side-effects
often associated with this class of analgesics
He & Hersh 1879
 Current Medical Research and Opinion Volume 28, Number 12 December 2012
(e.g., drowsiness and constipation). This review was
limited by the small number of randomized studies. In
addition, the use of supplement PCA morphine in some
studies can act as a potential confounding factor although
this represents a typical standard of care. Post-operative
procedures studied in this review include abdominal, gyne-
cologic, orthopedic, and oral surgery models. These proce-
dures are frequently performed in clinical practice and they
are representative of both inpatient and outpatient set-
tings. Other patient populations who require treatment
for acute pain should be studied in the future. No studies
were available that compared intranasal ketorolac with
oral NSAIDs or opioids. Future research should include
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14
comparative, economic, and post-marketing surveillance
studies.
Conclusion
Based on the literature reviewed, intranasal ketorolac is
efficacious in acute pain relief in adult patients with
good tolerability.
For personal use only.
Transparency
Declaration of funding
The creation of this manuscript was requested by Luitpold
Pharmaceuticals. No funding was provided to the authors for
the preparation of this manuscript.
Declaration of financial/other relationships
A.H. is an employee of St. John’s University and is currently in a
fellowship at American Regent, Inc. E.H. is an employee of
University of Pennsylvania and receives research funding from
Luitpold Pharmaceuticals.
CMRO peer reviewers may have received honoraria for their
review work. The peer reviewers of this manuscript have dis-
closed that they have no relevant financial relationships.
Acknowledgments
Employees of Luitpold Pharmaceuticals, Inc. reviewed the
manuscript.
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