CLINICAL THERAPEUTICS®/VoL.2 6 , N o .

12, 2 0 0 4

Combination Oxycodone 5 mg/Ibuprofen 400 mg for the
Treatment of Postoperative Pain: A Double-Blind, Placeboand Active-Controlled Parallel-Group Study
Thomas Van Dyke, DDS, PhD, 1 Leonard J. Litkowski, DDS, MS, z
Theodore A. Kiersch, DDS, 3 Nooshin Majd Zarringhalam, DMD, 1
Hongjie Zheng, PhD, 4 and Kenneth Newman, MD 4
~Boston University Goldman School of Dental Medicine, Boston, Massachusetts, 2University of Maryland Dental
School, Baltimore, Maryland, SCranial Pain Research, Tucson, Arizona, and 4Forest Research Institute, Jersey City,
New Jersey

ABSTRACT

Objective: This study compared the efficacy and safety of a single dose of oxycodone 5 mg/ibuprofen 400 mg
versus its individual components and placebo in a third-molar extraction model.
Methods: In this multicenter, double-blind, double-dummy, parallel-group investigation, subjects with moderate to severe pain within 5 hours after extraction of >2 ipsflateral bony impacted third molars were randomized to single doses of oxycodone 5 mg/ibuprofen 400 mg, ibuprofen 400 mg, oxycodone 5 mg, or placebo.
Primary efficacy variables were the sum of pain intensity difference over 6 hours (SPID6) and total pain relief
through 6 hours (TOTPAR6). The pharmacokinetics of oxycodone and ibuprofen, alone and in combination,
were also determined in a subset of patients.
Results: A total of 498 subjects were randomized to treatment (187 to oxycodone 5 mg/ibuprofen 400 mg,
186 to ibuprofen 400 mg, 63 to oxycodone 5 mg, and 62 to placebo). Baseline demographics were generally similar among treatment groups, despite differences in sex (P = 0.041) and race (P = 0.023). Combination therapy
was associated with greater analgesia than ibuprofen alone, oxycodone alone, or placebo (mean [SE] TOTPAR6:
13.3 [0.52], 12.2 [0.52], 4.3 [0.82], and 4.2 [0.83], respectively [P < 0.001 vs oxycodone or placebo, P = 0.012 vs
ibuprofen]; mean [SE] SPID6:6.54 [0.42], 5.41 [0.44], 0.14 [0.60], and 0.32 [0.59], respectively [P < 0.001 vs oxycodone or placebo, P = 0.002 vs ibuprofen]). Combination therapy was well tolerated. Pharmacokinetic results
implied no interaction between oxycodone and ibuprofen.
Conclusions: In this study, a single dose of oxycodone 5 mg/ibuprofen 400 mg was fast-acting, effective, and
well tolerated in subjects with moderate to severe pain after dental surgery. Oxycodone 5 mg alone did not provide an efficacy benefit over placebo in this study. (Clin Ther. 2004;26:2003-2014) Copyright © 2004 Excerpta
Medica, Inc.
Key words: analgesia, dental pain, NSAID, opioid, ibuprofen, oxycodone.
Accepted Jor publication November 8, 2004.
Express Track online publication December 6, 2004.
Printed in the USA. Reproduction in whole or part is not permitted.

Copyright © 2004 Excerpta Nedica, Imc.

doi: I O. I 016/j.clinthera.2004.12.002
0149 2918/04/$19.00

2003

CLINICALTHERAPEUTICS®

INTRODUCTION

Nearly 9 in 10 Americans aged >18 years (89%) suffer from pain at least once a month. 1 Pain is commonly divided into 2 subcategories: acute pain and chronic pain. Acute pain is generally related to a recent
identifiable injury, involves a specific sympathetic
nervous system arousal, and serves as a defensive
mechanism for the prevention of further damage to
the body. 2-~ Chronic pain is generally considered to be
pain that has persisted well beyond the normal healing period (more than 3-6 months) and is often
unmanageable, resulting in physical disability, sleep
deprivation, sexual dysfunction, depression, and
poor self-rated health. 5
The use of combination opioid/nonopioid analgesics for acute pain is common medical practice. 2,6
The rationale behind the use of these compounds is
based on the principle that combinations of opioid
and nonopioid analgesics, which have different
modes of action, produce greater analgesia without
potentiating side effects. 6 In contrast, increasing the
dose of either agent alone results in modestly
enhanced efficacy but may increase adverse events to
an intolerable level. This approach also allows the
addition of therapeutic characteristics not present in
the other component (eg, achieving improved antiinflammatory activity over opioid-only treatments by
adding a nonopioid analgesic with anti-inflammatory
properties such as ibuprofen). 7,8
Opioids, which act on opiate receptors at inhibitory synapses, predominantly work on the central pathway by preventing pain messages from reaching the
brain and activating descending analgesic pathways. 9,1° Oxycodone is an opioid analgesic that is
similar in potency to morphine and up to 1.5 times
as potent as hydrocodone. 11 Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen predominantly act peripherally at the first stage of pain
transmission by inhibiting prostaglandin synthesis in
damaged cells. 12 When comparing the efficacy of the
3 commonly used nonopioid analgesics, ibuprofen
400 mg has been shown to produce greater pain relief
than aspirin 650 mg, acetaminophen 1000 mg, or
ibuprofen 200 mg using the dental pain model. 13,1~
Combination therapies that lack anti-inflammatory
properties may provide inadequate relief in many subjects because inflammation, a major underlying cause
of pain production, is not adequately addressed. 15
2004

Tissue damage at the site of injury produces inflammation that stimulates the nerve endings or nociceptots and results in increased sensitivity of the peripheral nociceptors. 11,16 The first compound to combine
an opioid with ibuprofen that was approved by the
US Food and Drug Administration became available
commercially in 1997 (hydrocodone 7.5 mg/ibuprofen
200 mg). 17 However, this preparation used 200 mg of
ibuprofen, which may not provide an optimal analgesic benefit, m NSAIDs such as ibuprofen primarily
reduce peripheral pain by inhibiting cyclooxygenases,
enzymes essential for prostaglandin synthesis; however, some NSAID action on central pain has also been
described. 19-21
The present study was undertaken to compare the
efficacy and safety of a single dose of oxycodone 5 mg/
ibuprofen 400 mg versus its individual components
and placebo in a third-molar extraction model. This
model is well validated for evaluating analgesics
because it produces a well-characterized, consistent,
and quantifiable level of moderate to severe pain,
with upside and downside sensitivities. 16 The thirdmolar extraction model is a clean model of acute pain
because subjects are free of nondental-related pain
before surgery, and those with previous chronic analgesic use are excluded from enrollment.
SUBJECTS A N D M E T H O D S
Institutional Review Boards

The study protocol was reviewed and approved by
the institutional review board at each of 3 participating study centers (Clinical Research Center, Boston
University Goldman School of Dental Medicine,
Boston, Massachusetts; Center for Clinical Studies,
University of Maryland, Baltimore, Maryland; and
Cranial Pain Research, Tucson, Arizona) in conformance with chapter 21 of the United States Code of
Federal Regulations.22
Inclusion and Exclusion Criteria

Male and female subjects aged >16 years who were
scheduled to have >2 ipsilateral partially or completely bony impacted third molars completely removed
were eligible for inclusion in this study. Women of
childbearing potential were required to have a negative urine pregnancy test on the day of surgery.
Subjects were required to abstain from alcohol, caffeine, and smoking for 8 hours before surgery and

T. Van Dyke et al.

until completion of the 6-hour postadministration
observation period. Subjects were required to remain
at the study site over the entire 6-hour observation
period. All subjects provided informed written consent, and those aged <18 years were required to give
verbal assent and have a parent or guardian indicate
approval on the consent form.
Excluded from this study were females who were
pregnant or lactating, as were other potential subjects
who had taken short-acting analgesics (eg, acetaminophen, aspirin, propoxyphene) within 6 hours of surgery, ibuprofen within 10 hours of surgery, long-acting
NSAIDs (eg, naproxen), piroxicam, or any opioid
analgesic within 48 hours of surgery, or steroids within 72 hours of surgery. Subjects were also excluded if
they met any of the following criteria: use of any psychoactive drug or opiate antagonist within 72 hours of
surgery; coexisting illness (gastrointestinal, hematologic, hepatic, renal/urologic, neurologic, endocrine,
cardiovascular, psychiatric, respiratory, or immune
system disease); presence of any condition that, in the
investigator's judgment, contraindicated administration of the study medication; pain in areas unrelated
to the teeth; or known or suspected abuse of drugs or
alcohol (subjectively determined by investigators).
Study Design

This was a multicenter, double-blind, doubledummy, randomized, parallel-group, single-dose,
placebo- and active-controlled investigation. To be randomized to receive study treatment, subjects were
required to have pain intensity rated as moderate to
severe in the patient diary (see "Efficacy and Safety
Evaluations" subsection) at baseline (within 5 hours
postsurgery prior to receiving study medications), with
a score >50 mm on a 100-mm visual analog scale (VAS)
o f pain intensity. Subjects were randomized (3:3:1:1)
to receive a single dose of oxycodone 5 mg/ibuprofen
400 mg, ibuprofen 400 mg, oxycodone 5 mg, or placebo. Study treatments were administered with 4 ounces
of water immediately after the patient met the criteria
for randomization. The timing of all efficacy evaluations (see "Efficacy and Safety Evaluations" subsection)
was defined from this time point.
Concomitant Pain Medication

Remedication was provided at the subject's request
if the study medication did not provide adequate pain

relief (PR) or if additional analgesia was required and
was selected at the discretion of the investigator;
options for remedication for subjects in the pharmacokinetic analysis portion of this trial were limited
to propoxyphene napsylate 50 mg/acetaminophen
325 mg or acetaminophen 1000 mg. Subjects were
able to remedicate with the rescue analgesic agent
provided at any time. However, they were encouraged to wait as long as possible (>2 hours) after
administration of the study drug before taking further
medication. Time to remedication was noted for each
patient who received rescue medication.
Efficacy and Safety Evaluations
Data were collected on standard case-report forms
(CRFs) customized for this study to ensure validity,
accuracy, and completeness at each investigator's center. Data from the CRFs were entered twice as part of
a database validation system. Subjects were given 2
stopwatches and instructed to start both watches
when they took the study medication. The first watch
was stopped as soon as the patient began to feel the
pain-relieving effect of the drug (confirmed perceptible relief). This interval was the time to first perceptible PR. The second watch was stopped when the
patient felt PR that was clinically meaningful. This
interval was the time to meaningful PR. The stopwatch
methodology has been validated in a previous study
of analgesia. 23
To further assess treatment efficacy, subjects were
also asked to complete diary cards assessing PR, pain
intensity, and whether pain was half gone. This was
done 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hours
postadministration. To rate PR, subjects completed
the following: "My relief from starting pain is: 0 =
none; 1 = a little; 2 = some; 3 = a lot; 4 = complete."
To rate pain intensity, subjects completed the following statement: "My pain at this time is: 0 = none; 1 =
slight; 2 = moderate; 3 = severe." A score of 2 (moderate) or 3 (severe) on this statement within 5 hours
of surgery was required for randomization into the
study. Pain intensity scores were used to calculate the
pain intensity difference (PID). Subjects also completed the following sentence at each time point: "My
pain at this time is half gone: 1 = yes; 2 = no." At
6 hours postadministration (or at the time of remedication with rescue medication or at premature termination, whichever occurred earlies0, subjects answered
2005

CLINICALTHERAPEUTICS@

this additional global evaluation diary question:
"How would you rate the study medication you
received for pain?: 0 = poor; 1 = fair; 2 = good; 3 =
very good; 4 = excellent."
In this study, the safety profile was evaluated in all
subjects who received the study medication by
recording adverse events (ie, any change in general
condition, symptoms reported by the patient, objective signs observed by the investigator, concurrent
diseases, and physical findings). Vital signs (ie, blood
pressure, heart rate, and respiratory rate) were
recorded before and at 2 and 6 hours after treatment,
when rescue medication was taken, and when treatment was terminated early for any other reason. All
vital signs were recorded while patients were reclining and had been resting >5 minutes.
Efficacy End Points
The primary efficacy variables were the following:
the sum of pain intensity difference over 6 hours
(SPID6), derived from the PID from baseline pain
intensity and defined as the area under the observed
PID-time curve (AUC) from 0 to 6 hours; and total
pain relief through 6 hours (TOTPAR6), derived from
the PR score and defined as the area under the
observed PR-time curve from 0 to 6 hours, with PR =
0 at time 0. The range of potential scores for TOTPAR6
is 0 to 24; the range for SPID6 is - 6 to 12.
Secondary efficacy measures included the SPID and
TOTPAR over 3 hours (SPID3 and TOTPAR3), peak
PR, peak PID, time to onset of PR, proportion reporting pain half gone, time to remedication, and patient
global evaluation. The range of potential scores for
TOTPAR3 is 0 to 12; the range for SPID3 is -3 to 6.
As described previously in this report, time to onset
of PR was defined as the time from study medication
administration (time 0) to the time the first stopwatch
was stopped for subjects who stopped both stopwatches. For those subjects who did not stop either
stopwatch, or who stopped only the first stopwatch
by the end of the observation period, time to onset of
PR was calculated as a censored value at the last time
point at which a pain intensity or a PR measurement
was taken.
Time to remedication was defined as the elapsed
time from study medication administration (time 0)
to the time when the patient was administered rescue
medication. For subjects who did not remedicate by

2006

the end of the efficacy evaluation period, time to
remedication was calculated as a censored value at
the last time point when a pain intensity or a PR
measurement was taken.
Pharmacokinetic Analysis
A subset of 32 subjects from 1 investigative site
participated in a pharmacokinetic substudy. Blood
samples were drawn from this subset of subjects prior
to and at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4,
5, and 6 hours after administration. Concentrations
of oxycodone in plasma samples were determined by
a validated gas chromatography/mass spectroscopy
method. 2~
Concentrations of R(-)- and 5(+)-ibuprofen were
determined by a validated high performance liquid
chromatography (HPLC) technique. To 0.5 mL of
plasma, 50 I~L of the internal standard solution
(100 l~g/mL of fenoprofen) and 50 I~L of 8.5% phosphoric acid were added. After vortexing for 20 seconds, 2 mL of N-butyl chloride was added. After slow
manual inversion of the tubes 10 to 15 times, samples
were vortexed for 3 minutes and subsequently centrifuged for 4 minutes. The organic phase was transferred to a separate tube and evaporated. Samples
were reconstituted in 100 I~L of 50 mM triethylamine
in acetonitrile and 50 I~L of 60 mM ethylchloroformate in acetonitrile and vortexed for 30 seconds. After
addition of 50 I~L of 0.1 M L-leucinimide (chiral
derivatization agent) in methanol/triethylamine, the
derivatization reaction proceeded for 2 minutes. After
further addition of 50 t~L of water (quenching of the
derivatization reaction), 40 t~L of the sample were used
for the HPLC analysis. Analyses were separated on a
reverse phase Betasil C18 column (250 X 4.6 mm;
Keystone Scientific, Bellefonte, Pennsylvania) with
5-t~m particle size and a Zorbax C18 guard column
(DuPont, Wilmington, Delaware) at a temperature of
25°C. The mobile phase consisted of 2000 mL of acetonitrile, 2000 mL of 0.06 M potassium phosphate
monobasic, and 4 mL of triethylamine at a flow rate
of 1.8 mI_/min. Ultraviolet detection was achieved at
225 n m using a Waters 486 UV detector (Millipore
Corporation, Billerica, Massachusetts). The limit
of quantitation for R(-)- and 5(+)-ibuprofen was
0.25 l~g/mL, using a 0.5-mL plasma sample. Total or
racemic ibuprofen plasma concentrations were calculated by adding the corresponding R(-)- and 5(+)-

T. Van Dyke et al.

ibuprofen concentrations obtained, and represent the
values presented throughout the "Results" section.
Plasma concentration data were used to determine
Cmax, Tmax, AUG from the time of administration to
the last measurement (AUCo_s), and T1/2. Both CmaX
and Tmax were determined by observation, and
AUCo_s was calculated by numeric integration using
the linear trapezoidal rule.

ANOVA with treatment as effect was performed on
all of the pharmacokinetic parameters. For the statistical comparison of ibuprofen pharmacokinetic parameters, P values from the ANOVA were considered.
This study was not designed to determine statistically significant differences between arms for
adverse events; therefore, a statistical analysis of
reported adverse events was not possible and is not
reported.

Statistical Analyses

Potential differences among treatment groups for
demographic data and pain intensity (percent moderate or severe and VAS) were analyzed using an analysis of variance (ANOVA) for continuous variables 25
and a Cochran-Mantel-Haenszel test for categoric
variables. 26 All analyses were performed with SAS
software, version 6.12, for UNIX system microcomputers using the general linear model procedure (SAS
Institute Inc., Cary, North Carolina). 27
Efficacy analyses were performed on the intentto-treat population, which consisted of all randomized subjects who took the study medication
and had >1 postbaseline efficacy assessment. A
last-observation-carried-forward approach was
used to extrapolate missing pain intensity and PR
values. 28
SPID6, SPID3, and peak PID were analyzed using a
3-way ANOVA model with treatment group, study
site, and baseline pain intensity as factors. TOTPAR6,
TOTPAR3, peak PR, and patient global evaluation
were analyzed using a 2-way ANOVA model with
treatment group and study site as factors. For primary
efficacy parameters SPID6 and TOTPAR6, the
prospectively assigned normality assumption on the
residuals was examined. Because the normality
assumption was rejected for both SPID6 and TOTPAR6
by Shapiro-Wilk test (P < 0.001), a normal score transformation was applied on both SPID6 and TOTPAR6
before applying the ANOVA model.
Time to onset of PR and time to remedication were
analyzed using the log-rank test for censored data.
Median time to onset of PR and median time to
remedication were calculated using the KaplanMeier product limit estimator. The proportion of
subjects reporting pain half gone was analyzed using
the Cochran-Mantel-Haenszel test stratified by study
site. Estimates of mean values obtained for pharmacokinetic parameters were performed with SAS.

RESULTS

A total of 515 subjects underwent the dental surgery,
and 498 of these subjects developed moderate to
severe pain with a VAS of >50 mm and were randomized to treatment (187 to oxycodone 5 mg/ibuprofen
400 rag, 186 to ibuprofen 400 rag, 63 to oxycodone
5 rag, and 62 to placebo). One patient from the oxycodone 5 mg/ibuprofen 400 mg group did not have
any postbaseline efficacy assessment and was excluded from the efficacy analyses. The most commonly
used medications during surgery over the total study
were midazolam (78.5% [391/498]), nitrous oxide
(72.5% [361/498]), mepivacaine (77.5% [386/498]),
and lidocaine (62.7% [312/498]); there was no difference in medication used during surgery among the
treatment arms. Baseline demographic and pain intensity data for all subjects are summarized in Table I.
There were no significant differences among groups
with respect to baseline pain intensity (either percent
moderate vs severe or mean VAS; both, P = NS), and
the groups were generally well matched with respect
to most demographic characteristics. There were significant differences among groups with respect to sex
(P = 0.041) and race (P = 0.023). When further analyzed by pairwise group comparisons, the only significant difference among treatment arms was between
the oxycodone 5 mg/ibuprofen 400 mg combination
and the placebo group for both sex (P = 0.007) and
race (P = 0.012). However, additional analyses on the
primary end points adjusting for sex and race showed
that these 2 characteristics had no impact on treatment efficacy (data not shown).
Dropout rates were more than twice as great in the
placebo and oxycodone groups than in the combination or ibuprofen groups: 52/62 (83.9%) and 52/63
(82.5%) versus 69/187 (36.9%) and 71/186 (38.2%),
respectively (P < 0.001 for combination and ibuprofen groups vs oxycodone and placebo groups). The
2007

CLINICAL THERAPEUTICS@

Table I. Demographic characteristics and baseline pain intensity in intent-to-treat population of subjects randomized to
receive analgesic medication or placebo after dental surgery.

CharacLeristic
Sex, no. (%) or subjects
Female

Oxycodone 5 mg/
Ibuprofen 400 mg
(n = 187)

Ibuprofen 400 mg
(n = 186)

Oxycodone 5 mg
(n = 63)

Placebo
(n = 62)

0.041
I 18 (63.1)

101 (54.3)

33 (52.4)

27 (43.5)

69 (36.9)
24.7 (5.3)

85 (45.7)
24. I (5.1)

30 (47.6)
24.3 (5.2)

35 (56.5)
24.8 (5.5)

White

116 (62.0)

138 (74.2)

48 (76.2)

48 (77.4)

Black
Asian
Other

19 (I 0.2)
17 (9.1)
35 (I 8.7)

16 (8.6)
14 (7.5)
18 (9.7)

7 (I I. I)
2 (3.2)
6 (9.5)

9 (I 4.5)
3 (4.8)
2 (3.2)

Male
Age, mean (SD),y
Race, no. (%) of subjects

Body weight, mean (SD), Ib
Height, mean (SD), in
Baseline pain intensity, no. (%) of subjects
Moderate

Severe
Baseline painVAS,mean (SD),mm

P

0.667
0.023

154.7 (34.0)

159.6 (37.0)

158.8 (28.3)

163.8 (36.0)

0.291

66.5 (4.4)

67. I (4.3)

67.6 (3.7)

67.4 (3.5)

0.16 I
0.804

169 (90.4)

173 (93.0)

58 (92.1)

56 (90.3)

18 (9.6)

13 (7.0)

5 (7.9)

6 (9.7)

59.0 (8.8)

58.0 (7.2)

57.8 (7.2)

58.5 (8.5)

0.629

VAS = visual analog scale (range of possible scores, 0 100 mm).

reason for discontinuation in all but 3 subjects was
insufficient therapeutic response.
Efficacy

The combination of oxycodone 5 mg and ibuprofen
400 mg appeared to provide greater PR versus either
drug alone or placebo, with greater peak pain control
and a more rapid onset of action. Primary efficacy end
points and statistical analyses can be found in Table II.
TOTPAR6 scores for combination therapy were better
than those for oxycodone 5 mg alone (P < 0.001),
ibuprofen 400 mg alone (P = 0.012), or placebo (P <
0.001). TOTPAR6 scores for ibuprofen 400 mg were
also better than those for placebo (P < 0.001). However,
oxycodone 5 mg was found to be no better than placebo (Table II). Analysis of SPID6 scores provided the
same pattern of results: the oxycodone 5 mg/ibuprofen
400 mg combination was associated with better scores
than oxycodone 5 mg alone (P < 0.001), ibuprofen
400 mg alone (P = 0.002), or placebo (P < 0.001). Here
again, ibuprofen 400 mg, but not oxycodone 5 mg, was
associated with better scores than placebo (P < 0.001
and P = NS, respectively; Table II).

2008

Results from analysis of secondary end points in
this study can be found in Table III. Analysis of
TOTPAR3 results indicated that the oxycodone 5 mg/
ibuprofen 400 mg combination was associated with
better scores than all other groups (all, P < 0.001) and
that ibuprofen 400 mg, but not oxycodone 5 mg, was
associated with better scores than placebo (P < 0.001
and P = NS, respectively). Assessment of SPID3 results
yielded similar findings. The combination therapy
was associated with better scores than all other
groups (P < 0.001); ibuprofen 400 mg, but not oxycodone 5 mg, was associated with better scores than
placebo (P < 0.001 and P = NS, respectively).
Both peak mean PR values and peak mean PID
values were greatest for subjects randomized to the
oxycodone 5 mg/ibuprofen 400 mg combination
(Figures 1 and 2). Onset of PR was experienced by
168 (90.3%), 153 (82.3%), 20 (31.7%), and 22
(35.5%) patients in the oxycodone 5 mg/ibuprofen
400 mg combination, ibuprofen 400 mg, oxycodone
5 mg, and placebo groups, respectively (P < 0.001 for
combination and ibuprofen groups vs oxycodone and
placebo groups). Meaningful analgesia occurred 28%

T. Van Dyke et al.

Table II. Total pain relief through 6 hours CI'OTPAR6) and sum of pain intensity difference through 6 hours (SPID6) in
intent-to-treat population of subjects randomized to receive analgesic medication or placebo after dental surgery.*
TOTPAR6

SPID6

Least Squares
Treatment G r o u p

lean

Oxycodone 5 mg/
ibuprofen 400 mg
(n = 186)

Least Squares
95% CI

P

13.3 (0.52)

12.3 to 14.4

P < 0.001 vs oxycodone
5 mg or placebo;
P = 0.012 vs ibuprofen
400 mg alone

Ibuprofen 400 mg
(n = 186)

12.2 (0.52)

I 1.3 to 13.2

Oxycodone 5 mg
(n - - 63)

4.3 (0.82)

2.7 to 5.9

Placebo

4.2 (0.83)

2.5 to 5.8

(n

--

(SE)

lean

(SE)

95% CI

P

6.54 (0.42)

5.51 to 7.37

P < 0.001 vs oxycodone 5 mg or placebo;
P = 0.002 vs ibuprofen
400 mg alone

P < 0.001 vs oxycodone
5 mg or placebo

5.41 (0.44)

4.56 to 6.27

P < 0.001 vs oxycodone 5 mg on placebo

P = 0.91 I vs placebo

0.14 (0.60)

1.03 to 1.3 I

P -- 0.805 vs placebo

0.32 (0.59)

~).85 to 1.48

62)

%tati~ical analysis was performed on normalized data because the error term in the analysis o f variance model for the raw data forTOTPAR6 and SPID6
revealed that the normality assumption was not valid. The range of potential scores forTOTPAR6 is 0 to 24; the range for SPID6 is 6 to 12.

more rapidly in subjects taking oxycodone 5 mg/
ibuprofen 400 mg compared with subjects taking ibuprofen 400 mg alone (21.4 minutes vs 29.7 minutes;
P < 0.001). One hour after drug administration,
140 (74.9%) subjects taking oxycodone 5 mg/ibuprofen 400 mg reported that their pain was half gone
compared with 110 (59.1%) subjects taking ibuprofen 400 mg and 12 (19.0%) subjects taking oxycodone 5 mg. Slightly more than one third of the subjects receiving oxycodone 5 mg/ibuprofen 400 mg
(36.4% In = 68]) or ibuprofen 400 mg (37.6% In = 70])
required rescue medication compared with 82.5%
(n = 52) of subjects receiving oxycodone 5 mg or
83.9% (n = 52) of those receiving placebo (P < 0.001).
Global evaluation scores were highest in subjects randomized to combination therapy.
Pharmacokinetics

Thirty-one subjects (12 taking combination therapy,
12 taking ibuprofen, 3 taking oxycodone, and 4 taking
placebo) contributed results to the pharmacokinetic
analysis. The mean (SD) Cmax and AUCo_T values for
ibuprofen 400 mg were 24.6 (6.4) pg/mL and 72.7
(20.7) pg.h/mL, respectively. When ibuprofen 400 mg
was administered in combination with oxycodone
5 mg, mean (SD) values for Cmax and AUCo_T were 18.5

(8.1) pg/mL and 58.7 (26.6) pg.h/mL, respectively. The
mean (SD) Tmax for ibuprofen 400 mg alone was 2.4
(1.0) hours versus 3.1 (1.6) hours for the combination.
The mean (SD) T1/2 was 1.9 (0.6) hours for ibuprofen
400 mg alone and 2.6 (1.0) hours for the combination.
Although numeric differences in mean pharmacokinetic parameters were observed between ibuprofen administered alone compared with the combination, no
statistically significant differences were noted for any
of the pharmacokinetic parameters of ibuprofen.
The mean (SD) values for Cmax and AUCo_s for
oxycodone 5 mg alone were 13.6 (4.2) ng/mL and
35.9 (3.7) ng.h/mL, respectively. When oxycodone 5 mg
was administered in combination with ibuprofen
400 mg, these values were 11.6 (6.3) ng/mL and 35.8
(10.6) ng.h/mL. The mean (SD) Tmax values for oxycodone 5 mg alone and oxycodone 5 mg/ibuprofen
400 mg were 1.1 (0.4) and 2.1 (1.0) hours, respectively, and the mean (SD) T1/2 values were 3.2 (0.6)
and 2.9 (0.6) hours. Although this study was not
designed or statistically powered to determine bioequivalence, combining oxycodone 5 mg and ibuprofen 400 mg did not appear to alter the pharmacokinetic parameters for either drug. This is in line with
the results obtained from a previously conducted
pharmacokinetic study in healthy subjects. 29
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400 mg (n = 186)
-0- Ibuprofen 400 mg (n = 186)
-~- Oxycodone 5 mg (n = 63)
t
Placebo (n = 62)

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400 mg (n = 186)
-0- Ibuprofen 400 mg (n = 186)
-~- Oxycodone 5 mg (n = 63)
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T i m e (h)

T i m e (h)

Figure I. Mean pain relief (PR) scores over time in the
intent-to-treat population of subjects randomized to receive analgesic medication or placebo
after dental surgery. Subjects completed the following statement: "My relief from starting pain is:
0 = none; I = a little; 2 = some; 3 = a lot; 4 =
complete."

Figure 2. Mean pain intensity difference (PID) scores
over time in the intent-to-treat population of
subjects randomized to receive analgesic medication or placebo after dental surgery. Subjects
completed the following statement: " M y pain at
this time is: 0 = none; I = slight; 2 = moderate;

Safety

tion, discontinued due to adverse events (nausea and
vomiting in one and nausea in the other).
Mean values for vital signs remained within the
predefined normal range for subjects in all treatment
groups. Blood pressure increased slightly (systolic,
increased 8-11 mm Hg; diastolic, increased 4-6 m m
Hg) in patient groups who experienced only minimal
PR (ie, subjects randomized to oxycodone 5 mg or
placebo). Blood pressure decreased slightly (systolic,
decreased 1-5 mm Hg; diastolic, decreased 4-7 m m
Hg) in those who experienced adequate PR (ie, subjects
randomized to oxycodone 5 mg/ibuprofen 400 mg or
ibuprofen 400 mg).

The oxycodone 5 mg/ibuprofen 400 mg combination was well tolerated. The overall adverse-event rate
was highest in subjects randomized to oxycodone 5 mg
(27.0% [17/63]), followed by oxycodone 5 mg/ibuprofen 400 mg (15.5% [29/187]), placebo (11.3% [7/62]),
and ibuprofen 400 mg (10.8% [201186]). Treatmentemergent adverse events experienced by >3% of subjects in any treatment group are summarized in Table
IV. Nausea was the most frequent adverse event in all
3 active treatment groups. There were no serious
adverse events in this study Two subjects, both treated
with the oxycodone 5 mg/ibuprofen 400 mg combina-

3 = severe."

2011

CLINICALTHERAPEUTICS®

Table IV. Adverse events (given as number [%] of patients in study arm) experienced by >3% of subjects after randomization to receive analgesic medication or placebo after dental surgery.
Oxycodone 5 mg/Ibuprofen 400 mg
(n = 187)

Ibuprofen 400 mg
(n = 186)

Oxycodone 5 mg
(n = 63)

Placebo
(n = 62)

19 (10.2)
14 (7.5)
5 (2.7)

7 (3.8)
5 (2.7)
2 (I.I)

6 (9.5)
5 (7.9)
3 (4.8)

I (I.6)
I (I.6)
0 (0.0)

Hypertension

0 (0.0)

2 (I. I)

4 (6.3)

5 (8. I)

Sweating

0 (0.0)

0 (0.0)

2 (3.2)

0 (0.0)

Adverse Event

Nausea
Vomiting
Dizziness

DISCUSSION

In this randomized, double-blind, placebo-controlled
trial, the combination of oxycodone 5 mg and
ibuprofen 400 mg was significantly more effective
(P < 0.05) than either of its components in relieving
acute moderate to severe pain associated with third
molar extraction. Combination therapy provided significantly greater analgesia, both clinically and statistically, compared with ibuprofen 400 mg (P = 0.012)
or oxycodone 5 mg (P < 0.001) alone, with a more
rapid onset of action and greater peak pain control.
Enhanced analgesia was measured by TOTPAR and
SPID over a 6-hour evaluation period. The greatest
difference in incremental pain relief with the combination versus the individual components was seen in
the first 2 hours after administration, which corresponds to the period of the highest pain intensity
Although other studies have shown an analgesic benefit for oxycodone alone at a 5-mg dose versus place])0,30 in our study there was no statistical difference
seen. This study was not powered to show superiority
between these 2 arms. However, our study did suggest
that oxycodone 5 mg, when combined with ibuprofen,
provided more pain relief than either component alone.
This supports the concept that if additive analgesia
exists between components of a combination treatment, then lower opioid doses could be effective.
Combination analgesics have been used rationally
and successfully over the past 3 decades for the management of acute pain 3~ and studies have shown an
additive analgesic effect when combining oxycodone
with ibuprofen. <32 Although the goal of combination
therapy with analgesics that have different mechanisms of action is to produce greater analgesia, it is
also intended to reduce or limit adverse events. ~8
2012

In this study, the oxycodone 5 mg/ibuprofen 400
mg combination resulted in fewer overall adverse
events than were seen with oxycodone 5 mg alone.
The incidence of adverse events appeared to be lower
in the ibuprofen and placebo groups than in the oxycodone 5 mg/ibuprofen 400 mg combination group,
although the design of the study did not allow for
assessment of the statistical significance of this perceived difference. Treatment with oxycodone, either
alone or in combination with ibuprofen, seemed to
result in a small increase in the incidence of gastrointestinal side effects (nausea and vomiting) over placebo; again, however, the design of the study did not
allow for assessment of the statistical significance of
this observation. Nausea and vomiting are common
events associated with opioid medications. 33
The clinical impact of the oxycodone 5 mg/ibuprofen
400 mg combination is attributable to the strength
and distinctive actions of each analgesic component.
Oxycodone, which exerts its effects through specific
opioid receptors within the central nervous system, is
more potent than codeine or hydrocodone. 9,1°
Ibuprofen 400 mg, which primarily exerts its effects
peripherally, provides significantly more PR than
acetaminophen 1000 mg; it also has a longer duration of action (6 vs 4 hours) and possesses antiinflammatory activity, which appears to be a critical
factor in the amplification of pain. r,m Both oxycodone and ibuprofen are significantly metabolized
by the liver prior to elimination. Each is metabolized
by a different cytochrome P (CYP) 450 isozyme system. The metabolism of ibuprofen involves CYP 2C9
and, to a lesser extent, CYP 2C8, 3~ whereas oxycodone is metabolized primarily by CYP 2D6 to its
active metabolite oxymorphone.35 This difference and

T. Van Dyke et al.

the results of our study suggest that there is little
pharmacokinetic interaction between the 2 drugs.
CONCLUSIONS

In this study, the combination of oxycodone 5 mg and
ibuprofen 400 mg was fast-acting, effective, and well
tolerated in subjects with moderate to severe pain after
dental surgery. Oxycodone 5 mg alone did not provide
an efficacy benefit over placebo. The results further
suggest that administration of the 2 compounds
together may produce an additive analgesic effect.
ACKNOWLEDGHENT

Editorial assistance was provided by Michael Craig,
MSc, Carolyn Oddo, Maggie Skillman, and Mary Ward,
Phase Five Communications, New York, New York.
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Address correspondence to: Thomas Van Dyke, DDS, PhD, Professor and Director, Clinical Research Center,
Boston University Goldman School of Dental Medicine, 100 East Newton Street, Room 107, Boston, MA 02118.
E-mail: tvandyke@bu.edu

2014