dental pain oxy not better

CLINICAL THERAPEUTICS/VoL. 26, No. 12, 2004

Combination Oxycodone 5 mg/Ibuprofen 400 mg for the Treatment of Postoperative Pain: A Double-Blind, Placebo- and 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.

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

Copyright 2004 Excerpta Nedica, Imc. 2003

CLINICAL THERAPEUTICS

INTRODUCTION Nearly 9 in 10 Americans aged >18 years (89%) suf- fer 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 heal- ing 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 anti- inflammatory 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 inhibito- ry synapses, predominantly work on the central path- way by preventing pain messages from reaching the brain and activating descending analgesic path- ways. 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 anti- inflammatory 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

Tissue damage at the site of injury produces inflammation that stimulates the nerve endings or nocicep- tots 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 third- molar 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 AND METHODS Institutional Review Boards

The study protocol was reviewed and approved by the institutional review board at each of 3 participat- ing 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 confor- mance 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 nega- tive urine pregnancy test on the day of surgery. Subjects were required to abstain from alcohol, caf- feine, and smoking for 8 hours before surgery and

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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 con- sent, and those aged 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 percepti- ble relief). This interval was the time to first percepti- ble 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 termi- nation, whichever occurred earlies0, subjects answered

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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 reclin- ing 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

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% phos- phoric 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 cen- trifuged for 4 minutes. The organic phase was trans- ferred 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 ethylchlorofor- mate 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 25C. 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 nm 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(+)-

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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 Cma X and Tma x were determined by observation, and AUCo_ s was calculated by numeric integration using the linear trapezoidal rule.

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 microcom- puters using the general linear model procedure (SAS Institute Inc., Cary, North Carolina). 27

Efficacy analyses were performed on the intent- to-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 trans- formation 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 Kaplan- Meier 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.

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.

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

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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.

Oxycodone 5 mg/ Ibuprofen 400 mg Ibuprofen 400 mg Oxycodone 5 mg Placebo

CharacLeristic (n = 187) (n = 186) (n = 63) (n = 62) P

Sex, no. (%) or subjects 0.041 Female I 18 (63.1) 101 (54.3) 33 (52.4) 27 (43.5) Male 69 (36.9) 85 (45.7) 30 (47.6) 35 (56.5)

Age, mean (SD), y 24.7 (5.3) 24. I (5.1) 24.3 (5.2) 24.8 (5.5) 0.667

Race, no. (%) of subjects 0.023 White 116 (62.0) 138 (74.2) 48 (76.2) 48 (77.4) Black 19 (I 0.2) 16 (8.6) 7 (I I. I) 9 (I 4.5) Asian 17 (9.1) 14 (7.5) 2 (3.2) 3 (4.8) Other 35 (I 8.7) 18 (9.7) 6 (9.5) 2 (3.2)

Body weight, mean (SD), Ib 154.7 (34.0) 159.6 (37.0) 158.8 (28.3) 163.8 (36.0) 0.291

Height, mean (SD), in 66.5 (4.4) 67. I (4.3) 67.6 (3.7) 67.4 (3.5) 0.16 I

Baseline pain intensity, no. (%) of subjects 0.804 Moderate 169 (90.4) 173 (93.0) 58 (92.1) 56 (90.3) Severe 18 (9.6) 13 (7.0) 5 (7.9) 6 (9.7)

Baseline painVAS, mean (SD), mm 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).

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%

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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 Least Squares Treatment Group lean (SE) 95% CI P lean (SE) 95% CI P

Oxycodone 5 mg/ 13.3 (0.52) 12.3 to 14.4 P < 0.001 vs oxycodone 6.54 (0.42) 5.51 to 7.37 ibuprofen 400 mg 5 mg or placebo; (n = 186) P = 0.012 vs ibuprofen

400 mg alone

Ibuprofen 400 mg 12.2 (0.52) I 1.3 to 13.2 P < 0.001 vs oxycodone 5.41 (0.44) 4.56 to 6.27 (n = 186) 5 mg or placebo

Oxycodone 5 mg 4.3 (0.82) 2.7 to 5.9 P = 0.91 I vs placebo 0.14 (0.60) 1.03 to 1.3 I (n - - 63)

Placebo 4.2 (0.83) 2.5 to 5.8 0.32 (0.59) ~).85 to 1.48 (n - - 62)

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

P < 0.001 vs oxycodone 5 mg on placebo

P -- 0.805 vs placebo

%tati~ical analysis was performed on normalized data because the error term in the analysis of 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.

Pharmacokinet ics 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) Cma x 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 Cma x and AUCo_ T were 18.5

(8.1) pg/mL and 58.7 (26.6) pg.h/mL, respectively. The mean (SD) Tma x 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 Cma x 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) Tma x 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 bio- equivalence, 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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T. Van Dyke et al.

Time (h)

Figure I. Mean pain relief (PR) scores over time in the

intent-to-treat population of subjects random-

ized to receive analgesic medication or placebo

after dental surgery. Subjects completed the fol-

lowing 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 medi-

cation or placebo after dental surgery. Subjects

completed the following statement: "My pain at

this t ime is: 0 = none; I = slight; 2 = moderate;

3 = severe."

Safety The oxycodone 5 mg/ibuprofen 400 mg combina-

tion 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]). Treatment- emergent 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-

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 mm 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 mm Hg) in those who experienced adequate PR (ie, subjects randomized to oxycodone 5 mg/ibuprofen 400 mg or ibuprofen 400 mg).

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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 Ibuprofen 400 mg Oxycodone 5 mg Placebo Adverse Event (n = 187) (n = 186) (n = 63) (n = 62)

Nausea 19 (10.2) 7 (3.8) 6 (9.5) I (I.6) Vomiting 14 (7.5) 5 (2.7) 5 (7.9) I (I.6) Dizziness 5 (2.7) 2 (I.I) 3 (4.8) 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)

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 corre- sponds 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.

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: [email protected]

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dental pain oxy not better

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