http://www.jclinpharm.org

PharmacologyThe Journal of Clinical

1996; 36; 595 J. Clin. Pharmacol.A Sunshine, NZ Olson, A Colon, J Rivera, RF Kaiko, RD Fitzmartin, RF Reder and PD Goldenheim

Analgesic efficacy of controlled-release oxycodone in postoperative pain

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ANALGESIA

J CIln Pharmacol 1996;36:595-603 595

Analgesic Efficacy of Controlled-ReleaseOxycodone in Postoperative Pain

Abraham Sunshine, MD, FCP, Nancy Z. Olson, MPS, Ariel Colon, MD, Juana Rivera, MD,

Robert F. Kaiko, PhD, Ronald D. Fitzmartin, PhD, Robert F. Reder, MD,and Paul D. Goldenheim, MD

The efficacy and safety of graded doses (10, 20, and 30 mg) of controlled-release (CR)

oxycodone was compared with that of immediate-release (IR) oxycodone (15 mg), imme-

diate-release oxycodone 10 mg in combination with acetaminophen 650 mg (APAP), and

placebo in a single-dose, double-blind, randomized, parallel-group study. The partici-

pants, 182 inpatients experiencing moderate to severe pain after abdominal or gyneco-

logic surgery, provided hourly ratings of pain intensity and relief for 12 hours after ad-ministration. All active treatments were significantly superior to placebo for many hourly

measurements and for the sum of pain intensity differences (SPID) and total pain relief

(TOTPAR). A dose response was found among the three levels of CR oxycodone for pain

relief and peak pain intensity difference (PID), with the 20- and 30-mg doses being sig-

nificantly better than the 10-mg dose. For all active treatments, peak PID and peak pain

relief occurred approximately 2 to 4 hours after administration. The median time to onset

of relief was 32 minutes for oxycodone plus APAP, 41 minutes for IR oxycodone, and 46minutes for CR oxycodone 30mg. Duration of pain relief showed that the 10-, 20-, and 30-

mg doses of CR oxycodone had durations of action of 10 to 12 hours compared with IR

oxycodone and oxycodone plus APAP (both approximately 7 hours). Typical adverseevents, particularly somnolence. occurred in all active treatment groups. Treatment with

CR oxycodone was safe and effective in this study, and its characteristics will be beneficial

in the treatment of pain.

Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is

a semisynthetic opioid agonist derived from the-baine, with clinical use first reported in 1917.1 In thepast, it was treated as a mild opioid2 and was onlyavailable in the United States as a constituent offixed combination analgesics with aspirin or acet-aminophen.3 More recently, however, oxycodonehas been recognized as a strong opioid suitable athigher dosages for the treatment of moderate and se-vere pain.4’5 Because aspirin and acetaminophen in

From the Department of Medicine, New York University Medical Center

(Dr. Sunshine), Analgesic Development Ltd., New York (Dr. Sunshine

and Ms. Olson), Caguas Regional Hospital, Caguas, Puerto Rico (Dr.Colon), Carolina Area Hospital, Carolina, Puerto Rico (Dr. Rivera), andthe Purdue Frederick Company, Norwalk, Connecticut (Drs. Kaiko,

Fitzmartin, Reder, and Goldenheim). Supported by a grant from The

Purdue Frederick Company, Norwalk, Connecticut. Address for re-

prints: Abraham Sunshine, MD, Analgesic Development Ltd. 23 East73rd Street, Suite 5F, New York, NY 1002 1-3522.

fixed combination may become toxic and cause un-acceptable adverse effects at elevated doses,3 oxyco-done is now available as a single-entity analgesic.

Like morphine, oxycodone has a short eliminationhalf-life (t112)5 and is considered to be a versatile andflexible analgesic.6 Oxycodone, however, has beenfound to have a higher oral bioavailability (60%-87%)78 than morphine (20%_25%),9h1 probably dueto the methoxy group at carbon 3 (not present in mor-phine), which protects it from extensive first-passglucuronidation.12 These bioavailability values foroxycodone are in accord with the higher oral: paren-teral efficacy ratio (0.50_0.75)1213 for oxycodone com-pared with that of morphine (0.17).1314

Results of well-controlled clinical studies indicatethat oxycodone is effective and safe for relief of mod-erate to severe pain in cancer patients12’15’16 and isalso an appropriate postoperative analgesic.1723 Forexample, 10mg of intramuscular oxycodone and 100mg of meperidine compared favorably for pain reliefafter abdominal surgery.17 In a study by Kalso et al,2#{176}

SUNSHINE ET AL

596 #{149}J ClIn Pharmacol 1996;36:595-603

patients self-administered oxycodone and morphineintravenously during the first 2 hours after abdomi-nal surgery until comparable degrees of analgesiawere obtained; the patients taking oxycodone expe-rienced more effective, more rapid, and more lastingrelief.

To alleviate cancer-related pain, less oxycodone

than morphine is required orally, but more oxyco-done than morphine is needed intravenously.15’24According to Beaver et al,12’16twice the amount ofoxycodone in milligrams is required orally than in-tramuscularly for equianalgesia; intramuscular oxy-codone is two thirds as potent as intramuscular mor-phine.

Typical opiate-related adverse effects have beenreported for oxycodone. In one study,18 nausea wasnot observed as frequently with oxycodone as withmeperidine after administration for pain from ab-dominal surgery. In another study of pain after ab-dominal surgery,2#{176} no difference in the incidence ofside effects was found between intravenous oxyco-done and intravenous morphine. In cancer patients,less nausea occurred after administration of oxyco-done than after morphine.15 In addition, 25% of thesepatients experienced hallucinations after takingmorphine but not after taking oxycodone.15 The po-tential for abuse of oxycodone was found to be equiv-alent to that of morphine.25

Although oral controlled-release morphine is pres-ently in common use for the management of moder-ate to severe pain requiring more than a few days oftreatment, to date no alternative strong oral analge-sic that lasts for 12 hours is available. In answer tothis need, a new tablet formulation of oral oxycodonein a controlled-release (CR) delivery system has beendeveloped. We conducted a double-blind study todetermine the analgesic efficacy and safety of CR ox-ycodone tablets in 10-, 20-, and 30-mg doses in com-

parison to immediate-release (IR) oxycodone as a 15-

mg dose alone or as a 10-mg dose in combinationwith 650 mg acetaminophen (APAP) and placebo inpatients experiencing moderate to severe pain afterabdominal or gynecologic surgery.

PATIENTS AND METHODS

Patient Selection

A total of 182 inpatients were enrolled in the study.Women who were experiencing moderate or severepain after abdominal or gynecologic surgery that hadinvolved abdominal incision were selected.

To qualify for entry into this study, patients had tobe 18 years of age or older and free of anesthesia.They also had to be able to communicate meaning-

fully with the nurse-observer and to have given writ-ten, informed consent to participate. Patients withknown medical conditions that could be aggravatedby analgesics, that might confound pain assessment,or that might significantly affect the physiology ormetabolism of the study drugs were excluded. Pa-tients also were excluded if they were tolerant to ordependent on narcotic analgesics or alcohol, or ifthey had taken medications within 3 hours beforeadministration that might confound analgesic evalu-ation (or ifthey had received methadone or bupren-orphine within 6 hours before administration). In ad-dition, patients with known sensitivity to any of thestudy medications or related agents were excluded.

Study Design

This was a single-dose, double-blind, randomized,parallel-group, placebo-controlled study conductedat the Carolina Area Hospital in Carolina, PuertoRico and the Caguas Regional Hospital in Caguas,Puerto Rico. The study protocol was approved by theCommittee for the Protection of Human Rights andWelfare of the University of Puerto Rico School ofMedicine.

Patients were stratified at entry according to theirbaseline pain intensity (moderate or severe) to en-sure that the treatment groups were balanced withrespect to baseline pain. Study medications were notgiven until the day after surgery, when oral admin-istration was permitted. Until this time, pain wastreated with parenteral analgesics. Using a com-puter-generated randomization code, each patientwas randomly assigned to one of six treatmentgroups: three 5-mg IR oxycodone tablets (Roxico-done; Roxane Laboratories, Columbus, OH); one,two, or three 10-mg CR oxycodone tablets (OxyCon-tin; Purdue Pharma LP, Norwalk, CT); two tabletscontaining 5 mg IR oxycodone and acetaminophen325 mg (Percocet; DuPont Pharma, Wilmington, DE);or placebo. Each unit dose consisted of one capsuleand two tablets.

Before taking the study medication, patients wereasked to assess their pain intensity (moderate to se-vere). After administration of the study medication,they were instructed to reevaluate their pain everyhour for 12 hours using a Patient Self-Assessmentform. The study nurse evaluated the patient at eachassessment point to ensure that the evaluations weredone correctly and in a timely fashion. Pain intensitywas rated on a four-point categorical scale as none(0), mild (1), moderate (2), or severe (3). Pain reliefwas rated on a five-point categorical scale as none (0),a little (1), moderate (2), a lot (3), or complete (4) andon a 100-mm visual analog scale (VAS) with end

ANALGESIC EFFICACY OF CR OXYCODONE

ANALGESIA 597

TABLE I

Patient Characteristics

Treatment Group

CR Oxycodone IR OxycodoneCharacteristic 10 mg 20 mg 30mg 5 mg

Oxycodone+ APAP Placebo Total

Sample size 30 30 30 30 30 30 180Mean age (yrs) 31.6 30.5 35.2 31.9 31.9 30.5 31.9Race (no.)

Asian 0 1 0 0 0 1Hispanic 30 30 29 30 30 30 179

Mean Height(cm) 160.0 158,0* 161.6 162.0 160.6 159.4 160.3Mean Weight(kg) 65.5 61.1 64,5 66.2 66.7 67.1 65.2

i different (P � 0.05) from IR Oxycodone and 30’mg dose of CR oxycodone.

CR, controlled.release; IR, immediate release; Oxycodone + APAP, immediate-release oxycodone (10mg) in co mbination with aceta minophen (650 mg).

points of no relief (0 mm) and complete relief (100mm). After 12 hours or at the time of remedication,patients used five-point scales to evaluate their over-all pain relief as none (0), a little (1), good (2), verygood (3), or excellent (4) and their global rating of thestudy medication as poor (1), fair (2),good (3),verygood (4), or excellent (5).

Patients were permitted to remedicate anytime af-ter the first hour of the study. If patients remedicatedduring the 12-hour period after administration, theirbaseline pain intensity and a zero pain relief scorewere carried forward for the remaining hourly eval-uations. The time of first remedication with rescueanalgesic was recorded for 24 hours after study drugadministration.

Adverse events that occurred during the evalua-tion period were recorded for each patient based onreports by the patient or observations by the researchnurse. Vital signs were measured before administra-tion of study medication and at the time of study ter-mination or discharge.

Efficacy Parameters

Pain intensity difference (PID) scores on the categor-ical scale were calculated by subtracting each obser-vational pain intensity score from the baseline painintensity level; these scores were then totalled overthe 12-hour study period to obtain the sum of thepain intensity difference (SPID). Similarly, total painrelief (TOTPAR) and total pain relief at six hours(TOTPAR6) were calculated by summing the obser-vational pain relief scores. Peak measures for PID(PPID) and peak pain relief (PPAR) were calculatedas the highest hourly PID and pain relief scores, re-

spectively, for each patient; the associated times topeak (TPPID and TPPAR) also were calculated.

Onset of meaningful pain relief in minutes was de-termined by the patient using a stopwatch and re-corded by the research nurse. Duration of pain relief,defined as the time from onset of meaningful relief tothe return of a significant, meaningful, or unpleasantpain level (offset), also was measured by the patientusing a stopwatch.

Other calculated efficacy measurements includedderived onset of pain relief (the midpoint of the timeinterval between baseline and the firstobservation atwhich a patient reported a one-unit or greater in-crease in either relief scale), derived duration of painrelief (time from onset to the midpoint of the timeinterval for relief score to return to zero), time to re-medication, and the number of patients remedicat-ing with an analgesic.

Statistical Analysis

A two-way analysis of variance (ANOVA) was em-ployed to assess each efficacy measure.26’27 When sig-nificant differences (P � 0.05; two-sided) were found,pairwise comparisons were performed using Fisher’sprotected least significant difference test.28 In addi-tion, Fisher’s exact tests27 were used to evaluatedifferences for race and the incidence of patients re-porting adverse events among treatment groups. Alogistic regression was used to assess differences inthe numbers of patients requiring remedication.27

Survival analysis methodology was used to ana-lyze onset of relief, duration of relief, and time to re-medication. The distribution functions of onset, du-ration, and time to remedication were estimated us-

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Observation Time (Hr)

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SUNSHINE ET AL

598 #{149}J Clin Pharmacol 1996;36:595-603

Figure 1. Time-effect curves for mean pain intensity difference

(PID) scores (categorical scale) plotted against time. At 1 hour, 10mg oxycodone plus 650 mg acetaminophen (APAP) and immedi-

ate-release (IR) oxycodone 15 mg were significantly better (P � 0.05)

than controlled-release (CR) oxycodone 20 and 30 mg. 0 At 9, 10,

and 11 hours, CR oxycodone 20 mg was significantly better (P �

0.05) than lB oxycodone 15 mg. tAt 9 and 11 hours, CR oxycodone

20 mg was significantly better (P � 0.05) than oxycodone plus

APAP. § At 10 hours, CR oxycodone 30 mg was significantly better

(P � 0.05) than oxycodone plus APAP.

ing the nonparametric Kaplan-Meier product-limitestimator procedure for those patients who had onsetof relief.26

RESULTS

Patient Population

Of the 182 patients who were assigned in random-ized fashion to receive the study drugs, all were eval-uable for safety. Two patients were excluded fromthe efficacy analysis, however: one patient from the

placebo group was inadvertently remedicated duringthe study, and another patient from the IR oxyco-done group vomited within an hour of administra-tion, before full absorption of the medication waspresumed to have occurred. Therefore, data from180 patients (6 groups of 30 each) were consideredvalid for efficacy evaluation.

As shown in Table I, the demographic characteris-tics of the patients were homogeneous among treat-ment groups, with the exception of height. For thischaracteristic, patients taking 20 mg CR oxycodonewere significantly shorter (P � 0.05) than those taking

Figure 2. Time-effect curves for mean pain relief scores (VAS) plot-ted against time. Categorical scale was similar to VAS. * At 1 hour,

10 mg oxycodone plus 650 mg acetaminophen (APAP) and imme-

diate-release (IR) oxycodone 15 mg were significantly better (P �

0.05) than controlled-release (CR) oxycodone 20 and 30 mg. 0 At

10, 11, and 12 hours, CR oxycodone 20 mg was significantly better

(P � 0.05) than lR oxycodone 15mg. fAt 9, 10, 11, and 12 hours,

CR oxycodone 20 and 30 mg were significantly better (P � 0.05)

than oxycodone plus APAP.

ANALGESIC EFFICACY OF CR OXYCODONE

ANALGESIA 599

TABLE II

Measures of Analgesic Efficacy

Treatment Group

CR Oxycodone IR OxycodoneParameter* 10mg (N = 30) 20mg (N = 30) 30mg (N = 30) (N = 30)

Oxycodone +APAP (N = 30)

Placebo(N = 30)

SPIDt 12.80(1.98)1: 16.33(2.01)1: 16.80 (1.87)1: 13.50(1.69)1: 15.17(1.47)1: 6.37(1.48)TOTPAR6t 11.67(1.44)1: 15.60 (1.15) 16.27 (1.22) 15.43(1.49)1: 18.53 (0.80) 7.53(1.24)TOTPARI- 20.87(2.86)1: 27.23(2.81)1: 27.07(2.67)1: 22.27(2.55)1: 24.53(1.76)1: 11.20(2.35)PPIDI- 1.70(0.20) 2.20(0.15) 2.23(0.16) 2.10(0.20)1: 2.50(0.09) 1.30(0.21)TPPIDf 4.80(0.73) 3.10 (0.37) 3.00 (0.48) 3.70(0.65)1: 2.23(0.2 1) 5.73 (0.87)PPARt 2.67(0.29) 3.50(0.16) 3.40(0.19) 3.20(0.26)1: 3.83(0.08)11 2.10(0.29)TPPARf 4.63 (0.72) 3.13(0.36)1: 2.67 (0.37) 3.70(0.65) 2.27 (0.20) 5.20(0.82)Overallpainrelieft 2.40(0.27)f 3.17(0.19) 3.13(0.21) 2.90(0.24)1: 3.37(0.14) 1.76(0.27)

Global ratingf 2.87 (0.24) 3.43 (0.23)1: 3.63 (0.23) 3.47 (0.25)1: 3.67 (0. 16) 2.17 (0.23)REMED 12 hrs no. (%) 17(56.6)1! 15(50.0)11 18 (60.0) 22(73.3) 25(83.3) 25(83.3)REMED 24 hrs no. (%) 23 (76.6)** 21 (70.0)tt 25(83.3) 28(93.3) 29(96.6) 27(90.0)

* Categorical scores (VAS were similar).

t Mean (standard error).f Significantly different (P � 0.05) from placebo.

§ Significantly different (P � 0.05) from placebo and 10mg CR oxycodone.

II Significantly different (P � 0.05) from placebo, 10mg CR oxycodone, and IS’ oxycodone.#{182}Significantly different (P � 0.05) from placebo and Oxycodone + APAP.* * Significantly different (P � 0.05) from Oxycodone + APAP.

ft Significantly different (P 0.05) from Oxycodone + APAP and IR oxycodone.CR. controlled-release; IR, immediate’release; APAP, acetaminophen; SPIEl, sum of pain intensity difference;

TOTPAR6, total pain relief at 6 hours; TOTPAR, total pain relief at 12 hours: PPID. peak pain intensity difference; TPPID,time to PPID; PPAR, peak pain relief; TPPAR, time to PPAR; REMED 12 hrs, patients remedicating within 12 hours;REMED 24 firs, patients remedicating within 24 hours.

IR oxycodone and 30 mg CR oxycodone; however,this difference was not considered to be clinicallysignificant. Baseline pain intensity scores were sim-ilar among treatment groups, with no significantdifferences observed. The distribution of patientswith moderate (30%-37%) or severe (63%-70%) painwithin and across treatment groups was comparable.

Efficacy Results

All active treatments were significantly superior (P <

0.05) to placebo for many of the hourly PID and reliefmeasures (Figures 1 and 2). Oxycodone plus APAPand JR oxycodone were better (P < 0.05) than placebofor PID and relief measures from 1 hour to 7 hoursafter administration. The CR oxycodone treatmentswere significantly better than placebo for PID and re-lief at 2 hours (20- and 30-mg doses) and at 3 hours(10-mg dose), and this was maintained through 11hours after administration. For the active treat-ments, peak analgesic effects occurred 2 to 4 hoursafter drug administration. All active treatments weresignificantly superior to placebo for the summary

variables SPID, and TOTPAR at 6 and 12 hours (Ta-ble II).

As judged by pain relief scores and peak PID, adose response was seen among the three dose levelsof CR oxycodone, with the 20- and 30-mg doses re-

sulting in higher scores than the 10-mg dose (TableII; Figures 1 and 2). All three doses of CR oxycodoneexhibited a prolonged level of pain relief throughoutthe 12-hour study period. In comparison, analgesialasted only 6 to 8 hours and then declined in thegroups taking oxycodone plus APAP and JR oxyco-done.

At one hour after administration, patients treatedwith oxycodone plus APAP reported higher (P <

0.05) PID and relief scores than those taking 20 and30 mg CR oxycodone. At several time points between9 and 12. hours after administration, CR oxycodone10 mg, 20 mg, and 30 mg resulted in higher (P < 0.05)PID and relief scores than IR oxycodone and oxyco-done plus APAP (Figures 1 and 2). The 20- and 30-mgdoses of CR oxycodone and oxycodone plus APAPdemonstrated significantly greater (P < 0.05) efficacythan CR oxycodone 10 mg for TOTPAR6 (Table II).Comparison of IR oxycodone and CR oxycodone 30

SUNSHINE ET AL

600 #{149}J Clln Pharmacol 1996;36:595-603

TABLE III

Onset and Duration of Relief, Time to Remedicatlon, and Number of Patients Remedicated During the 12-hourStudy Period (for Patients with Subjective Onset of Relief)

Time to Onset byPatients with Percentile (mm)

OnsetNo.(%) 25 50 75

Duration of Relief byPercentile (hrs)

Time to Remedicationby Percentile (hrs) PatIents

25 50 75 25 50 75Remedicated

No.(%)

CR oxycodone10mg 22 (73.3) 39.0 61.5* 102.0 5.6 12.0* 12.0 7.2 12.Of 12.0 8(36.4)*20mg 28 (93.3)1: 30.0 58.0* 88.0 4.6 9.8* 12.0 6.3 12.0 12.0 13(46.4)30mg 27 (90.0)1: 29.0 46.Ofl 90.0 7.3 9.6* 12.0 8.2 11.4 12.0 15(55.6)

IROxycodone 25 (83.3)1: 30.0 41.0 47.0 5.6 7.4 9.0 7.2 9.0 12.0 18(72.0)Oxycodone+APAP 30(100.0)1: 26.0 32.0 46.0 5.0 7.1 8.4 6.4 8.1 10.0 25(83.3)Pacebo 16 (53.3) 24.5 50.0 70.0 2.9 4.6 12.0 5.0 7.4 12.0 11(68.7)

* Significantly different (P � 0.05) from Oxy’IR and Oxy APAP.

f Significantly different (P � 0.05) from placebo, Oxy-lR, and Oxy-A PA P.f Significantly different (P 0.05) from placebo.§ Significantly different (P � 0.05) from Oxy-A PAP.

Significantly different (P � 0.05) from Oxy’IR 15 mg.

CR, controlled-release; IR, immediate.re!ease; Oxycodone + APAP, immediate’re lease oxycodone (10 mg) plus acet’

aminophen (650 mg).

mg revealed comparable measures of analgesicefficacy, with no significant differences (Table II).

For the patients’ ratings of overall pain relief (Ta-

ble II), all active treatments were significantly (P �

0.05) more analgesic than placebo, and CR oxyco-done 20 and 30 mg and oxycodone plus APAP weresignificantly better (P � 0.05) than CR oxycodone 10

mg. The patients’ global medication ratings indicatedthat all active treatments except for CR oxycodone10 mg were significantly better (P � 0.05) than pla-cebo. In addition, CR oxycodone 30 mg and oxyco-done plus APAP were rated as significantly better (P

� 0.05) than CR oxycodone 10 mg.Among all patients in the study, fewer (P � 0.05) in

the groups taking CR oxycodone 10 and 20 mg re-quired remedication at the 12- and 24-hour periodsafter drug administration compared with those tak-ing oxycodone plus APAP. In addition, fewer pa-tients (P � 0.05) in the group taking CR oxycodone 20mg required remedication over the 24-hour intervalcompared with those taking IR oxycodone (Table II).

Among patients with onset of pain relief, the pro-portion of patients requiring remedication during thefirst 12 hours was lower in the groups taking CR oxy-codone 10, 20, and 30 mg (P � 0.05) than in the grouptaking oxycodone plus APAP (Table III).

The distribution functions for time to remedica-tion of the treatments differed significantly, witheach of the three doses of CR oxycodone resulting ina longer median time to remedication than oxyco-done plus APAP. Patients receiving CR oxycodone

10, 20, or 30 mgdid not require remedication until 11

to 12 hours after administration, compared with 8.1hours for those taking oxycodone plus APAP (P �

0.05) and 9.0 hours for those taking IR oxycodone(Table III).

The proportion of patients experiencing onset ofpain relief as determined by the stopwatch methodwas greater after the 20- and 30-mg doses of CR oxy-codone, after IR oxycodone, and after oxycodoneplus APAP than placebo (Table III).The distribution

functions for onset of relief of the treatments differedsignificantly, with the 10- and 20-mg doses of CR ox-ycodone each resulting in longer times to onset thaneither IR oxycodone or oxycodone plus APAP, andthe 30-mg dose of CR oxycodone resulting in a longeronset time than IR oxycodone. The median time toonset among active treatments was 32 minutes foroxycodone plus APAP, 41 minutes for JR oxycodone,46 minutes for CR oxycodone 30 mg, 58 minutes forCR oxycodone 20 mg, and 61.5 minutes for CR oxy-

codone 10 mg.The distribution functions for duration of relief of

the treatments differed significantly, with each of thethree doses of CR oxycodone resulting in a longer du-ration of relief than either IR oxycodone or oxyco-done plus APAP. Among the CR oxycodone treat-ments, the median duration of pain relief rangedfrom 9.6 hours for the 30-mg dose to 12 hours for the10-mg dose. In contrast, duration of pain relief wassignificantly shorter for the immediate-release for-mulations tested, with median duration times of 7.1

ANALGESIC EFFICACY OF CR OXYCODONE

ANALGESIA 601

TABLE IV

Patient Incidence and Number of Reports of Adverse Events Before Remedication

CR Oxycodone IR Oxycodone +

Adverse Oxycodone APAPEvent 10 mg(N = 30) 20 mg(N = 30) 30mg (N = 30) (N = 31) (N = 30) Placebo (N = 31) Total (N = 182)

Somnolence 7(23) 7 7(23) 7 10(33)10 11(11)35 9(30) 9Fever 8(27) 8 6(20) 6 10(33)10 7 (23) 7 8(27) 8Dizziness 1 (3) 1 3(10) 3 0 (0) 0 2 (6) 2 1 (3) 1Headache 1 (3) 1 1 (3) 1 3(10) 3 1 (3) 1 0 (0) 0Pain* 0 (0) 0 1 (3) 1 0 (0) 0 2 (6) 2 1 (3) 1Nausea 0 (0) 0 0 (0) 0 0 (0) 0 1 (3) 2 0 (0) 0

Palpitations 1 (3) 1 0 (0) 0 0 (0) 0 0 (0) 0 0 (0) 0Otherf 1 (3) 1 0 (0) 0 0 (0) 0 2 (6) 2 1 (3) 1

4(13) 47 (23) 70 (0) 00 (0) 02 (6) 2

0 (0) 00 (0) 00 (0) 0

48(26) 4846(25) 46

7 (4) 76 (3) 66 (3) 6

1 (1) 21 (1) 13 (2) 3

Total 14(47)19 15(50)18 22(73)23 22 (71)27 19(20)63 12(39)13 104 (57) 120

Values are presented as the number of patients reporting one or more events (% patients reporting events out of totalpatients in treatment group), and then the number of reported events.

* Includes abdominal, back, chest, and neck pain.

f Includes asthma, dyspnea, amblyopia, and hematuria; none of these occurred in more than one patient.CR, controlled-release; IR, immediate’release; oxycodone + APAP, immediate’release oxycodone (10 mg) given with

acetaminophen (650 mg).

and 7.4 hours for oxycodone plus APAP and IR oxy-codone, respectively. The derived measures of onsetand duration of pain relief were comparable to thoseobtained using the stopwatch method (data notshown).

Safety Results

All 182 patients who received study drugs were eval-uable for safety; of these, 104 (5 7%) reported adverseevents (Table IV). The proportion of patients experi-encing adverse events was greatest in the groups tak-ing oxycodone plus APAP (63.3%), IR oxycodone(70.9%), and CR oxycodone 30 mg (73.3%). Somno-lence was the most commonly reported adverseevent. Fever was the next most common adverseevent reported, but was considered to be a result ofthe surgical procedures. Dizziness and, less fre-quently, headache also were reported. All adverseevents disappeared or resolved with symptomatictreatment and none of the events was severe.

Vital signs, including body temperature, bloodpressure, heart rate, and respiration were evaluatedbefore treatment and before discharge; althoughsome changes were statisticallysignificant, none wasclinically significant.

DISCUSSION

As documented in scientific reviews30 and regulatorydocuments,31 single-dose studies have been well es-

tablished as an appropriate method of comparing

efficacy, potency, and onset, peak, and duration ofeffects of analgesics. A surgical pain model is com-monly used in studies for the evaluation of strongopioids.

This single-dose, randomized, double-blind, paral-lel-group investigation compared the effectivenessand safety of a CR oral tablet of oxycodone with anIR tablet of oxycodone (considered to be a regulatorystandard), an IR oxycodone-acetaminophen tablet(selected as an appropriate clinical reference stan-dard), and placebo in patients experiencing moder-ate to severe pain after abdominal or gynecologic sur-gery. The pain model used in the present study dem-onstrated good assay sensitivity, with separation ofthe known active agents, IR oxycodone and oxyco-done plus APAP, from placebo. In addition, for themajor parameters measured, the three dosages of CRoxycodone also were separated from one another.

Our results demonstrated that all active treat-ments were significantly superior to placebo formany of the hourly pain relief measures and for SPIDand TOTPAR. For patients given 10, 20, or 30 mg ofCR oxycodone, onset of pain relief occurred withinapproximately 1 hour of administration, and thepeak effect was noted between 2 and 4 hours afteradministration. The shortest times to onset wereseen with the two JR oxycodone treatments, with a5-minute difference in onset between CR oxycodone30 mg and IR oxycodone. In this single-dose study,

SUNSHINE ET AL

602 S .JClin Pharmacol 1996;36:595-603

the duration of analgesia for the CR oxycodone prep-arations was approximately 10 to 12 hours. For pain-relief scores and PID, a dose response was seenamong the three dose levels of CR oxycodone, vali-dating this comparative analgesic model.

In this study, CR oxycodone was shown to be aneffective oral analgesic with longer duration of painrelief than either IR oxycodone or oxycodone plusAPAP. Among the treatments studied, the compari-sons between CR oxycodone 30 mg and IR oxyco-done 15 mg were considered most clinically relevantbecause in settings requiring repeated administra-tion of analgesics, these doses of CR oxycodone every12 hours and IR oxycodone every 6 hours result inequivalent total daily oxycodone dosages. The fasteronset (by 5 minutes) of pain relief seen with IR oxy-codone was not considered clinically meaningful forsettings in which repeated analgesic administrationis anticipated.

Adverse events occurred in all of the treatmentgroups. However, all effects disappeared or resolvedeither spontaneously or with symptomatic treatmentas necessary. Overall, somnolence was the mostprevalent adverse effect, occurring in 23% to 35% ofthe patients treated with oxycodone. Somnolencemay be a result of the medication, a response to painrelief, or both. Fever was almost certainly a result ofthe surgical procedures and not the active treat-ments.

From these results, we conclude that CR oral oxy-codone tablets at appropriate doses produce compa-rable analgesia and safety with a longer duration ofaction than IR oxycodone tablets or oxycodone-acet-aminophen tablets.

The development of an oral CR preparation of ox-ycodone represents an advancement over the IRpreparations by providing prolonged analgesia. Con-trolled-release oxycodone also offers clinicians ananalgesic alternative to controlled-release morphinefor treating patients with postoperative pain. Thispreparation can be expected to improve patient com-pliance, allow greater convenience, and provide un-interrupted nighttime sleep for patients in pain.

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