The Journal of Clinical Pharmacology

http://www.jclinpharm.org Analgesic efficacy of controlled-release oxycodone in postoperative pain

A Sunshine, NZ Olson, A Colon, J Rivera, RF Kaiko, RD Fitzmartin, RF Reder and PD Goldenheim J. Clin. Pharmacol. 1996; 36; 595 The online version of this article can be found at: http://www.jclinpharm.org/cgi/content/abstract/36/7/595

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ANALGESIA

Analgesic Efficacy of Controlled-Release Oxycodone in Postoperative Pain

Abraham Sunshine,
Robert

MD, F. Kaiko,

FCP,
PhD,

Nancy Z. Olson, MPS, Ronald D. Fitzmartin, and Paul D. Goldenheim,

Ariel Colon, PhD, Robert MD

MD,

Juana

Rivera,

MD,

F. Reder,

MD,

of graded doses (10, 20, and 30 mg) of controlled-release (CR) with that of immediate-release (IR) oxycodone (15 mg), immediate-release 10 mg in combination with acetaminophen 650 mg (APAP), and placebo in a single-dose, double-blind, randomized, parallel-group study. The participants, 182 inpatients experiencing moderate to severe pain after abdominal or gynecologic surgery, provided hourly ratings of pain intensity and relief for 12 hours after administration. 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 significantly 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 46 minutes for CR oxycodone 30mg. Duration of pain relief showed that the 10-, 20-, and 30mg 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 adverse events, 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.
The efficacy and safety

oxycodone

was

compared oxycodone

is thebaine, with clinical use first reported in 1917.1 In the past, it was treated as a mild opioid2 and was only available in the United States as a constituent of fixed combination analgesics with aspirin or acetaminophen.3 More recently, however, oxycodone has been recognized as a strong opioid suitable at higher dosages for the treatment of moderate and severe pain.45 Because aspirin and acetaminophen in

Oxycodone (14-hydroxy-7,8-dihydrocodeinone) a semisynthetic opioid agonist derived from

From the Department of Medicine, New (Dr. Sunshine), Analgesic Development

York University Medical Center Ltd., New York (Dr. Sunshine

and Ms. Olson), Colon), Carolina

the Purdue Fitzmartin, Purdue prints: Reder, Frederick Abraham

Caguas Regional Hospital, Caguas, Puerto Rico (Dr. Area Hospital, Carolina, Puerto Rico (Dr. Rivera), and
Company, and Sunshine, Goldenheim). Norwalk, MD, Analgesic Company, Norwalk, Connecticut Connecticut. Development (Drs. from for Address Ltd. Kaiko, The reSupported by a grant

Frederick

23 East

73rd Street,

Suite 5F, New York, NY 1002 1-3522.

fixed combination may become toxic and cause unacceptable adverse effects at elevated doses,3 oxycodone is now available as a single-entity analgesic. Like morphine, oxycodone has a short elimination half-life (t112)5 and is considered to be a versatile and flexible analgesic.6 Oxycodone, however, has been found to have a higher oral bioavailability (60%87%)78 than morphine (20%_25%),9h1 probably due to the methoxy group at carbon 3 (not present in morphine), which protects it from extensive first-pass glucuronidation.12 These bioavailability values for oxycodone are in accord with the higher oral: parenteral efficacy ratio (0.50_0.75)1213 for oxycodone compared with that of morphine (0.17).1314 Results of well-controlled clinical studies indicate that oxycodone is effective and safe for relief of moderate to severe pain in cancer patients121516 and is also an appropriate postoperative analgesic.1723 For example, 10mg of intramuscular oxycodone and 100 mg of meperidine compared favorably for pain relief after abdominal surgery.17 In a study by Kalso et al,2#{176}

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1996;36:595-603

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patients self-administered oxycodone and morphine intravenously during the first 2 hours after abdominal surgery until comparable degrees of analgesia were obtained; the patients taking oxycodone experienced more effective, more rapid, and more lasting relief. To alleviate cancer-related pain, less oxycodone than morphine is required orally, but more oxycodone than morphine is needed intravenously.1524 According to Beaver et al,1216 twice the amount of oxycodone in milligrams is required orally than intramuscularly for equianalgesia; intramuscular oxycodone is two thirds as potent as intramuscular morphine. Typical opiate-related adverse effects have been reported for oxycodone. In one study,18 nausea was not observed as frequently with oxycodone as with meperidine after administration for pain from abdominal surgery. In another study of pain after abdominal surgery,2#{176} no difference in the incidence of side effects was found between intravenous oxycodone and intravenous morphine. In cancer patients, less nausea occurred after administration of oxycodone than after morphine.15 In addition, 25% of these patients experienced hallucinations after taking morphine but not after taking oxycodone.15 The potential for abuse of oxycodone was found to be equivalent to that of morphine.25 Although oral controlled-release morphine is presently in common use for the management of moderate to severe pain requiring more than a few days of treatment, to date no alternative strong oral analgesic that lasts for 12 hours is available. In answer to this need, a new tablet formulation of oral oxycodone in a controlled-release (CR) delivery system has been developed. We conducted a double-blind study to determine the analgesic efficacy and safety of CR oxycodone tablets in 10-, 20-, and 30-mg doses in comparison to immediate-release (IR) oxycodone as a 15mg dose alone or as a 10-mg dose in combination with 650 mg acetaminophen (APAP) and placebo in patients experiencing moderate to severe pain after abdominal or gynecologic surgery. PATIENTS Patient AND Selection METHODS

fully with the nurse-observer and to have given written, informed consent to participate. Patients with known medical conditions that could be aggravated by analgesics, that might confound pain assessment, or that might significantly affect the physiology or metabolism of the study drugs were excluded. Patients also were excluded if they were tolerant to or dependent on narcotic analgesics or alcohol, or if they had taken medications within 3 hours before administration that might confound analgesic evaluation (or ifthey had received methadone or buprenorphine within 6 hours before administration). In addition, patients with known sensitivity to any of the study medications or related agents were excluded. Study Design

A total of 182 inpatients were enrolled in the study. Women who were experiencing moderate or severe pain after abdominal or gynecologic surgery that had involved abdominal incision were selected. To qualify for entry into this study, patients had to be 18 years of age or older and free of anesthesia. They also had to be able to communicate meaning-

This was a single-dose, double-blind, randomized, parallel-group, placebo-controlled study conducted at the Carolina Area Hospital in Carolina, Puerto Rico and the Caguas Regional Hospital in Caguas, Puerto Rico. The study protocol was approved by the Committee for the Protection of Human Rights and Welfare of the University of Puerto Rico School of Medicine. Patients were stratified at entry according to their baseline pain intensity (moderate or severe) to ensure that the treatment groups were balanced with respect to baseline pain. Study medications were not given until the day after surgery, when oral administration was permitted. Until this time, pain was treated with parenteral analgesics. Using a computer-generated randomization code, each patient was randomly assigned to one of six treatment groups: three 5-mg IR oxycodone tablets (Roxicodone; Roxane Laboratories, Columbus, OH); one, two, or three 10-mg CR oxycodone tablets (OxyContin; Purdue Pharma LP, Norwalk, CT); two tablets containing 5 mg IR oxycodone and acetaminophen 325 mg (Percocet; DuPont Pharma, Wilmington, DE); or placebo. Each unit dose consisted of one capsule and two tablets. Before taking the study medication, patients were asked to assess their pain intensity (moderate to severe). After administration of the study medication, they were instructed to reevaluate their pain every hour for 12 hours using a Patient Self-Assessment form. The study nurse evaluated the patient at each assessment point to ensure that the evaluations were done correctly and in a timely fashion. Pain intensity was rated on a four-point categorical scale as none (0), mild (1), moderate (2), or severe (3). Pain relief was rated on a five-point categorical scale as none (0), a little (1), moderate (2), a lot (3), or complete (4) and on a 100-mm visual analog scale (VAS) with end

596

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1996;36:595-603

ANALGESIC

EFFICACY

OF

CR

OXYCODONE

TABLE Patient

Characteristics
Treatment Group Oxycodone + APAP

CR Oxycodone Characteristic Sample size 10 mg 20 mg 30mg

IR Oxycodone 5 mg

Placebo 30

Total 180

Mean age (yrs) Race (no.) Asian Hispanic

Mean Mean Height(cm) Weight(kg)
i different

30 31.6 0 30
160.0 65.5
(P
0.05) from

30 30.5

30 35.2 1 29
161.6 64,5
dose of CR oxycodone. + APAP,

30 31.9 0 30
162.0 66.2
oxycodone (10mg) in co mbination

30
31.9

30.5 0 30
159.4 67.1
(650 mg).

31.9 1 179
160.3 65.2

30
158,0* 61.1
IR Oxycodone and 30mg

0 30
160.6 66.7

CR, controlled.release;

IR, immediate

release;

Oxycodone

immediate-release

with aceta minophen

points of no relief (0 mm) and complete relief (100 mm). After 12 hours or at the time of remedication, patients used five-point scales to evaluate their overall pain relief as none (0), a little (1), good (2), very good (3), or excellent (4) and their global rating of the study medication as poor (1), fair (2),good (3), very good (4), or excellent (5). Patients were permitted to remedicate anytime after the first hour of the study. If patients remedicated during the 12-hour period after administration, their baseline pain intensity and a zero pain relief score were carried forward for the remaining hourly evaluations. The time of first remedication with rescue analgesic was recorded for 24 hours after study drug administration. Adverse events that occurred during the evaluation period were recorded for each patient based on reports by the patient or observations by the research nurse. Vital signs were measured before administration of study medication and at the time of study termination or discharge. Efficacy Parameters

spectively, for each patient; the associated times to peak (TPPID and TPPAR) also were calculated. Onset of meaningful pain relief in minutes was determined by the patient using a stopwatch and recorded by the research nurse. Duration of pain relief, defined as the time from onset of meaningful relief to the return of a significant, meaningful, or unpleasant pain level (offset), also was measured by the patient using a stopwatch. Other calculated efficacy measurements included derived onset of pain relief (the midpoint of the time interval between baseline and the firstobservation at which a patient reported a one-unit or greater increase in either relief scale), derived duration of pain relief (time from onset to the midpoint of the time interval for relief score to return to zero), time to remedication, and the number of patients remedicating with an analgesic. Statistical
A

Analysis

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

two-way analysis of variance (ANOVA) was employed to assess each efficacy measure.2627 When significant differences (P 0.05; two-sided) were found, pairwise comparisons were performed using Fishers protected least significant difference test.28 In addition, Fishers exact tests27 were used to evaluate differences for race and the incidence of patients reporting adverse events among treatment groups. A logistic regression was used to assess differences in the numbers of patients requiring remedication.27 Survival analysis methodology was used to analyze onset of relief, duration of relief, and time to remedication. The distribution functions of onset, duration, and time to remedication were estimated us-

ANALGESIA

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S
U C

1.5

0
C

placebo group was inadvertently remedicated during the study, and another patient from the IR oxycodone group vomited within an hour of administration, before full absorption of the medication was presumed to have occurred. Therefore, data from 180 patients (6 groups of 30 each) were considered valid for efficacy evaluation. As shown in Table I, the demographic characteristics of the patients were homogeneous among treatment groups, with the exception of height. For this characteristic, patients taking 20 mg CR oxycodone were significantly shorter (P 0.05) than those taking

.8 C
0.
C C

0.5

90

80

0 0123456789101112
Observation Time (Hr)

70

60 E

OXY-IR

15 MG

PLACEBO OXY-CR 20 MG

#{149} OXY-CR
OXY-CR

10MG
30 MG

--

--

OXY-APAP

:
20 10 0 0123456789101112 Observation
-I-

1. Time-effect curves for mean pain intensity difference scores (categorical scale) plotted against time. At 1 hour, 10 mg oxycodone plus 650 mg acetaminophen (APAP) and immediate-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 Figure
(PID)

APAP. At 10 hours, CR oxycodone 30 mg (P 0.05) than oxycodone plus APAP.

was

significantly

better

Time (Hr)
-*-

OXY-JR 15 MG
OXY-CR

PLACEBO
OXY-CR

ing the nonparametric estimator procedure of relief.26 RESULTS Patient Population

Kaplan-Meier for those patients

product-limit who had onset

--

10 MG 30 MG

-h..

20 MG

-e-

OXY-CR

-0-

Of the 182 patients who were ized fashion to receive the study uable for safety. Two patients the efficacy analysis, however:

assigned in randomdrugs, all were evalwere excluded from one patient from the

for mean pain relief scores (VAS) plotscale was similar to VAS. * At 1 hour, mg acetaminophen (APAP) and imme15 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
Figure 2. Time-effect curves ted against time. Categorical 10 mg oxycodone plus 650 diate-release (IR) oxycodone (P 0.05) than CR oxycodone than oxycodone lR oxycodone 20 and 30 mg plus APAP. 15mg. were fAt 9, 10, significantly 11, and better 12 hours, (P 0.05)

598

#{149} Pharmacol J Clin

1996;36:595-603

ANALGESIC

EFFICACY

OF CR OXYCODONE

TABLE Measures

II Efficacy
Group IR Oxycodone (N = 30) Oxycodone + APAP (N = 30)
Placebo

of Analgesic

Treatment CR Oxycodone Parameter* 10mg (N

=

30)

20mg

(N

30)

30mg

(N

30)

(N

30)

SPIDt TOTPAR6t

12.80(1.98)1: 11.67(1.44)1:

16.33(2.01)1: 15.60 (1.15)

16.80 (1.87)1: 16.27 (1.22)

13.50(1.69)1: 15.43(1.49)1:

15.17(1.47)1: 18.53 (0.80)

6.37(1.48) 7.53(1.24)

TOTPARIPPIDITPPIDf PPARt TPPARf Overallpainrelieft

Global ratingf REMED 12 hrs no. REMED 24 hrs no.
*

20.87(2.86)1: 1.70(0.20)
4.80(0.73) 2.67(0.29) 4.63 (0.72) 2.40(0.27)f

27.23(2.81)1: 2.20(0.15)
3.10 (0.37) 3.50(0.16) 3.13(0.36)1: 3.17(0.19)
3.43 (0.23)1: 15(50.0)11 21 (70.0)tt

27.07(2.67)1: 2.23(0.16)
3.00 (0.48) 3.40(0.19) 2.67 (0.37) 3.13(0.21)
3.63 (0.23) 18 (60.0) 25(83.3)

22.27(2.55)1: 2.10(0.20)1:
3.70(0.65)1: 3.20(0.26)1: 3.70(0.65) 2.90(0.24)1:
3.47 (0.25)1: 22(73.3)

24.53(1.76)1: 2.50(0.09)
2.23(0.2 1) 3.83(0.08)11 2.27 (0.20) 3.37(0.14)
3.67 (0. 16) 25(83.3)

11.20(2.35) 1.30(0.21)
5.73 (0.87) 2.10(0.29) 5.20(0.82) 1.76(0.27)
2.17 (0.23) 25(83.3)

(%) (%)

2.87 (0.24) 17(56.6)1! 23 (76.6)**

28(93.3)

29(96.6)

27(90.0)

Categorical
Mean

scores

(VAS were similar). (P 0.05) (P 0.05) (P 0.05) (P 0.05) (P 0.05)

from from placebo. placebo and 10mg CR oxycodone.

(standard

error).

f Significantly Significantly II Significantly #{182} Significantly * * Significantly

different different different different different

from placebo, 10mg CR oxycodone, and IS oxycodone. from placebo and Oxycodone + APAP. from Oxycodone + APAP.

ft Significantly different (P 0.05) from Oxycodone + APAP and IR oxycodone. CR. controlled-release; IR, immediaterelease; 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 this difference significant. ilar among differences with moderate within and Efficacy
All

and 30 mg CR oxycodone; however, was not considered to be clinically Baseline pain intensity scores were simtreatment groups, with no significant observed. The distribution of patients (30%-37%) or severe (63%-70%) pain across treatment groups was comparable.

Results

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

variables SPID, and TOTPAR at 6 and 12 hours (Table II). As judged by pain relief scores and peak PID, a dose response was seen among the three dose levels of CR oxycodone, with the 20- and 30-mg doses resulting in higher scores than the 10-mg dose (Table II; Figures 1 and 2). All three doses of CR oxycodone exhibited a prolonged level of pain relief throughout the 12-hour study period. In comparison, analgesia lasted only 6 to 8 hours and then declined in the groups taking oxycodone plus APAP and JR oxycodone. At one hour after administration, patients treated with oxycodone plus APAP reported higher (P < 0.05) PID and relief scores than those taking 20 and 30 mg CR oxycodone. At several time points between 9 and 12. hours after administration, CR oxycodone 10 mg, 20 mg, and 30 mg resulted in higher (P < 0.05) PID and relief scores than IR oxycodone and oxycodone plus APAP (Figures 1 and 2). The 20- and 30-mg doses of CR oxycodone and oxycodone plus APAP demonstrated significantly greater (P < 0.05) efficacy than CR oxycodone 10 mg for TOTPAR6 (Table II). Comparison of IR oxycodone and CR oxycodone 30

ANALGESIA

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TABLE Onset and Duration of Relief, Time to Remedicatlon, Study Period (for Patients
Patients with Onset No.(%) Time to Onset by Percentile (mm) 25 50 75

III During the 12-hour

and Number of Patients Remedicated with Subjective Onset of Relief)

Duration of Relief by Percentile (hrs) 25 50 75

Time to Remedication by Percentile (hrs) 25 50 75

PatIents Remedicated No.(%)

CR oxycodone 10mg 20mg 30mg IROxycodone Oxycodone+APAP Pacebo

*

22 (73.3) 28 (93.3)1: 27 (90.0)1: 25 (83.3)1: 30(100.0)1: 16 (53.3)

(P (P (P (P (P
0.05) from OxyIR

39.0 30.0 29.0 30.0 26.0 24.5

Oxy-lR,

61.5* 58.0* 46.Ofl 41.0 32.0 50.0

and Oxy-A PA P.

102.0 88.0 90.0 47.0 46.0 70.0

5.6 4.6 7.3 5.6 5.0 2.9

12.0* 9.8* 9.6* 7.4 7.1 4.6

12.0 12.0 12.0 9.0 8.4 12.0

7.2 6.3 8.2 7.2 6.4 5.0

12.Of

12.0

8(36.4)*

12.0 11.4 9.0 8.1 7.4

12.0 12.0 12.0 10.0 12.0

13(46.4) 15(55.6) 18(72.0) 25(83.3) 11(68.7)

Significantly

different different different different different

and Oxy APAP.

f Significantly f Significantly Significantly Significantly

CR, aminophen

0.05) 0.05)
0.05) 0.05)

from placebo, from placebo.

from from

Oxy-A PAP. OxyIR 15 mg. Oxycodone + APAP, immediatere lease oxycodone (10 mg) plus acet

controlled-release; (650 mg).

IR, immediate.re!ease;

mg revealed comparable measures of analgesic efficacy, with no significant differences (Table II). For the patients ratings of overall pain relief (Table II), all active treatments were significantly (P 0.05) more analgesic than placebo, and CR oxycodone 20 and 30 mg and oxycodone plus APAP were significantly better (P 0.05) than CR oxycodone 10 mg. The patients global medication ratings indicated that all active treatments except for CR oxycodone 10 mg were significantly better (P 0.05) than placebo. In addition, CR oxycodone 30 mg and oxycodone 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 required remedication at the 12- and 24-hour periods after drug administration compared with those taking oxycodone plus APAP. In addition, fewer patients (P 0.05) in the group taking CR oxycodone 20 mg required remedication over the 24-hour interval compared with those taking IR oxycodone (Table II). Among patients with onset of pain relief, the proportion of patients requiring remedication during the first 12 hours was lower in the groups taking CR oxycodone 10, 20, and 30 mg (P 0.05) than in the group taking oxycodone plus APAP (Table III). The distribution functions for time to remedication of the treatments differed significantly, with each of the three doses of CR oxycodone resulting in a longer median time to remedication than oxycodone plus APAP. Patients receiving CR oxycodone

10, 20, or 30 mgdid not require remedication until 11 to 12 hours after administration, compared with 8.1 hours 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 of pain relief as determined by the stopwatch method was greater after the 20- and 30-mg doses of CR oxycodone, after IR oxycodone, and after oxycodone plus APAP than placebo (Table III). The distribution functions for onset of relief of the treatments differed significantly, with the 10- and 20-mg doses of CR oxycodone each resulting in longer times to onset than either IR oxycodone or oxycodone plus APAP, and the 30-mg dose of CR oxycodone resulting in a longer onset time than IR oxycodone. The median time to onset among active treatments was 32 minutes for oxycodone plus APAP, 41 minutes for JR oxycodone, 46 minutes for CR oxycodone 30 mg, 58 minutes for CR oxycodone 20 mg, and 61.5 minutes for CR oxycodone 10 mg. The distribution functions for duration of relief of the treatments differed significantly, with each of the three doses of CR oxycodone resulting in a longer duration of relief than either IR oxycodone or oxycodone plus APAP. Among the CR oxycodone treatments, the median duration of pain relief ranged from 9.6 hours for the 30-mg dose to 12 hours for the 10-mg dose. In contrast, duration of pain relief was significantly shorter for the immediate-release formulations tested, with median duration times of 7.1

600

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1996;36:595-603

ANALGESIC

EFFICACY

OF

CR

OXYCODONE

TABLE Patient
Adverse Event

IV of Adverse
IR Oxycodone (N = 31) 11(11)35

Incidence

and Number

of Reports

Events

Before

Remedication

CR Oxycodone 10 mg(N
=

30)

20 mg(N

30)

30mg

(N

30)

Oxycodone + APAP (N = 30)

Placebo 4(13)

(N

31) 4 7

Total (N 48(26) 46(25)

182) 48 46

Somnolence Fever

7(23) 8(27)

7
8

7(23)
6(20)

7
6

10(33)10 10(33)10

9(30)

Dizziness
Headache
Pain*

1 (3)
1 0 0
1

1
1 0

3(10)
1 1 (3) (3)

3
1 1

(0)

0
3 0

7 (23) 2 (6)
1 2 (3) (6)

7 2
1 2

8(27) 1 (3)
0 1 (0) (3)
(0)

8 1
0 1 0 1

7 (23) 0 (0)
0 2 (0) (6) (0) (0)

0
0 2 0 0

7 (4)
6 6 1 3 (3) (3) (1) (2)

7
6 6

(3) (0)

3(10) 0 (0)

Nausea Palpitations Otherf

Total

(0) 0 (3) 1
(3) 1

0 0
0

(0) 0 (0) 0
(0) 0

0 0
0

(0) 0 (0) 0
(0) 0

1 (3) 2 0 (0) 0
2 (6) 2 22 (71)27

0 0
1

(0) 0
(3)

0
0 0

(0) 0

1 (1)

2
1 3 120

14(47)19

15(50)18

22(73)23

19(20)63 events out of total

12(39)13

104 (57)

Values are presented as the number of patients reporting one or more events patients in treatment group), and then the number of reported events. * Includes abdominal, back, chest, and neck pain. f Includes

(% patients

reporting

asthma, dyspnea, amblyopia, and hematuria; none of these occurred in more than one patient. CR, controlled-release; IR, immediaterelease; oxycodone + APAP, immediaterelease oxycodone (10 mg) given acetaminophen (650 mg).

with

7.4 hours for oxycodone plus APAP and IR oxycodone, respectively. The derived measures of onset and duration of pain relief were comparable to those obtained using the stopwatch method (data not shown).

and

tablished
efficacy,

effects monly opioids.

as an appropriate method of comparing potency, and onset, peak, and duration of of analgesics. A surgical pain model is comused in studies for the evaluation of strong

Safety

Results

All 182 patients who received study drugs were evaluable for safety; of these, 104 (5 7%) reported adverse events (Table IV). The proportion of patients experiencing adverse events was greatest in the groups taking oxycodone plus APAP (63.3%), IR oxycodone (70.9%), and CR oxycodone 30 mg (73.3%). Somnolence was the most commonly reported adverse event. Fever was the next most common adverse event reported, but was considered to be a result of the surgical procedures. Dizziness and, less frequently, headache also were reported. All adverse events disappeared or resolved with symptomatic treatment and none of the events was severe. Vital signs, including body temperature, blood pressure, heart rate, and respiration were evaluated before treatment and before discharge; although some changes were statisticallysignificant, none was clinically significant. DISCUSSION As documented documents,31 in scientific reviews30 and regulatory single-dose studies have been well es-

This single-dose, randomized, double-blind, parallel-group investigation compared the effectiveness and safety of a CR oral tablet of oxycodone with an IR tablet of oxycodone (considered to be a regulatory standard), an IR oxycodone-acetaminophen tablet (selected as an appropriate clinical reference standard), and placebo in patients experiencing moderate to severe pain after abdominal or gynecologic surgery. The pain model used in the present study demonstrated good assay sensitivity, with separation of the known active agents, IR oxycodone and oxycodone plus APAP, from placebo. In addition, for the major parameters measured, the three dosages of CR oxycodone also were separated from one another. Our results demonstrated that all active treatments were significantly superior to placebo for many of the hourly pain relief measures and for SPID and TOTPAR. For patients given 10, 20, or 30 mg of CR oxycodone, onset of pain relief occurred within approximately 1 hour of administration, and the peak effect was noted between 2 and 4 hours after administration. The shortest times to onset were seen with the two JR oxycodone treatments, with a 5-minute difference in onset between CR oxycodone 30 mg and IR oxycodone. In this single-dose study,

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the duration of analgesia for the CR oxycodone preparations was approximately 10 to 12 hours. For painrelief scores and PID, a dose response was seen among the three dose levels of CR oxycodone, validating this comparative analgesic model. In this study, CR oxycodone was shown to be an effective oral analgesic with longer duration of pain relief than either IR oxycodone or oxycodone plus APAP. Among the treatments studied, the comparisons between CR oxycodone 30 mg and IR oxycodone 15 mg were considered most clinically relevant because in settings requiring repeated administration of analgesics, these doses of CR oxycodone every 12 hours and IR oxycodone every 6 hours result in equivalent total daily oxycodone dosages. The faster onset (by 5 minutes) of pain relief seen with IR oxycodone was not considered clinically meaningful for settings in which repeated analgesic administration is anticipated. Adverse events occurred in all of the treatment groups. However, all effects disappeared or resolved either spontaneously or with symptomatic treatment as necessary. Overall, somnolence was the most prevalent adverse effect, occurring in 23% to 35% of the patients treated with oxycodone. Somnolence may be a result of the medication, a response to pain relief, or both. Fever was almost certainly a result of the surgical procedures and not the active treatments. From these results, we conclude that CR oral oxycodone tablets at appropriate doses produce comparable analgesia and safety with a longer duration of action than IR oxycodone tablets or oxycodone-acetaminophen tablets. The development of an oral CR preparation of oxycodone represents an advancement over the IR preparations by providing prolonged analgesia. Controlled-release oxycodone also offers clinicians an analgesic alternative to controlled-release morphine for treating patients with postoperative pain. This preparation can be expected to improve patient compliance, allow greater convenience, and provide uninterrupted nighttime sleep for patients in pain. REFERENCES
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