pharmacodynamic study of controlled-release oxycodone

pharmacodynamic study of controlled-release oxycodone

Vol. 13 No. 2 February 1997 Journal oJPain and SymptomManagement 75 h“ginal Article A Pharmacokinetic/Pharmacodynamic Study of Controlled-Release ...

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Vol. 13 No. 2 February 1997

Journal oJPain and SymptomManagement

75

h“ginal Article

A Pharmacokinetic/Pharmacodynamic Study of Controlled-Release Oxycodone David P. Benziger, PhD, Jahanara Miotto, BS, Robert P. Grandy, MS, Gordon B. Thomas, BS, Ruth E. Swanton, MPH, and Ronald D. Fitzmartin, PhD D+artment of Pharmacokinetics and Drug Metabolism(D.I?B., J.M.), PurduePharmaL.l?, Yonkers,New York,and MedicalDepartment(R.PG., G.B.T, R.E.S., R.D.E), ThePurdue Fredm”ckCompany, Norwalk, Connecticut, USA

Abstract A single-dose,analyticallyblinded, randomized,crossoverstudy was conductedin 22 healthymale voluntems to compare the bioauailabilityof one 20 mg with two 10 mg controlkd-rehase (CR) oxycodonetablets.In addition,pharmacodynamiceffects were assessedusing both ob]ectiueand subjective measuresfor up to 48 h~ after dosing. The two treatmentswere bioequivalent,with comparablerates (C~aXof one 20 mg tablet was 109% of two 10 mg tablets; 90 YOconjiderwelimits: 98.4 ~0-12070) and extents (A UCo_: 1077o; 100%-114%) of absorption.In addition, no significant dzffmencesbetween Correlationsbetween tabletswerefound for mean values of T~aX,Tf12abs, or Tktiim. plasma oxycodoneconcentrationsand mostpharmacodynamicmeasureswere significant. The strongest correlationswere observedfor pupil size (r = – 0.53) and subjects’ assessment of drug effect (r = 0.53), with changes in plasma concentrationaccountingfor more than 25% of the observed changes in these variables. This study demonstratedbioequivalenceof two 10 mg and one 20 mg CR oxycodonetablet, with signi$cant correlation between plasma oxycodoneconcentrationsand Pharmacodynamiceffects in normal volunteers. J Pain Symptom Manage 1997; 13:75-82. 0 US. CancerPain Relief Committee,1997. Key Wh Oxycodone, OxyContin’”, Pharmacokinetic,pharmacodynamic,bioequivalence,opioids

Introdu&”on Oxycodone

is a strong,

semisynthetic,

that provides effective relief for moderate-to-severe pain in cancer1>2 and postoperative patients.’ The pharmacokinetic

p-opioid

agonist

Address reprint requests to: David P. Benziger, PhD, Department of Pharmacokinetics and Drug Metabolism, Purdue Pharma L.P., 99 Saw Mill River Road, Yonkers, NY 10701, USA. Acc@edfbr publication:June 27, 1996. 0 U.S. Cancer Pain Relief Committee, 1997 Published by Elsevier,New York,New York

profile of oxycodone is similar to that of morphine,4 with a parenteral potency approximately 0.75 that of parenteral morphine.5 In contrast, the relative potency of oral oxycodone is approximately twice that of oral morphine, which is consistent with the higher oral bioavailability (60% -87%)6>7 of oxycodone compared to morphine (20 Y0-25Yo).8’9 During the first 24 hours following oral administration of oxycodone, only 8Y0-14Y0 of the dose is excreted as free oxycodone, with a 0885-3924/97/$17.00 PII S0885-3924(96)0030fL4

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Benzigeret al.

much higher proportion of oxycodone undergoing N-dealkylation and appearing in plasma as noroxycodone, a relatively inactive metabolite.6 Oxymorphone, an active metabolize of oxycodone, also appears in plasma following oral administration but only at very low concentrations, and pharmacodynamic effects observed after oxycodone administration appear to be more directly related to oxycodone plasma concentration than to oxymorphone concentration.10 In the present study, we have compared the pharmacokinetics of one controlled-release (CR) oxycodone 20 mg tablet with two CR oxycodone 10 mg tablets in healthy adult volunteers. In addition, we have estimated the correlations of plasma oxycodone concentrations with objective and subjective measures of drug effect, as rated by both subjects and observers.

Methods SubjectSelection Twenty-four healthy male volunteers were enrolled into the study. To quali~ for entry, subjects had to provide written, informed consent. Only subjects free from significant abnormal findings, based upon prestudy physical exam, laboratory testing, and medical history, were chosen. Subjects with known medical conditions that might interfere with the interpretation of data and those with a history of hypersensitivity to opioids or a history of drug abuse were precluded from entering the study. Subjects who used opioids during the 3 months prior to entry or any medication within 7 days preceding or during the study were also excluded.

Study Design This was a single-dose, randomized, analytiphartwo-way, crossover cally blinded, macokinetic/pharmacodynamic study. The study protocol was approved by the Research Consultants’ Review Committee Institutional Review Board. The clinical portion of the study was performed by Pharmaco LSR, 706A Bannister Lane, Austin, TX, and was supported by The Purdue Frederick Company. During the first study period, 12 subjects received one 20 mg CR oxycodone tablet (OxyContinTMTablets, Purdue Pharma L.P, Norwalk,

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CT) and 12 subjects received two 10 mg CR oxycodone tablets. The 10 and 20 mg tablets contained 9.1 and 18.2 mg oxycodone base, respectively.Doses were administered at approximately 8:00 am, after an 8-hr overnight fast. Subjects continued fasting for an additional 4 hours after dosing. A seven day washout period followed the first dose, after which subjects were dosed with the alternate tablet strength based on their original dosing assignments.

Pharmacokinetic Evaluations Blood samples were collected and assayed for plasma oxycodone concentration. These samples were obtained just prior to ingestion of the study medication (O hr) and at 0.25, 0.50, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 18, 24, 30, 36, and 48 hr after dosing. Plasma oxycodone analyses were conducted using a validated gas chromatography/mass spectrome try procedure, as previously described10 but with the following modifications. Deuterated hydromorphone (50 ng) was used as the internal standard. Two microliters of the dissolved residue were injected into a Hewlett Packard gas chromatograph/mass spectrophotometer (GCMS) equipped with a 30 M X 0.32 mm 0.25 mm film DB5-5% column. After an initial hold at 100”C for 1 rein, the temperature was increased to 290”C at 40°C/min. For this procedure, the retention times were approximately 6.8 min (oxycodone) and 7.0 min (deuterated hydromorphone). The mass spectrophotometer was operated in the single-ion monitoring mode with negative chemical ionization using methane as the reagent gas. The peak area ratios of the M+ ions (M/Z) of the acetyl derivatives were used to construct the standard curves: oxycodone (357) /hydromorphone (330). The assay had a limit of quantitation of 0.2 ng/mL and was linear over the range of 0.2-100 ng/mL. The mean values ( * %RSD) for the low (0.2 ng/mL) and high (100 ng/mL) oxycodone quality control standards were 0.21 ng/mL (* 11.6Yo) and 97.7 ng/mL (+5.8 ’70), respectively. Among the parameters that were evaluated for oxycodone were the AUCO-A8(area under curve; hrmg/mL), which was estimated by the trapezoidal sum from zero to the last measurable oxycodone concentration, and the AUCo-m (AUC extrapolated to infinite time;

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PK/PD Stud-yof CR Oxycodone

hrmg/mL), which was determined by dividing the last measurable concentration by the elimination rate constant (~) and adding it to AUCO-48. The C~.X (maximum plasma concentration; ng/mL) was the highest observed plasma concentration, and the T~,X (time to maximum plasma concentration; hours) was the time from dosing to C~m. In order to derive the T~2abs (apparent half-life of absorption; hours) and the T~2elim (apparent half-life of elimination; hours), & (apparent plasma absorption rate constant) and K. (apparent plasma elimination rate constant) were estimated by nonlinear least squared regression analysis.

Pharmacod-ynamic Evaluations Pharmacodynamic assessments were conducted immediately before blood sampling at baseline and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, and 48 hr post-dose. Subjects used 100-mm visual analogue scales (VAS) to rate mood (VAS; O mm = worst, 100 mm = best) and sedation (O mm = asleep, 100 mm = awake) within 10 min before each blood sample was taken. A ten-item drug-effect questionnaire modified from Preston et al.,ll and described earlier,10 was also completed by each subject and observer immediately before each blood sample was taken. Subjects and observers responded to each item using a 100-mm VAS. In order to characterize the pharmacokinetic/pharmacodynamic relationship appropriately, VAS scores assessing sedation, energy, nervousness, and need to talk were inverted before analysis. Within 5 min before each blood sample was taken, the observer also determined respiratory rate and photographed the left eye of each subject for pupil size determination. Pupil diameters were measured from photographs taken with a Polaroid CWP-5 camera equipped with a 75-mm lens and built-in ring flash, as described by Czarnecki et al.*2

SafetyEvaluations Vital signs, including body temperature, blood pressure, heart rate, and respirations, were evaluated during pre-study screening, at baseline (O hr) and at 12, 24, 36, and 48 hr after dosing. Adverse events that occurred during the evaluation period were recorded for each subject based on reports by the subject and observations by study personnel.

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StatisticalAnalysis Analysis of variance (ANOVA; SAS Institute, Inc., Cary, NC), with effects for each treatment, period, sequence, and subjects within sequence, was used to assess differences between treatments for each pharmacokinetic parameter. For AUCO-48, AUCo-~, and c~,x, ANOVA was performed using log-transformed data. Ninety percent confidence intervals (80%-125%, log transformed; 80%-120%, arithmetic) around the ratios of the formulations were calculated using the error mean square from the ANOVA analysis. For each pharmacodynamic variable, by subject and treatment, a linear regression of the form Y = a + ~“X, where Y denotes one of the pharmacodynamic variables and X denotes the observed oxycodone plasma concentration, was fitted by least squares to the observed data points. ANOVA of the subject slopes (~) was performed for each pharmacodynamic variable to assess significant (P ~ 0.05) differences between treatments. In addition, a weighted Pearson product correlation analysis of the pharmacodynamic variables and plasma oxycodone concentrations, based on the regression sum of squares (described above), was performed.

Results Study Conduct Twenty-four subjects (mean age, 28 ~ 8 years; mean weight, 75 * 9 kg) were enrolled, randomized to treatment, and received at least one dose of study drug. All of these subjects were included in the safety analysis. Two subjects included in the safety analysis were excluded from the pharmaco kinetic/ pharmacodynamic analysis: one withdrew from the study for personal reasons after receiving a single 20 mg CR oxycodone tablet; a second completed both phases of the study, but technical difficulties prevented measurement of plasma oxycodone concentrations.

Pharmacokinetics Both the rate and extent of oxycodone absorption were comparable for one 20 mg and two 10 mg CR oxycodone tablets (Figure 1). Based upon the ratio of the geometric mean values, the C~,X of one 20 mg CR oxyc-

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Bsmz@r et al.

= E g

16 –

% :

,0

2 &? L :4 z

14–

6-

~–

0 046

12

16

20

24

28

32

36

40

44

48

Time from Dose (hr)

Fig. 1. Single-dose bioequivalence of one 20 mg controlled-release (CR) oxycodone tablet (~) and two 10 mg oxycodone tablets (0). Mean plasma oxycodone concentration plotted against time from administration.

odone tablet was 109Yo of the two 10 mg CR oxycodone tablets, with a 90Y0 confidence interval ranging from 98.4’%0to 12070 (Table 1). T~a values for one 20 mg and two 10 mg CR oxycodone tablets were also comparable. Thus, the two treatments were bioequivalent with respect to rate of absorption. Similarly, the ratio and 90% confidence limits based upon geometric mean values for AUCO-. (107%; 100%-114%) indicated that the two treatments were bioequivalent with respect to extent of absorption. In addition, no statistically significant differences were found between one 20 mg CR oxycodone tablet and two 10 mg CR oxycodone tablets for the mean T~,X, the mean TAz.bs, or the mean ‘hzelim.

Pharmacodynamics Because no differences between the pharmacodynamic response to one 20 mg CR oxycodone tablet and two 10 mg CR oxycodone tablets were detected, data from both treatments were combined for the estimation of pharmacokinetic/pharmacodynamic correlations. Based on the combined analysis, significant (F’ ~ 0.05) linear relationships were detected between oxycodone concentration and pupil diameter, respiratory rate, and sedation, but not mood (Table 2). Of these four pharmacodynamic parameters, changes in pupil diameter were most strongly correlated with plasma oxycodone concentration (Table 2), with changes in plasma concentration accounting for more than 25 YO of the observed changes in pupil size.

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Analysis of responses to the ten-item drugeffect questionnaire indicated that eight of the ten items rated by subjects and nine of the ten items rated by observers were significantly correlated with plasma oxycodone concentration (Table 2). For both subject- and observer-rated items, the variable, drug effect, showed the highest correlation with plasma concentration, with greater than 2570 of the change in drug effect attributed to changes in plasma oxycodone concentration. The pharmacodynamic effect vs time curves generally paralleled the oxycodone concentration vs time curves as shown for changes in pupil size (Figure 2) and subjects’ assessment of drug effect (Figure 3). Measurable changes from baseline values for both of these parameters were observed during the first scheduled pharmacodynamic assessment at 0.5 hr after dosing, and measurable changes from baseline were sustained through the CR dosing interval (12 hr). Minimal, if any, hysteresis (the time lag in the occurrence of drug effect relative to plasma concentration) was observed for most of the pharmacodynamic variables. Maximal peak effect for pupil size and drug effect occurred at about 3.7 hours, only slightly after the observed C~a (2.4-3.2 hr) for oxycodone. The magnitude of the observed changes in pharmacodynamic measures differed considerably among the pharmacodynamic effects that were assessed. All parameters returned to baseline values between 12 and 24 hr after dosing; therefore, analysis of pharmacodynamic response did not include values from the 24, 3&, and 48-hr assessments.

Safety Of the 24 subjects who received study medication, 8 subjects reported a total of 13 drugrelated adverse events after receiving one 20 mg CR oxycodone tablet, and 7 subjects reported a total of 13 drug-related adverse events after receiving two 10 mg CR oxycodone tablets (Table 3). Most adverse events were rated as mild; a few were moderate. None required treatment, and all subjects recovered without further incident.

h“scussim Most of the individual pharmacodynamic effects assessed in this study were significantly

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PK/PD Studv of CR Oxvcodone

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Table1

Bioequivalenceof Controlled-Release(CR) Oxycodone with 90% Confidence Intervals Pharmacokinetic parameter c (ng/mL) A~?,,-48 (hr-ng/mL) AUCO-. (hr-ng/mL) T~= (hr) Tl,2a~, (hr) T ,/~elim (hr)

One 20 mg CR oxycodone tablet”

Two 10 mg CR oxycodone tablets”

Ratiob (90% CI)

20.1 194 194 3.2fl.9 1.2k0.9 6.521.7

18.5 182 182 2.431.1 o.9fo.5 6.7~2.O

109 (98.4-120) 107 (100-114) 107 (100-114) 133 (98-168) 131 (90.6-172) 96.4(80.1-113)

C, concentration;T, time; AUC,areaunderthecurve, “ Geometricmeansfor C~.X,AUCWAS, andAUC(~.-;arithmeticmeans~ standardde~ationfor T,_, T,,2,~,, and T1,2e,i,,,; eachmean is basedon 22 subjects. bOne 20 mg CR oxycodone tablet/two 10 mg CR oxycodone tablets (%).

correlated with oxycodone plasma concentrations. Although previous studies have not demonstrated clear pharmacokine tic/ pharmacodynamic cor~elations for other strong opioid analgesics, the results reported here are supported by an earlier study of oxycodone in normal volunteers]o and by findings of a recent study in children who received intravenous oxycodone after ophthalmic surgery. 13In the latter study, a pharmacokinetic\ pharmacodynamic model was used to predict end-tidal C02 concentrations following IV administration of oxycodone. Comparison of the predicted values to measured end-tidal C02 values yielded correlation coefficients in the range of 0.838-0.979.13 The significant correlations observed between plasma oxycodone concentrations and selected pharmacodyrtamic effects may reflect a more straightforward concentrationeffect relationship for oxycodone than for other opioid analgesics. In the case of morphine, for example, pharmacokinetic/ pharmacodynamic assessments are complicated by the high plasma concentrations of me tabolite, morphine-6the active glucuronide, that occur following morphine administration.14 There is even evidence that the excessive clinical effects observed after administration of morphine to patients with kidney failure may be related to accumulation of morphine-6-glucuronide and not to the accumulation of morphine itself.15In contrast, we are not aware of any reports in which oxycodone metabolizes have been shown to contribute significantly to pharmacodynamic effects following dosing with oxycodone. The strongest correlations with oxycodone plasma concentrations occurred with changes

in pupil diameter and with the subject’s rating of overall drug effect. The time course o-f changes in the~e variables was in accord with changes in plasma oxycodone concentrations, with minimal hysteresis between peak plasma oxycodone concentration and peak pharmacodynamic effect. These results suggest that there was little or no delay in pharmacologic effect after oxycodone had reached the systemic circulation. Taken together, the onset, Table2 Correlationof PharmacodynamicEffect with Plasma Concentrationsof Oxycodone Pharmacodynamic variable Mood Sedation Respiration Pu~il size Subject’s questionnaire Drug effect Itchy Relaxed Sleepy Drunk Nervous Energetic Need to talk Sick to stomach Dizzy Observer’s questionnaire Drug effect Scratching Relaxed Drunk Nervous Talking Vomiting Confused Restless Perspiring

Correlation coefficient (r) Oxycodone” –0.06 0.26” –0.10” —-0.53” 0.53” 0.19” 0.16” 0.30” 0.25” 0.04 0.26” 0.03 0.12* 0.26” 0.32” 0.18” 0.04 0.20* 0.25” 0.23” 0.11” 0.23” 0.22” 0.25”

‘Correlation is significant (P< 0.05). “Mean visual analogue scale score, except for pupil diameter and respiratory cycles per min (0-12 hr), from subjects given one 20 mg or two 10 mg controlled-release oxycodone tablets; 12 subjects per group.

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‘“~’”

o~50

9 10 11

12

Time (hr)

Fig. 2. Subjects’ pupil size inverse scale (*) and mean plasma oxycodone concentration (u) plotted against time. Mean values after administration of 20 mg controlled-release (CR) oxycodone given as either one 20 mg or two 10 mg CR oxycodone tablets.

peak, and duration of pharmacodynamic responses, following a single dose of CR oxycodone, correlated well with the initial rapid rise, peak, and gradual decline in plasma oxycodone concentrations. Individual pharmacodynamic responses to opioid analgesics vary widely, with some subjects experiencing significant effects, such as nausea, while others do not. Given thisvariabilityin individual responses to opioids, it is not surprising that ratings of overall drug effect were most strongly correlated with plasma oxycodone concentration. The overall drug effect provides a composite rating of all effects experienced by each individual, including those specific effects that were rated on the drug effect questionnaire (for example, nausea, vomiting, etc.), as well as any additional effects that were experienced but not rated individually.Thus, this single collective measure permits the comparison of the entire constellation of drug effects between individuals even though the specific pharmacodynamic effects contributing to individual ratings may differ from subject to subject or from one asses% ment to another for the same subject. The time-action curve for pharmacodynamic responses observed in this study was comparable to the time course of analgesic response (onset, peak, and duration of analgesia) reported for 120 women who received immediate-release (IR) oxycodone, CR oxycodone, or an oxycodone/acetaminophen combination during a double-blind, placeb~ontrolled study of pain after abdominal surgery.16Most patients in the study experienced analgesic onset within 1 hour

0

0

012345678

9

10

11

12

Time (hr)

Fig. 3. Subjects’ drug effect, visual analogue scale (VAS) score (*) and mean plasma oxycodone concentration (u) plotted against time. Mean values after administration of 20 mg controlled-release (CR) oxycodone given as either one 20 mg or two 10 mg CR oxycodone tablets.

of dosing with one of the active treatments. In this single-dose postoperative setting, the median duration of pain relief for patients receiving 20 mg CR oxycodone was significantly longer than for patients receiving IR oxycodone or the oxycodone/acetaminophen combination. The apparent correspondence between the time-action curves for pharmacodynamic responses in normal volunteers and analgesic response in postoperative patients suggest that it may be possible to use selected pharmacokinetic/pharmacodynamic variables to obtain a preliminary evaluation of the analgesic activity of new opioid analgesics during Phase I clinical trials in normal volunteers. The results of this study establish the bioequivalence of one 20 mg CR oxycodone tablet with two 10 mg CR oxycodone tablets and indicate that the two tablet strengths are dose proportional. Based upon a comparison of AUC values, the oral bioavailability of oxycodone in the CR tablets was found to be similar to that reported previously for IR oxycodone solution,l 7 whereas the C~aX was approximately 50~0 less and the T~u was considerably greater than immediate-release oxycodone administered in comparable doses.18 The lower C~,X and longer T~,X values observed are consistent with a prolonged release of oxycodone from tablets formulated using the Acrocontin TM delivery system (The Purdue Frederick Company, Norwalk, CT). Controlled-release oxycodone tablets were formulated in the AcrocontinTM system to pro-

PK/PD Study of CR Oxycodone

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Table3 Subject Incidence and Number of Reports of Adverse Events 20 mg CR oxycodone tablet (N= 24) Adverse event Headache Nausea Urinary retention Abdominal pain Dizziness Nervousness Paresthesia Ear discharge Hypotension Vomiting Total

Subjectsa : 3 ; o : 1 k

(%)’ (4) (8) (13) (4) (8) (o) (4) (o) (4) (4) (33)

Reports’ : 3 : o 1 o : 13

Two 10 mg CR oxycodone tablets (N= 24) Subjectsa

(%)’

ReportsC

3 2 2 1 1 1 0 1 o 2 7

(13) (8) (8) (4) (4) (4) (o) (4) (o) (o) (29)

3 2 2 1 1 1 o 1 o 2 13

“ Number of subjects reporting one or more adverse events. “ Percent of subjects reporting adverse events out of total subjects in group ‘ Number of reported adverse events.

vide prolonged analgesia without markedly lengthening the time to onset of analgesic activity. A pharmacokinetic model based upon previous single-dose and steady-state dosing in normal volunteers revealed two different absorption constants for the CR oxycodone formulation.lg The dual absorption proposed by the model predicts the pharmacokinetic profiles observed for the 10 and 20 mg tablets under study, both of which provided a rapid initial rise in oxycodone concentration followed by gradual decline over the 12-hr dosing interval. Although the benefits of controlled-release dosage forms that permit less frequent dosing are well established, it has been suggested that the maintenance of nearly constant plasma concentrations of opioids may lead to tolerance development. ZO,Z1The CR oxycodone tablets under study were developed to reduce the number of C~in/C~aX fluctuations during the 12-hr dosing interval while matching the degree of fluctuation (C~i~/C~m) in plasma oxycodone concentrations observed during steady-state dosing with comparable doses of IR oxycodone. Z2 By retaining the degree ‘f fluctuation in plasma concentrations, the possibility of diminished pharmacodynamic effects over time may be minimized as compared to CR formulations that maintain comparatively constant blood levels.

Acknowledgment This study was supported by a grant from The Purdue Frederick Company, Norwalk, Connecticut.

Rejbnmces 1. Glare PA, Walsh TD. Dose-ranging study of oxycodone for chronic pain in advanced cancer. J Clin Oncol 1993; 11:973-978. 2. Kalso E, Vainio A. Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther 1990; 47:639-646. 3. Kalso E, Poyhia R, Onnela P, Linko K, Tigerstedt I, Tammisto T. Intravenous morphine and oxycodone for pain after abdominal surgery. Acta Anaesthesiol Scand 1991 ;35:642–646. 4. Poyhia R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 1993; 8:63-67. 5. Beaver WT, Wallenstein SL, Rogers A, Houde RW. Analgesic studies of codeine and oxycodone in patients with cancer. II. Comparisons of intramuscular oxycodone with intramuscular morphine and codeine. J Pharmacol Exp Ther 1978; 207:101–108. 6. Poyhia R, Seppala T, Olkkola KT, Kalso E. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. BrJ Clin Pharmacol 1992;33:617621. 7. Leow KP, Smith MT, Williams B, Cramond T. Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clin Pharmacol Ther 1992; 52:487–495. 8. Hoskin PJ, Hanks GW, Aherne GW, Chapman D, Littleton P, Filshie J. The bioavailability and pharmacokinetics of morphine after intravenous, oral, and buccal administration in healthy volunteers. BrJ Clin Pharmacol 1989; 27:499-505. 9. Osborne R, Joel S, Trew D, Slevin ML. Morphine and metabolize behavior after different routes of administration; demonstration of the importance of the active metabolize morphine-6glucuronide. Clin Pharmacol Ther 1990; 47:12-19. 10. Kaiko RF, Benziger DP, Fitzmartin RD, Burke BE, Reder RF, Goldenheim PD. Pharmacokinetic/

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11. Preston KL,Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 1991;27:7-17. 12. Czarnecki JS, Pilley SF, Thompson HS. The analysis of anisocoria. The use of photography in the clinical evaluation of unequal pupils. Can J Opthalmol 1979; 14:297-302. 13. Olkkola KT, Hamunen K, Seppala T, Maunuksela E-L. Pharmacokinetics and ventilator effects of intravenous oxycodone in postoperative children. BrJ Clin Pharmacol 1994; 38:71-76. 14. Portenoy ~ Foley KM, Stulman], et al. Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure. Pain 1991; 17:13-19. 15. Osborne R, Joel S, Grebnik K, Trew D, Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin PharmaCO1Ther 1993; 54:158–167. 16. Sunshine A, Olson NZ, Colon A, et al. Analgesic efficacy of controlled-release oxycodone in postoperative pain. J Clin Pharmacol 1996; 36:595–603. 17. Reder R, Kaiko R, Grandy R, Fitzmartin R, Bashaw D. Steady-state bioavailability comparison of controlled release oxycodone (OxyContinTM) tab-

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lets vs. oxycodone oral liquid. Poster number 94604, presented at the Thirteenth Annual Scientific Meeting of the American Pain Society in Miami Beach, FL; November 10-13, 1994. 18. Benziger DP, Thomas G, Miotto J, Grandy R, Kaiko R, Reder R. Bioavailability and pharmacokinetics of controlled release oxycodon-e (OxyContinTM)tablets vs oxycodone oral liquid. Poster number 94732, presented at the 13th Annual Scientific Meeting of the American Pain Society in Miami Beach, FL; November 10-13, 1994. 19. Mandema JW, Kaiko RF, Oshlack B, Reder RF, Stanski DR. Characterization and validation of a pharmacokinetic model for controlled-release oxycodone. Br J Clin Pharmacol 1996; 42:747-756. LK. Pharmacokinetic/pharmaco20. Paalzow dynamic aspects of controlled-release products. Presented at the FIP-Satellite Symposium on Optimizing Therapy Using Controlled Release Products in Stockholm, Sweden; August 25-26, 1995. 21. Marshall H, Porteous C, McMillan I, McPherson SG, Nimmo WS. Relief of pain by infusion of morphine after operation: does tolerance develop? BMJ 1985; 291:19-21. 22. Reder RF, Oshlack B, Miotto J, Benziger DD, Kaiko RF. Steady-state bioavailability of controlledrelease oxycodone in normal subjects. Clin Ther 1996; 18:95-105.