Comparison of Controlled-Release and Immediate-Release Oxycodone Tablets in Patients With Cancer Pain By Ronald Kaplan, Winston C.-V. Parris, Marc L. Citron, Donna Zhukovsky, Robert F. Reder, Barbara J. Buckley, and Robert F. Kaiko Purpose: This study compared the clinical efficacy of oxycodone hydrochloride controlled-release (CR) tablets administered every 12 hours with immediaterelease (IR)oxycodone tablets administered four times daily in patients with cancer-related pain. Patients and Methods: Cancer patients who required therapy for moderate to severe pain were randomized to CR oxycodone every 12 hours (n = 81) or IR oxycodone four times daily (n = 83) for 5 days in a multicenter, double-blind study. Pain intensity was assessed four times daily (categorical scale of none, slight, moderate, and severe); acceptability of therapy was assessed twice daily (categorical scale of very poor, poor, fair, good, and excellent). Results: Pain intensity remained slight during the study, with mean oxycodone doses of 114 mg/d (range, 20 to 400 mg/d) for CR and 127 mg/d (range, 40 to 640 mg/d) for IR. Acceptability of therapy was fair to good

with both treatments. While standard conversion ratios provided an acceptable dose for many patients, a protocol amendment that allowed initial titration and use of rescue medication reduced the discontinuation rate for lack of acceptable pain control (from 34%to 4%with CR and from 31% to 190/%with IRbefore and after amendment, respectively) without increasing the discontinuation rate for adverse events (from 8% to 7%with CR and from 13% to 11% with IR). Fewer adverse events were reported with CR (109) than with IR (186) oxycodone (P = .006). Conclusion: CR oxycodone every 12 hours was as effective as IRoxycodone four times daily in managing moderate to severe cancer-related pain and was associated with fewer reports of adverse events. J Clin Oncol 16:3230-3237. © 1998 by American Society of ClinicalOncology.

T

morphine, has been in clinical use for more than 75 years.2 Like morphine, oxycodone is a pure opioid agonist suitable for the treatment of moderate to severe pain. Oxycodone is characterized by a rapid onset of action,3 a high oral/ parenteral potency ratio,4 and no analgesic ceiling.1 It is available in single-entity formulations and as a component of fixed-dose combinations with aspirin or acetaminophen. In the United States, oxycodone is most often prescribed in such fixed-dose combinations. Step 2 of the World Health Organization (WHO) analgesic ladder 5 recommends that an opioid analgesic be added when pain is no longer controlled solely with nonopioid analgesics. In this setting, these fixed-dose opioid/nonopioid analgesics play an important role in pain management. 6 However, these drugs are often prescribed on a pro re nata (prn) basis and the total dose of oxycodone that can be given safely in these combinations is limited by the maximum daily dose of the nonopioid component. Using the WHO's recommendation of a maxi5 mum of 6,000 mg/d of acetaminophen for cancer patients, the maximum dose of a fixed combination containing 5 mg of oxycodone and 325 mg of acetaminophen would be 18 tablets per day. This would provide an oxycodone dose of 90 mg/d, which may be inadequate in patients with moderate to severe cancer pain. As a consequence, the potential of using 7 oxycodone to treat more severe pain has not been realized. In addition, oxycodone has a relatively short elimination half-life,8 which has been a disadvantage for its use in the treatment of chronic pain because frequent dosing has been

HE CLINICAL PRACTICE GUIDELINE for Management of Cancer Pain' describes the essential elements for the assessment of cancer pain and provides recommendations for a multidisciplinary approach to cancer pain management. The Guideline includes a comprehensive review of both nonpharmacologic and pharmacologic modalities of pain control and recognizes drug therapy as the cornerstone of cancer pain management. Among the recommendations for the pharmacologic management of cancer pain are the tailoring of pain therapy for each patient and the initiation of treatment with the simplest dosage schedules and least invasive pain management modalities possible. As applied to the management of moderate to severe pain, these recommendations support around-the-clock administration of oral opioid analgesics, including oxycodone. Oxycodone, an opioid agonist with activities similar to

From the Department of Anesthesiology Pain Service, Montefiore Medical Center, Bronx: Institute of Oncology, Long Island Jewish Medical Center New Hyde Park: Don Monti Division of Hematology/ Oncology, North Shore University Hospital, Manhasset, NY: Department of Anesthesiology, Vanderbilt University Hospital, Nashville, TN: and Purdue Pharma LP Norwalk, CT Submitted September 30. 1997; acceptedMay 29, 1998. Supportedby Purdue PharmaLP, Norwalk, CT Address reprint requests to RobertF Reder, MD, Purdue Pharma LP, 100 Connecticut Ave, Norwalk, CT 06850-3590: Email drrobert. [email protected]. © 1998 by American Society of Clinical Oncology. 0732-183X/98/1610-0017$3.00/0

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CONTROLLED- VERSUS IMMEDIATE-RELEASE OXYCODONE required. Until recently, the only opioid available in a controlled-release (CR) formulation for oral administration was morphine. Oxycodone is now available in an oral CR tablet that provides every-12-hour dosing for around-theclock treatment of moderate to severe pain. The bioavailability of CR oxycodone is comparable with an oral solution of oxycodone with respect to extent of absorption when the same amount of oxycodone is administered. 9 CR oxycodone can be given alone or with nonopioid analgesics, and offers the flexibility of titrating the opioid and nonopioid separately to achieve optimal balance between pain control and side effects. The CR formulation was developed to combine the prompt onset of action characteristic of oral immediaterelease (IR) oxycodone preparations with a prolonged duration of effect. It is characterized by a biphasic absorption pattern: an initial rapid absorption phase followed by a slow absorption phase. 10 A study in postoperative pain demonstrated that these characteristics provide for an extended duration of analgesia without adversely affecting the onset of analgesia compared with IR formulations. 1 This randomized, controlled clinical trial was performed to compare the efficacy, acceptability of therapy, and safety of CR oxycodone tablets with IR oxycodone tablets in patients with cancer-related pain. A limited pharmacokineticpharmacodynamic evaluation was performed in a subset of the patients to examine the relationship between plasma oxycodone concentrations and analgesia. PATIENTS AND METHODS Patients Male and female patients with cancer-related pain were enrolled at 17 centers. The study received institutional review board approval at each center and all patients gave written informed consent. At the time of enrollment, patients were being treated with a strong single-entity opioid or 10 or more tablets per day of a fixed-dose opioid/nonopioid analgesic; were receiving a stable opioid dose; and had stable coexistent disease. Under the original protocol, patients were excluded if they were receiving any other analgesics (opioid or nonopioid) or if they were to receive radiotherapy immediately before enrollment or during the study period. After the study had begun, these exclusion criteria were eliminated by an amendment to facilitate enrollment into the study, which had been slow. Study Design In this double-blind, repeated-dose, parallel-group study, patients were randomly assigned to receive either IR or CR oxycodone over 6 consecutive calendar days. Patients discontinued prestudy opioid analgesics at least 4 hours before they received the first dose of study medication. To maintain the blind, all doses were encapsulated in green, size #00, lactose-filled capsules. The first dose and the first evaluation were at 8 PM on the first day, designated as day 0. The last dose was at 2 PM and the last evaluation at 8 PM on day 5. IR oxycodone tablets (Roxicodone 5 mg; Roxane Laboratories, Columbus, OH; or oxycodone

hydrochloride [HCl] 5 mg, United States Pharmacopeia [USP]; Purdue Pharma LP, Norwalk, CT) were given four times daily. CR oxycodone tablets (OxyContin Tablets 10 mg; Purdue Pharma LP) were given every 12 hours. Patients randomized to IR oxycodone received their active treatment at 8 PM, bedtime (at least 3 hours after the 8 PM dose, but not after 2 AM), 8 AM, and 2 PM. Patients randomized to CR oxycodone received capsules that contained active medication at 8 PM and 8 AM, and placebo capsules at bedtime and 2 PM. A previous study in normal volunteers showed that the steady-state bioavailability of CR oxycodone given every 12 hours was equal to that of an IR oxycodone solution given every 6 hours at the same total daily dose.9 In the present study, patients were dosed four times daily rather than every 6 hours (ie, at bedtime rather than at 2 AM) to avoid waking the patients and to enhance compliance. Compliance was verified by telephone contacts, pill counts, and reviews of patients' diaries. To assess compliance by inpatients, medication records were also used. The original study design did not allow dose titration or use of supplemental analgesic (rescue medication) for breakthrough or incident pain. Patients whose pain was not effectively controlled at the initial oxycodone dose calculated from previous opioid use were discontinued from the study. However, an interim analysis conducted to determine whether dose adjustments were required showed that dropout rates were too high for relevant conclusions. This suggested that the initial conversion dose estimate was not adequate for a subgroup of patients, and the protocol was amended to include open-label titration with IR oxycodone before the patients were randomized to double-blind treatment, as well as the use of IR oxycodone 5-mg tablets as supplemental analgesic throughout the trial. Supplemental doses could be taken no more frequently than every 4 hours at no more than approximately one sixth the daily dose of study medication. These conditions more closely approximated clinical practice and allowed more patients to complete the trial. Dose Conversions Daily oxycodone doses were calculated from the total daily doses of patients' prestudy opioids by multiplying their prestudy doses by the appropriate conversion factor derived from standard charts based on equianalgesic doses.12.13 The daily oral oxycodone doses were then divided into four equal doses of IR oxycodone for four times daily administration or two equal doses of CR oxycodone for every-12-hours administration, depending on the randomization code. The drugs were packaged and dispensed by a pharmacist not involved in patient contact and evaluation. ClinicalAssessments Patients scored their pain intensity using a categorical verbal scale of none (= 0), slight (= 1), moderate (= 2), or severe (= 3). The patient's assessment is widely accepted as the most reliable indicator of pain intensity, and the four-point categorical scale is one of the standard instruments used.1.14,15 Categorical scales are sensitive to treatments that are known to affect pain intensity'1617 and have shown consistent validity by significant correlation with other measures of pain intensity, such as the visual analog scale (VAS).14,15,18.19

At baseline (study initiation), pain intensity at the time of evaluation was recorded. Four times during each day of the study, at 8 AM, 2 PM, 8 PM, and bedtime, ratings were recorded for pain intensity during the preceding interval-overnight, morning, afternoon, and evening, respectively. Patients rated the acceptability of their therapy at baseline and twice daily (at 8 AM and 8 PM) using a five-point categorical verbal scale: very poor (= 1), poor (= 2), fair (= 3), good (= 4), and excellent (= 5). Adverse events spontaneously reported by the patients or

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KAPLAN ET AL

observed by the investigators were recorded. The severity of the adverse events and their relationship to the study drug (none, possible, probable, or definite) were assessed by each investigator. Pharmacokineticand PharmacodynamicAssessments Twelve patients randomized to CR oxycodone and eight patients randomized to IR oxycodone participated in pharmacokinetic and pharmacodynamic assessments. They underwent phlebotomies and pharmacodynamic assessments for pain intensity and drug effects on day 3, 4, or 5 at 0 hour (just before the 8 AM dose), 1 hour, and 3 to 4 hours after dosing. Pain intensity was scored using the categorical scale and a VAS ranging from 0 mm (no pain) to 100 mm (most extreme pain). To assess possible drug effects, 10 items from the Specific Drug Effect Questionnaire (SDEQ)20 that measure certain specific opioid effects were rated by patients and observers." Patients rated drug effects using a VAS from 0 mm (not at all) to 100 mm (an awful lot) and observers rated drug effects exhibited by the patients using a VAS from 0 mm (not at all) to 100 mm (extremely). StatisticalAnalysis Differences at baseline in pain-intensity scores and in patients' acceptability of therapy were tested using a two-way analysis of variance (ANOVA). Average daily pain intensity, pain intensity by time of day, average daily acceptability, and day and night acceptability were summarized by study day for both treatments. These data were analyzed using repeated measures ANOVA, with center, treatment, and study period (ie, no titration plus rescue v titration plus rescue) as main factors; treatment-by-center and treatment-by-study period as interaction effects; and study day as repeated factor. Overall average 5-day pain intensity and acceptability were analyzed using ANOVA, with center, treatment, and study period as main effects; and with treatmentby-center and treatment-by-study period as interaction effects. In all efficacy analyses, the last observed value was carried forward for patients who discontinued prematurely. For the purpose of these analyses, data from seven centers with fewer than two patients per treatment group were pooled into two pseudocenters to give a total of 12 centers with enrollments that ranged from six to 36 patients each. In comparing the two treatment groups, the ratio of the overall mean pain-intensity score was used to present the relative effectiveness of CR to IR oxycodone. A 95% confidence interval for this ratio was constructed. Fisher's exact test was used to assess differences between treatments in the number of patients who reported at least one adverse event, both overall and by body system, and the number of patients who reported common adverse events (occurring in - 5% of patients). The total number of adverse events was tested for treatment differences using the Kruskal-Wallis test. All tests were performed using two-sided tests with alpha = 0.05. Interactions were tested at alpha = 0.10. RESULTS PatientEnrollment A total of 180 patients were enrolled onto the study, 108 before the protocol amendment that allowed dose titration before randomization and 72 after the amendment. The first 108 patients were randomized to double-blind treatment directly from their prestudy opioid. The remaining 72 patients entered an open-label, dose-titration phase before randomization; 23 were randomized to double-blind treatment at the initial conversion dose, 33 were randomized

after dose titration, and 16 discontinued before randomization for the following reasons: lack of acceptable pain control, six patients; intercurrent illness, four patients; adverse event, two patients; death, one patient (from rapid progression of preexisting large-cell lymphoma); withdrawal of consent, one patient; and other reasons, two patients. In all, 164 patients were randomized to double-blind treatment, 81 to CR oxycodone and 83 to IR oxycodone. One hundred fifty-six patients were included in the analysis of efficacy. Four were excluded because they did not receive study medication: two could not swallow it, one did not begin the double-blind period because he was apprehensive about writing in his diary, and one was not given rescue medication (protocol violation). Among the other four excluded, three did not complete any efficacy ratings and one may have received unblinded treatment. All 160 patients who received at least one dose of study medication were included in the safety analysis upon which the incidence of adverse events is based. The majority of patients were white (74%) and male (58%). The mean age was 59 years (SE, 1.0 year). At the time of enrollment, patients were receiving a variety of single-entity opioids, high doses of fixed-dose opioid/ nonopioid analgesics, and mixed-opioid products, with most patients receiving oral morphine. The primary cancer diagnoses included gastrointestinal (22%), lung (21%), prostate (17%), breast (10%), and gynecologic (10%) cancer. The predominant pain sites were bone and viscera, with an additional 15 patients (nine in the CR oxycodone group and six in the IR oxycodone group) reporting neuropathic pain. There were no significant differences in the primary pain site, prestudy opioid, or cancer diagnosis between the two treatment groups. Doses Administered The overall daily dose of oxycodone administered during double-blind treatment did not differ significantly between treatments; mean doses were 114 mg (range, 20 to 400 mg) in the CR and 127 mg (range, 40 to 640 mg) in the IR oxycodone group. For patients who enrolled after the amendment that allowed titration and supplemental analgesic, the mean total daily oxycodone doses were 123 mg (range, 20 to 360 mg) in the CR and 137 mg (range, 40 to 600 mg) in the IR oxycodone group. Compliance with dosing of double-blind study drug was estimated using dosing records. Ninety-three percent of the patients took all doses and 96% of the patients took Ž 90% of the doses of study medication. Among patients enrolled after the amendment that allowed titration and rescue, 18 of 29 who received CR

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3233

CONTROLLED- VERSUS IMMEDIATE-RELEASE OXYCODONE oxycodone needed at least one supplemental (rescue) dose during double-blind treatment, compared with 19 of 27 patients who received IR oxycodone. The mean number of supplemental doses per day was 0.6 for CR and 1.0 for IR oxycodone (not significantly different). During the day (8 AM to 8 PM), the median time to first rescue use was 4 hours in the CR group and 3 hours in the IR group. During the night (8 PM to 8 AM), the median time to first rescue use was 7 hours in the CR group and 4 hours in the IR group. For the 18 of 29 patients who required at least one supplemental dose during double-blind treatment with CR oxycodone, only 25% of the first rescue doses were taken in the last 3 to 4 hours of either 12-hour dosing interval.

Severe (3)-

-- Se CR Oxycodone

Sm a CL

IR Oxycodone

Moderate(2)

0

I

LL (0) None

Evening

Night

Morning Afternoon

Mean

Fig 2. Five-day mean pain intensity by time of day in cancer pain patients (n = 156) treated with CR or IRoxycodone. Error bars represent the SE.

PainIntensity Pain-intensity scores at baseline were slight on the categorical scale and not significantly different between treatment groups (Fig 1). The mean baseline pain-intensity score was 1.3 ± 0.1 (± SE) for patients treated with CR oxycodone and 1.4 ± 0.1 for patients treated with IR oxycodone. For each study day, mean daily pain-intensity ratings were comparable for CR and IR oxycodone. Painintensity scores remained near slight, with no significant differences between treatments for the morning, afternoon, evening, or overnight ratings (Fig 2). The center effect was significant for average daily pain intensity (P = .0147) and evening pain intensity (P = .026). Other factors and interaction effects were not statistically significant. The overall average 5-day pain intensity (average of daily assessments for all 5 days) was slight in both treatment groups, with mean scores of 1.3 ± 0.1 for both CR and IR oxycodone (not significantly different). The relative effectiveness of CR oxycodone to IR oxycodone, determined from the ratio of the overall mean pain-intensity scores, was 98% (95% confidence interval, 78% to 119%). These results Severe (3)-

IR Oxycodone

"Moderate (2) iM E-

-

-'-

Slight (1)-

None (0) Baseline

1

2 Day

, 3

Acceptability of Therapy The mean scores for patients' acceptability of therapy at baseline and during each of the 5 following days were

CR Oxycodone --

confirm that CR oxycodone is equieffective to IR oxycodone with regard to pain control. The conclusions were similar when pain-intensity differences were examined: the overall difference from baseline was similar in the two treatment groups. No significant differences in pain-intensity scores were detected when patients were compared by their prestudy opioid (fixed-dose opioid/nonopioid v single-entity opioid). In contrast, the 15 patients with neuropathic pain had higher mean baseline pain intensity (1.7 ± 0.3) compared with the 141 patients with other primary pain sites (1.3 ± 0.1). During the study, the mean pain-intensity scores for patients with neuropathic pain were slightly higher than those for patients with other primary pain sites, but overall pain intensity decreased by a mean of 0.1 unit compared with baseline in neuropathic pain patients. The overall average pain intensity was 1.6 ± 0.2 for neuropathic pain patients and 1.3 ± 0.1 for nonneuropathic pain patients.

4

5

comparable for patients randomized to CR and IR oxycodone, as were the 5-day mean daytime and overnight scores. The overall acceptability of therapy was between fair and good at baseline (3.5 ± 0.1) and the end of the study (3.2 + 0.1) for both groups, with no significant difference between treatments. No significant factor or interaction effects were found. Patients with neuropathic pain reported lower baseline and overall acceptability of therapy scores compared with patients with nonneuropathic pain. At baseline, acceptability of therapy was 3.3 ± 0.3 in patients with neuropathic pain and 3.6 ± 0.1 in patients with nonneurowas 2.8 ± 0.3 pathic pain. Overall acceptability of therapy was 2.8 ± 0.3 of therapy

acceptability Fig 1. Mean daily pain-intensity ratings over the 5-day study period inverall for patients with neuropathic pain and 3.2 ± 0.1 for patients cancer pain patients (n = 156) treated with CR or IRoxycodone. Error bars

represent the SE.

with nonneuropathic pain.

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KAPLAN ET AL

Table 1. Premature Discontinuations With and Without Use of Dose Titration and Rescue Medication (n = 160) Titration and Rescue Allowed (n = 55)

Lack of acceptable pain control Adverse event Other reason* All reasons

No Titration or Rescue (n = 105)

CR (n = 28)

IR(n = 27)

CR (n = 50)

IR(n = 55)

No.

%

No.

%

No.

%

No.

%

1 2 3 6

4 7 11 21

5 3 2 10

19 11 7 37

17 4 6 27

34 8 12 54

17 7 5 29

31 13 9 53

*Includes intercurrent illness, protocol violations, withdrawn consent, and other reasons.

Pharmacokineticand PharmacodvnamicAssessments Figure 3 shows that, regardless of treatment, as plasma oxycodone concentrations increased, the associated mean pain-intensity scores (measured by the categorical scale) decreased. The same general trend was observed when pain intensity was measured by VAS. On the SDEQ items, for both treatments and at all time points, patients ranked the item, "relaxed," highest (a mean of - 46 mm out of 100 mm) and "itchy" the lowest (- 8 mm); observers ranked "'relaxed" the highest (- 57 mm) and "confused" the lowest (- 2 mm). For most of the other drug effects, mean VAS scores were less than 30 mm.

Discontinuation Total discontinuation rates were markedly different for patients who entered the trial before the protocol amendment allowing titration and rescue compared with those who enrolled after the amendment, with the largest difference in rate of discontinuation for lack of acceptable pain control (Table 1). The overall discontinuation rate for lack of acceptable pain control was significantly lower after amendment than before amendment (P = .003). For patients enrolled after the amendment, 4% in the CR group and 19% in the IR group discontinued for lack of acceptable pain control. In comparison, for patients enrolled before the amendment, the discontinuation rate for lack of acceptable pain control was 34% in the CR group and 31% in the IR group. The rate of discontinuation for adverse events was not affected by the use of titration and rescue. For patients enrolled after the amendment, 7% in the CR group and 11% in the IR group discontinued for adverse events. Rates were similarly low for patients enrolled before the amendment: 8% in the CR group and 13% in the IR group.

I

c 0

Oxycodone Concentration

Side Effects Of the 160 patients who received at least one dose of study medication, 104 reported a total of 295 adverse events that were considered by the investigators to be possibly, probably, or definitely related to the study drugs. Overall, significantly fewer adverse events were reported for CR oxycodone (109) compared with IR oxycodone (186) (P = .006). Most of the drug-related adverse events were associated with the digestive and nervous systems. There were significantly fewer (P = .02) adverse events associated with the digestive system in the CR oxycodone group than in the IR oxycodone group. Those adverse events reported most frequently (> 5% of patients) are listed in Table 2, and are consistent with those previously reported in cancer patients during opioid therapy. Fewer patients in the CR oxycodone group reported headache compared with the IR oxycodone group (P = .029). Six patients in the CR treatment group and 10 in the IR group discontinued the study because of adverse events during double-blind treatment, with gastrointestinal complaints the most common reason for discontinuation.

Severe (3)

Pain Intensity Co O 0

Moderate (2)

-J

=3

E

"a C-) 0) a,

5" 1n.

o

Slight (1)

0

Fig 3. Time-paired mean oxycodone plasma concentrations and mean pain-intensity scores in subgroup of cancer pain patients (n = 20) treated with CR or IR oxycodane. Hours refer to time after the 8 AM dose. Error bars represent the SE.

None (0)

CR

IR

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3235

CONTROLLED- VERSUS IMMEDIATE-RELEASE OXYCODONE Table 2. Side Effects CR Oxycodone (n = 78)

IROxycodone (n = 82)

Adverse Event

No.

%

No. of Reports

No.

%

No. of Reports

Nausea Somnolence Constipation Vomiting Dizziness Sweating Asthenia Nervousness Dry mouth Pruritus Insomnia Headache Anxiety

14 14 9 8 5 4 3 3 3 2 2 0 0

18 18 12 10 6 5 4 4 4 3 3 0* 0

16 16 9 11 6 5 4 3 3 3 2 0 0

21 17 17 14 11 3 8 5 5 4 4 6 4

26 21 21 17 13 4 10 6 6 5 5 7 5

30 18 17 23 14 3 9 5 5 4 4 7 4

Patients

Patients

NOTE. Reported by - 5% of patients and considered by the investigator to be possibly, probably, or definitely related to study medication. *Fewer patients reported headache with CR oxycodone than with IR oxycodone (P = .029).

DISCUSSION The principles that govern the pharmacologic therapy of cancer pain include the use of oral analgesics when possible, around-the-clock administration, initiation of therapy with acetaminophen or with aspirin or other nonsteroidal antiinflammatory drugs for mild pain, the addition or substitution of opioids for the management of moderate to severe pain, the use of dose titration and supplemental analgesic to meet the individual needs of patients, and the aggressive and prophylactic treatment of expected opioid-related adverse events.' In this double-blind study, oral CR oxycodone tablets administered every 12 hours were shown to have efficacy and patient acceptability equivalent to oral IR oxycodone tablets in patients with cancer-related pain who were previously receiving single-entity opioids or high doses of fixed-dose opioid/nonopioid analgesics. The original study design did not allow dose titration and rescue medication so that discontinuation rates following conversion of patients to either CR or IR oxycodone could be readily compared. During this part of the study, similar but rather high discontinuation rates for all reasons were observed for both treatment groups. This suggested that while conversion charts provide a safe starting point for therapy initiation and an acceptable dose for many patients, dose titration and the availability of supplemental analgesic are necessary for optimal pain management. This was confirmed by the postamendment data. Following the amendment that allowed oxycodone titration before double-blind dosing and the use of rescue medication, as would occur in usual clinical practice, significantly lower overall discontinuation rates were observed in both treatment groups. Discon-

tinuations for lack of acceptable pain control decreased most dramatically in the CR group (to 4%). These results not only demonstrate the clinical value of analgesic titration and use of supplemental analgesic in successful cancer pain management, but also demonstrate the utility of conversion ratios, which are based on equianalgesic ratios determined from single-dose, well-controlled, relative potency studies,12, 1 3 for calculating the initial dose. In the present study, the patients who had been treated with morphine were the major group converted to either CR or IR oxycodone. The recommended conversion ratio for therapy initiation was 1 mg of oral oxycodone for 2 mg of oral morphine. This conservative ratio is appropriate because there may be incomplete cross-tolerance among opioid analgesics. Even without titration and rescue, this conversion ratio provided adequate pain control for approximately 70% of the patients. The conversion factors used for other prestudy opioids also allowed a substantial number of patients to complete without titration or rescue. Still, the patient's response to the initial dose in terms of pain intensity and side effects must be carefully monitored, and the dose needs to be adjusted according to the individual 22 patient's requirements and response. 1 The patients' pain was as effectively controlled by CR and IR oxycodone as by a variety of prestudy single-entity opioids, and CR and IR oxycodone were equally effective in the management of cancer-related pain. At baseline, painintensity scores were slight in both groups, which indicates adequate control of pain by strong opioids or high doses of fixed-dose opioid/nonopioid analgesics. During the study, mean daily pain-intensity scores remained slight with no significant difference between CR and IR oxycodone. Because most patients were taking oral morphine for analgesia at the time of their enrollment, these results support those of an earlier trial,23 which demonstrated that patients can be successfully converted from morphine to oxycodone for the treatment of cancer-related pain. The present study included a small number of patients with neuropathic pain. The mean decrease from baseline observed among these patients indicates that oxycodone is effective in many patients with neuropathic pain, as has also been noted in a placebo24 controlled study of patients with postherpetic neuralgia. Further evidence of the efficacy of oxycodone is the relationship between plasma oxycodone concentrations and analgesia demonstrated in the present study. For both treatments, mean pain intensity decreased as mean plasma oxycodone concentrations increased. This association provides an internal demonstration of assay sensitivity. 25 Clinical evidence of the sensitivity of the study is provided by the decrease in rate of discontinuation for lack of adequate pain

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KAPLAN ET AL

control when dose titration and supplemental analgesic were allowed. The CR formulation was developed to extend the duration of effect of oxycodone without compromising the onset of action and effectiveness seen with IR formulations. The CR formulation is characterized by an initial rapid release of oxycodone followed by a prolonged release. 10 The initial release is fast enough to provide onset of analgesia similar to IR oxycodone," and the prolonged release of the remainder of the dose may reduce the occurrence of adverse events. While the magnitude of the peak-to-trough fluctuation in plasma oxycodone concentrations is similar with the CR and IR formulations, the CR formulation decreases the frequency of increases in plasma oxycodone concentrations from two in a 12-hour period with IR oxycodone to one with CR oxycodone.9 The decrease in frequency of increases may also reduce the occurrence of adverse events. However, it may be important to maintain the magnitude of the fluctuations in concentration in part because unvarying plasma opioid concentrations may be associated with the development of tolerance. 26 ,27 An unacceptably delayed onset of analgesia would also result without an appropriately high or prompt rise in plasma oxycodone concentrations. Potential differences in patients' acceptability of therapy based on the recommended dosing intervals for the CR and IR formulations could not be assessed because placebo doses were included in the CR oxycodone regimen to maintain the treatment blind. In an open-label trial comparing CR and IR morphine tablets, CR dosing regimens of every 8 hours and every 12 hours were judged to be better and more convenient for pain relief than a dosing regimen of every 4 hours.28 Comparison of the oxycodone formulations without placebo dosing for CR oxycodone would likely show a patient preference for the less frequent dosing needed with CR oxycodone tablets. The appropriateness of the 12-hour dosing interval for CR oxycodone was indicated by the timing of supplemental doses in patients who were enrolled after the amendment allowing rescue use. Only 25% of the first rescue uses occurred in the last 3 to 4 hours of the dosing intervals following the active doses at 8 AM and 8 PM. This indicates no increase in rescue medication use at the end of the dosing interval, and, therefore, a 12-hour duration of effect in patients treated with CR oxycodone. The 12-hour dosing interval was also supported by similar data in a 3-month, open-label trial in patients with chronic cancer pain. Each 12-hour dosing interval was divided into three 4-hour intervals and rescue medication use in each interval was examined. Rescue medication use did not increase in the last 4-hour interval, which indicates that analgesia was main29 tained for 12 hours with CR oxycodone. In the present study, the adverse event profiles of CR and

IR oxycodone were similar. Overall, however, significantly fewer adverse events were reported for CR oxycodone compared with IR oxycodone, which may be related to the controlled release of oxycodone. Increasing the oxycodone dose as a result of titration and use of rescue doses did not increase the rate of discontinuation because of adverse events. Differences among patients in their responses to various analgesics are well recognized.' Therefore, it is important to have a selection of nonopioid and opioid analgesics to meet the needs of individual patients. In this context, the CR oxycodone formulation represents a significant advance in the treatment of moderate to severe pain. CR oxycodone tablets provide patients and caregivers the benefits of every 12 hours dosing when opioids are indicated. For patients with cancer pain, therapy with CR oxycodone can be initiated to relieve pain no longer responsive to nonopioid analgesics. As pain severity increases, doses of CR oxycodone can be titrated upward to meet the increasing need for analgesia because oxycodone has no analgesic ceiling effect. Patients can be maintained on CR oxycodone as long as oral opioid analgesics are indicated. Because CR oxycodone is a single-entity product, it allows independent titration of oxycodone and nonopioid analgesics. In conclusion, this double-blind trial showed CR oxycodone to be as effective as IR oxycodone for the treatment of cancer pain. It also showed that, while many patients can be switched from one opioid to another, others will require titration of oxycodone in order to achieve optimal analgesia. In addition, pharmacokinetic data showed an inverse correlation between plasma oxycodone concentrations and pain levels. Finally, fewer adverse events were reported with CR oxycodone than IR oxycodone.

ACKNOWLEDGMENT We acknowledge the following principal investigators and their staffs who participated in this study: Joanne Blum. MD. PhD, Texas Oncology, PA. Dallas, TX: Stuart Grossman, MD, The Johns Hopkins Oncology Center. Baltimore, MD; Laurel Herbst, MD. San Diego Hospice, San Diego, CA; Howard Homesley, MD, Bowman Gray School of Medicine, Winston-Salem, NC: Ali Khojasteh, MD, Comprehensive Cancer Care Clinic, Columbia, MO; Allan Kliman. MD, Spaulding Rehabilitation Hospital, Boston, MA; Melvin Moore, MD, Grady Memorial Hospital, Atlanta, GA; Richard Patt, MD, University of Rochester Medical Center, Rochester, NY; Levi Pearson, MD, Georgetown University Medical Center, Washington, DC: Patricia Plezia, PharmD, University of Arizona Cancer Center. Tucson, AZ; P. Gregory Rausch, MD, FACP, Frederick Memorial Hospital, Frederick, MD: Richard Rosenbluth, MD, Northern New Jersey Cancer Center of Hackensack Medical Center. Hackensack, NJ; Monica Spaulding, MD. VA Medical Center, Buffalo, NY. We also acknowledge the following individuals from Purdue Pharma LP for their contributions to the study: James Komorowski and Claire Tan, MS. R.K., W.C.V.P., M.L.C., and D.Z. have no commercial or proprietary interest in oxycodone CR tablets.

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