Efficacy, Safety, and Steady-State Pharmacokinetics of Once-A-Day Controlled-Release Morphine (MS Contin XL ) in Cancer Pain

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1 80 Journal of Pain and Symptom Management Vol. 29 No. 1 January 2005 Original Article Efficacy, Safety, and Steady-State Pharmacokinetics of Once-A-Day Controlled-Release Morphine (MS Contin XL ) in Cancer Pain Neil A. Hagen, MD, Michael Thirlwell, MD, John Eisenhoffer, MD, Patricia Quigley, MSc, Zoltan Harsanyi, MBA, and Andrew Darke, PhD Departments of Oncology, Medicine, and Clinical Neurosciences (N.A.H.), University of Calgary, and Tom Baker Cancer Center (N.A.H.), Calgary, Alberta; Division of Medical Oncology (M.T.), Montreal General Hospital, Montreal, Quebec; and Department of Scientific Affairs (J.E., P.Q., Z.H., A.D.), Purdue Pharma Canada, Pickering, Ontario, Canada Abstract The efficacy, safety, and pharmacokinetics of a novel once-daily morphine formulation (OAD morphine) and a 12-hourly formulation (twice-daily CR morphine) were compared in a double-blind, multi-centered crossover study. Chronic cancer pain patients (n 25) were randomized to OAD morphine (mean mg q24h) or twice-daily CR morphine (mean mg q12h) for one week. They then crossed over to the alternate drug, which also was taken for one week. There was no difference between treatments for evaluations of overall pain intensity, analgesic efficacy, or adverse events. However, whereas pain scores increased during the day on twice-daily CR morphine (P ), they remained stable on OAD morphine. Most patients (68%) chose once-daily dosing for continuing pain management (P 0.015). The AUC ratio was 100.3%, indicating equivalent absorption. Fluctuation indices were % and % (P ) for OAD morphine and twice-daily CR morphine, respectively. OAD morphine provides analgesia similar to twice-daily CR morphine with reduced fluctuation in plasma morphine concentration and more stable pain control. J Pain Symptom Manage 2005;29: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Morphine, once-daily, controlled-release, clinical efficacy, cancer pain, pharmacokinetics Introduction The goal of chronic, analgesic therapy is to achieve continuous suppression of pain. This requires administration of analgesics on a regular Address reprint requests to: Neil Hagen, MD, Tom Baker Cancer Center, th Street N.W., Calgary, Alberta, T2N 4N2, Canada. Accepted for publication: April 15, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. basis, the next dose being given before the effects of the previous dose have worn off. Such a program can erase the memory and fear of pain, as well as reduce anxieties associated with its anticipated return. 1 Oral morphine has been described as an appropriate first choice for management of severe cancer pain. 2,3 Immediate-release morphine is generally administered every 3 4 hours, which may interrupt /05/$ see front matter doi: /j.jpainsymman

2 Vol. 29 No. 1 January 2005 Once-a-Day Morphine in Cancer Pain 81 sleep and lead to non-compliance. Oral or transdermal opioid products that have sustained delivery properties offer round-the-clock pain relief with less inconvenience to the patient. Available oral controlled-release formulations are designed to maintain effective plasma morphine levels throughout a 12-hour dose interval and have been shown to provide effective analgesia during chronic oral administration. 4,5 The 12-hourly dosing regimen is beneficial in terms of reduced frequency with which plasma morphine concentrations fluctuate a feature that may be clinically important in determining the extent of pain relief and incidence or severity of adverse events. Although twice-a-day administration of oral morphine represents a significant therapeutic advantage over 4-hourly immediate-release morphine, a further reduction in dosing frequency should provide less fluctuation in plasma concentrations at steady-state, along with greater patient convenience and compliance. 6 Compliance improves as dosing frequency is reduced and an important action that health care providers can take to improve compliance is to select medications that permit the lowest dose frequency possible. 7 Therefore, a once-daily morphine formulation that offers acceptable pain control is likely to enhance compliance and ensure optimal effectiveness of treatment. A number of oral sustained-release formulations of morphine have been developed with significant differences in their pharmacokinetics and bioavailability after single dose or steadystate administration. In clinical studies with other formulations, differences in pharmacokinetic variables such as fluctuation in plasma morphine concentration and time to maximum concentration have not been shown to translate into differences in extent of pain relief or the incidence or severity of adverse effects between 12- and 24-hourly formulations However, the decreased fluctuation in plasma concentration of longer-acting opioids may indeed provide more stable levels of pain control than their shorter-acting counterparts. Other controlledreleased formulations, using transdermal delivery of opioids such as fentanyl, also have the potential to produce more stable plasma levels. Although transdermal fentanyl is usually effective in patients with severe cancer pain and can be of particular value for patients who cannot tolerate oral medication, oral administration is relatively inexpensive and easy to titrate and there are several alternative long-acting oral opioid formulations available. Purdue Pharma has developed a once-a-day controlled-release morphine (OAD morphine) formulation with pharmacokinetic characteristics consistent with a 24-hour duration of action. In a single-dose bioavailability comparison with twice-daily controlled-release morphine (CR morphine), OAD morphine provided a comparable extent of absorption and a significantly reduced rate of absorption. 12 In a steady-state comparison with twice-daily morphine, the OAD formulation was characterized by a comparable extent of absorption and a significantly reduced fluctuation in plasma morphine concentration at the same total daily dose. 13 The potential clinical advantages of OAD morphine over twice-daily CR morphine include an extended duration of action, reduced dosing frequency, increased compliance and possibly, more stable clinical effects, and fewer side effects as a result of less fluctuation in plasma morphine concentration. The objective of this study was therefore to compare the clinical efficacy, safety, and steady-state pharmacokinetics of OAD morphine and twice-daily CR morphine in cancer patients with chronic pain. Methods Subjects Twenty-nine patients with chronic cancer pain and stable analgesic requirements were selected for participation. Stable analgesia was defined as that which required the administration of two or less rescue doses of opioid analgesic per 24-hour period, calculated as an average over three or more days. Patients were excluded from the study if they had intractable nausea or vomiting, a true allergy or intolerance to opioids, unstable renal function, were undergoing therapeutic procedures likely to influence pain during the study period, had a medical condition likely to interfere with drug absorption in the gastrointestinal tract, or if they were expected to use other opioid analgesics during the study. The study protocol and informed consent form were reviewed and approved by a research ethics board at each center, and all subjects gave written informed consent before participating in the study.

3 82 Hagen et al. Vol. 29 No. 1 January 2005 Medications Patients who were taking opioid analgesics other than oral controlled-release morphine received open-label twice-daily CR morphine (MS Contin, Purdue Pharma, Pickering, Ontario, Canada) and immediate-release morphine (MS IR, Purdue Pharma, Pickering, Ontario, Canada) for 3 days prior to randomization. If required, the dose was titrated to establish stable analgesia. Morphine was administered on a scheduled basis at an identical daily dose, either as OAD morphine (MS Contin XL, Purdue Pharma, Pickering, Ontario, Canada) administered every 24 hours or as a twice-daily CR formulation (MS Contin, Purdue Pharma, Pickering, Ontario, Canada). The normal dosing schedule for OAD morphine was 08:00h and the normal dosing schedule for twice-daily CR morphine was 08:00h and 20:00h. The dosing frequency was kept constant throughout the study period. Blinding was maintained using the double placebo technique. In the active treatment phases, patients received either active OAD morphine with placebos matching twice-daily CR morphine, or active twice-daily CR morphine with placebos matching OAD morphine. Dosage adjustments were not permitted during the trial. Breakthrough pain was managed with immediate-release morphine (MS IR, Purdue Pharma, Pickering, Ontario, Canada), each dose being equivalent to approximately 10% of the total daily morphine dose. No other opioids were permitted during the course of the study. Nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs, acetaminophen, adjuvant drugs that had been part of the patient s therapy at baseline (such as antidepressants, anticonvulsants, corticosteroids, and psychostimulants) were continued at the same dose level throughout the study period. Study Design The study was a randomized, balanced, double-blind multi-centered crossover comparison of the clinical efficacy and safety of OAD morphine given q24h and twice-daily CR morphine given q12h. In a previous study, we established the feasibility of this experimental design for comparison of efficacy and pharmacokinetics of controlled-release opioid formulations in cancer patients. 14 Patients who met the requirement for stable analgesia were randomized to OAD morphine or twice-daily CR morphine, each for a period of 7 days. At the end of Phase I, patients crossed over to the alternate treatment, at the same daily dose during Phase II, without an intervening washout period. The patient assessed pain intensity four times a day in a diary (08:00h, 12:00h, 16:00h, and 20:00h) on a 100-mm visual analog scale (VAS) (anchors: no pain to excruciating pain) and on a 5-point ordinal scale (0 no pain, 1 mild pain, 2 moderate pain, 3 severe pain, 4 unbearable pain). Nausea and sedation, two sensitive indicators of opioid toxicity, were also assessed on a 100-mm VAS at the same time (nausea anchors: no nausea to severe nausea; sedation anchors: no drowsiness to extreme drowsiness). At 08:00h and 20:00h, patients rated their least, worst, and average pain over the previous 12 hours (100-mm VAS scales, anchors: no pain to excruciating pain). At the clinic visits, the least, worst and average pain over the previous 7 days, average nausea and drowsiness over the previous 7 days, overall effectiveness of analgesic treatment (4-point ordinal scale, 0 not effective,1 slightly effective, 2 moderately effective, 3 highly effective), impact of pain on sleep, and preferred analgesic dosing frequency were assessed. The Pain and Sleep Questionnaire consisted of 8 items related to the impact of pain on sleep 7 items were rated on a 100-mm VAS (anchors: never to always) and one item was based on number of hours of sleep. The scores for Items 1 through 5 of the Pain and Sleep Questionnaire ( Trouble falling asleep due to pain [mm], Needed pain medication to sleep [mm], Needed sleeping medications to sleep [mm], Awakened by pain in night [mm] and Awakened by pain in the morning [mm] ) were summed to derive a composite score (0 500 mm). Blinded patient and investigator treatment preferences were recorded on completion of Phase II, and patients were also asked about their preference for OAD morphine or twice-daily CR morphine for continuing pain management. Spontaneously reported and investigator-observed adverse events were recorded at each visit. Assay Procedure For patients who consented to provide blood samples for pharmacokinetic analysis, a minicatheter was inserted into a peripheral vein

4 Vol. 29 No. 1 January 2005 Once-a-Day Morphine in Cancer Pain 83 prior to the morning dose. Blood samples (5 ml) were taken into vacutainers containing lithium heparin just before the morning dose, and every hour for 24 hours. The samples were centrifuged and the plasma harvested and stored pending analysis. Plasma samples were analyzed for morphine by a validated, sensitive, and specific high performance liquid chromatography procedure at Napp Pharmaceuticals, Cambridge, UK. Plasma samples were spiked with nalorphine hydrochloride as internal standards. The sample was transferred to a Chem Elut extraction column and morphine and internal standard nalorphine hydrochloride were extracted from 1 ml plasma aliquots using several alkaline extractions before analyzing. The validated method had: (a) a minimum correlation coefficient of for 20 separate calibration curves, demonstrating linearity; (b) a morphine recovery of 73.3%; and (c) appropriate specificity as demonstrated by lack of interfering peaks, including those from spiked samples of morphine-6-glucuronide and nalorphine, paracetamol and p-aminophenol. The intra-batch coefficients of variation were 15.3% and 15.2% at plasma morphine concentration of 0.25 and 0.5 ng ml 1 respectively, and less than 10% at all other plasma morphine concentrations. Inter-batch coefficients of variation at plasma morphine concentrations of 0.5, 1.0, 5.0, and 20 ng ml 1 were 8.0%, 9.2%, 3.5% and 2.5%, respectively. Clinical Data Analysis The primary measures of efficacy were the pain intensity VAS and ordinal scales from the daily diary. Previous studies in cancer pain suggested that standard deviations of 17 mm (pain VAS) 5 and 0.6 units (ordinal), 4 are reasonable to expect, and these values were adopted for the purpose of sample size estimation. With the patient serving as his or her own control, and assuming a low correlation between responses in a single subject in the two treatment periods, a total of 24 completed patients (12 per sequence) was calculated to provide 80% power to detect a difference of 15 mm in pain VAS and 0.6 units on the ordinal scale, at a statistical significance of The analysis of all efficacy outcome variables, including VAS and ordinal pain intensity, and sedation and nausea VAS, was restricted to patients completing both study phases. Safety variables were analyzed for all patients enrolled. The pain intensity (VAS and ordinal) and nausea and drowsiness data from the patient diaries were averaged across days and times, as well as overall. The diary scores for each patient were averaged across the 4 time points on each day. The average score over all days and times during each phase was calculated for each patient. Three-way analysis of variance was used to test for the effect of treatment, phase, and sequence (carryover) using data from the overall mean scores. The patient within sequence variance was used as the error term for testing sequence (carryover) effect. Multivariate repeated measures analysis was used to test for the effects of drug, day, time of day, and their interactions. Missing values were not replaced. The estimates of lowest, highest, and average pain intensity scores, feeling of being rested (08:00h diary), and the Pain and Sleep Questionnaire, were analyzed using 3-way analysis of variance. Treatment preference frequencies were compared using the binomial test. Rescue analgesic use was analyzed by determining, for each patient, the total number of rescue doses per day of study (7 days per phase). The mean daily use of rescue analgesics (number of doses and total dose) in all patients completing the study was computed. Three-way analysis of variance was used to test for the effect of drug, treatment sequence and phase, using data from the overall mean scores. Rescue use by time of day was computed by categorizing time of rescue into one of six, 4-hour segments. The interval from 08:00h to 12:00h was designated the first 4-hour segment. The number of doses for each patient during each of these time segments was determined (across all study days) and the average number of doses per time segment was computed. Multivariate repeated measures analysis was used to test for effects of drug, time segment, and their interaction. The smallest detectable treatment difference for overall pain intensity (100-mm VAS) was estimated using intrasubject correlations for pain intensity, the variance estimates from the data, and an assumed Type I error rate (α) of 0.05 and Type II (β) of 0.2. Adverse events were coded using preferred terms based on COSTART IV in order to standardize the terminology. McNemar s test was

5 84 Hagen et al. Vol. 29 No. 1 January 2005 used to determine the significance of differences in overall frequency of side effects between the two treatments. Statistical significance was defined as P 0.05 for a two-tailed hypothesis. Pharmacokinetic Analysis The maximum (C max ) and minimum (C min ) concentrations were determined for each patient based on the highest and lowest plasma concentrations (ng/ml) over the 24-hour sampling period. The area under the 24-hour concentration-time curve (AUC) for each patient was calculated using the trapezoidal rule. The Fluctuation Index (%) was calculated for each patient using the formula 100 (C max C min )/ C avg, where C avg is the average concentration over the 24-hour dosing interval, and is calculated as AUC 24. Time to maximum concentration (t max ) was determined using the first 12-hour interval during twice-daily CR morphine treatment and over the entire 24-hour interval for data collected during OAD morphine treatment. The time over which plasma concentration was 0.75 C max was determined from the individual plasma concentration-time curves. Pharmacokinetic parameters for each patient were normalized for the mean daily morphine dose in the group of patients who participated in the pharmacokinetic analysis. AUC (unadjusted for dose) and daily morphine dose were compared using correlation and one-way regression analysis (with no intercept) separately for each drug group. analgesic was mg and mg during twice-daily CR morphine and OAD morphine treatment, respectively. There was no difference in total daily analgesic consumption, including rescue, between the two groups. Pharmacokinetic Results Figure 1 shows the concentration-time curves (normalized to the mean morphine dose of 427 mg/day) for twice-daily CR morphine and OAD morphine for 10 patients who completed the 24-hour period of blood sampling for both formulations. The extent of absorption of OAD morphine was 100.3%, relative to twice-daily CR morphine, and mean maximum (C max ) and minimum (C min ) plasma morphine concentrations were respectively 70% and 155% for OAD morphine relative to twice-daily CR morphine (Table 1). There was a significantly reduced fluctuation in plasma morphine concentration with the OAD morphine formulation (P ). The time the plasma morphine concentration equalled or exceeded 75% of C max was significantly longer for OAD morphine than for twice-daily CR morphine (Table 1). There was a strong association between AUC and dose, for both OAD morphine and twicedaily CR morphine, as determined by Pearson correlations of (P ) and (P ), respectively. The slopes of the regression lines (intercept forced through the origin) of AUC on dose for OAD morphine and twice-daily CR morphine were (SE; P ) and (SE; P ) indicating similar dose-proportional bioavailabilities for the two formulations (Figure 2). Results Twenty-nine patients were enrolled, and 25 (12 men and 13 women, mean age years, mean weight kg) successfully completed the study. The two main sites of malignancy were breast and lung. Reasons for premature withdrawal included inadequate pain control in one patient (twice-daily CR morphine), adverse events in two patients (OAD morphine) and voluntary withdrawal by one patient (twice-daily CR morphine). The mean 12-hourly dose of twice-daily CR morphine and the total daily dose of OAD morphine were mg and mg, and the mean total daily dose of rescue Fig. 1. Mean plasma morphine concentration-time profiles following administration of OAD morphine and twice-daily CR morphine for 1 week. Plasma concentrations were normalized to a total daily dose of 427 mg.

6 Vol. 29 No. 1 January 2005 Once-a-Day Morphine in Cancer Pain 85 Table 1 Comparison of Steady-State Pharmacokinetic Parameters After Administration of OAD Morphine and Twice-Daily CR Morphine OAD Morphine (n 10) Twice-Daily CR Morphine (n 10) Ratio (90% CI) AUC (0 24) (ng hr/ml) a ( ) C max (ng/ml) a b b 69.7 ( ) C min (ng/ml) a b b ( ) t max (h) c c NA Time 0.75 C max (h) 8.0 c 3.6 c NA Fluctuation (C max C min /C avg 100) % b % b NA a Normalized to mean morphine dose (427 mg/day). b P c P Four patients took rescue medication (immediate-release morphine) during the pharmacokinetic assessments. In order to account for the effects of the rescue, AUC, C max and C min were adjusted for each of these patients by multiplying the parameter by the ratio of the nominal daily dose/ (nominal daily dose daily rescue dose). The AUC ratio (OAD morphine/ twice-daily CR morphine) was 100.1%, with 90% confidence limits of %. The values were minimally different from the values obtained with unadjusted parameters indicating that the effect of the rescue medication was essentially negligible. although there was an increase in pain intensity reported by patients toward the end of the 12- hour period at 8 p.m. (P ) with twicedaily CR morphine (Fig. 3b). There was also a trend for less nausea with OAD morphine ( ) compared to twice-daily CR morphine ( ; P ). Clinical Results All 25 patients experienced good pain control during the study. There were no significant differences between OAD morphine and twicedaily CR morphine for the mean overall VAS pain scores, mean overall ordinal pain, sedation Pharmacokinetic Pharmacodynamic Results Ten patients underwent blood sampling after 7 days of each treatment. Figure 3 shows the relationship between pain intensity scores and plasma morphine concentration over the first 12 hours of blood sampling. Pain scores remained constant with OAD morphine (Fig. 3a), Fig. 2. Relationship between daily dose of OAD morphine and twice-daily CR morphine and area under the plasma concentration-time curve (AUC 0 24 ). Fig. 3. Relationship between mean pain intensity and mean plasma morphine concentration for (a) OAD morphine and (b) twice-daily CR morphine for the pharmacokinetic patients.

7 86 Hagen et al. Vol. 29 No. 1 January 2005 or nausea scores (Table 2). A retrospective analysis indicated that the design had 80% power to detect a difference of 7.4 mm on the 100- mm VAS. For both VAS and ordinal pain scores, results of repeated measures analysis of variance by day showed no significant effect of day or day by treatment interaction (Table 3). However, results of multivariate repeated measures analysis of ordinal pain scores by time of day showed there was a significant time effect (P ) and a significant time by treatment interaction for both VAS and ordinal pain scores (P , ). Pain scores during OAD morphine treatment differed very little throughout the day, although during the twice-daily CR morphine treatment, the pain intensity tended to be lower and the pain scores increased throughout the day (P ). There was no evidence of a treatment sequence effect (P ) (Table 2). To determine if the efficacy of OAD morphine and twice-daily CR morphine was maintained over a 24-hour dosing interval, consumption of rescue analgesic during 4-hourly intervals was analyzed (Table 2). Repeated measures analysis of variance by time of day indicated there was no significant change in rescue use between time intervals (P ) or time by treatment interaction (P ). There was no significant treatment difference between OAD morphine and twice-daily CR morphine in mean lowest ( and mm, P ), average ( and mm, P ), and highest ( and mm, P ) VAS pain intensity determined from the twice-daily assessments in the diary. The corresponding scores from the weekly evaluation also indicated no significant differences between OAD morphine and twicedaily CR morphine (lowest: , , P ; highest: , , P ; average: , , P ). Weekly recall of nausea severity favoured OAD morphine over twice-daily CR morphine ( mm and mm, respectively, P ), whereas weekly recall of drowsiness scores for OAD morphine and twicedaily CR morphine scores were mm and mm, (P ). There was no significant treatment difference in mean pain and sleep scores ( mm and mm; P , for OAD morphine and twice-daily CR morphine, respectively). There was no difference between treatments in effectiveness score when rated by patients (P ) or investigators (P ). OAD morphine and twice-daily CR morphine were rated as moderately or highly effective by 76% and 84% of patients, respectively, and 80% and 88% of investigators, respectively. Investigator s blinded evaluation of treatment phase preference was: 12 (48%) no preference; 6 (24%) preferred OAD morphine; 7(28%) preferred twice-daily CR morphine (P 1.000). When patients were asked to rate the preferred treatment phase, 8 (32%) indicated Table 2 Comparison of Clinical Efficacy and Safety Variables by Time of Day After OAD Morphine and Twice-Daily CR Morphine 8:00 AM 12:00 PM 4:00 PM 8:00 PM Overall OAD Morphine Pain intensity VAS (0 100 mm) Pain intensity ordinal (0 4) Rescue analgesic use (mg/day) Sedation VAS (0 100 mm) l1.1 Nausea VAS (0 100 mm) Twice-Daily CR Morphine Pain intensity VAS (0 100 mm) Pain intensity ordinal (0 4) Rescue analgesic use (mg/day) Sedation VAS (0 100 mm) Nausea VAS (0 100 mm) Data represent mean score plus or minus standard deviation by time of day over 7 days. Overall score represents mean over all days and times.

8 Vol. 29 No. 1 January 2005 Once-a-Day Morphine in Cancer Pain 87 Table 3 Comparison of Clinical Efficacy and Safety Variable by Day of Treatment After OAD Morphine and Twice-Daily CR Morphine Day 1 Day 2 Day 3 Day 4 Day5 Day 6 Day 7 Overall OAD Morphine Pain intensity VAS (0 100 mm) Pain intensity ordinal (0 4) Rescue analgesic use (mg/day) Sedation VAS (0 100 mm) Nausea VAS (0 100 mm) Twice Daily CR Morphine Pain intensity VAS (0 100 mm) Pain intensity ordinal (0 4) Rescue analgesic use (mg/day) Sedation VAS (0 l00 mm) Nausea VAS (0 100 mm) Data represent mean daily dose plus or minus standard deviation over 4 assessment times (overall score represents mean over all days and times). no preference, 4 (16%) preferred the phase with OAD morphine and 13 (52%) preferred the phase with twice-daily CR morphine. The difference in blinded preference ratings was not statistically significant (P 0.108). However, when patients were asked to state their preference for a once-a-day or twice-a-day analgesic dosing in general, the majority (68%) preferred OAD morphine to twice-daily MS Contin (P 0.015). Safety There was no difference in the incidence of adverse events reported during the two treatments, with 15 and 14 patients reporting adverse events during OAD morphine and twice-daily CR morphine, respectively (P 0.796). The most common adverse events in terms of the number of patient reports for OAD morphine and twice-daily CR morphine, respectively, were nausea (3, 6), constipation (4, 1), somnolence (2, 2), asthenia (2, 1) and headache (2, 2). Discussion An effective analgesic strategy is an essential part of the care of patients with cancer. Current guidelines on the management of moderate to severe cancer pain recommend the use of scheduled doses of opioids for persistent pain combined with as needed doses of similar agents for breakthrough pain. Opioid formulations that combine prolonged effectiveness with a high level of pain control are more likely to enhance compliance. Twice-daily controlled-release morphine (CR morphine) is designed to maintain effective plasma morphine concentrations throughout a 12-hour dose interval and has been shown to provide effective analgesia during chronic oral administration. 4,5 In this study, a new OAD morphine formulation with pharmacokinetic characteristics consistent with a 24-hour duration of action has been compared to twice-daily CR morphine with respect to pharmacokinetics, efficacy, and safety, in cancer patients. Evaluations of pain intensity and other measures of relative analgesic effect (overall effectiveness evaluation; rescue analgesic consumption; patient and investigator preference) were consistent in demonstrating the 24-hour effectiveness of OAD morphine capsules in comparison

9 88 Hagen et al. Vol. 29 No. 1 January 2005 with twice-daily CR morphine tablets given 12-hourly. The steady-state plasma concentration-time profile and pharmacokinetic parameters obtained in cancer patients taking OAD morphine were similar to those previously obtained in healthy volunteers, 13 indicating that the prolonged release of morphine from the capsules reduces both the rate of absorption and the rate of decline of plasma morphine concentration. Furthermore, the extent of fluctuation in plasma morphine concentration was significantly less with OAD morphine (Table 1). The mean steady-state AUC (0 24) values were very similar for OAD morphine and twice-daily CR morphine, demonstrating equivalent bioavailability. In addition, there was a linear relationship between dose and extent of absorption for OAD morphine, with a slope similar to that of the corresponding regression for twice-daily CR morphine, indicating dose-proportional bioavailability (Fig. 2). Although there was no significant difference in the mean overall pain scores between twice-daily CR morphine and OAD morphine, there was a significant time by treatment interaction, with pain scores increasing during the day on twice-daily CR morphine while remaining stable on OAD morphine (Table 2). The observation of stable pain control throughout the day on OAD morphine is consistent with the pharmacokinetic observations of reduced fluctuation in plasma morphine concentrations and a longer mean time 0.75 C max for OAD morphine compared to twice-daily CR morphine (Table 1). This is further supported by the pharmacokinetic/pharmacodynamic comparisons, which show greater stability of both plasma morphine concentrations and pain levels with OAD morphine, over a 12- hour period (Fig. 3a), compared to twice-daily CR morphine, where pain levels increased toward the end of the dosing period as the morphine plasma levels decreased (Fig. 3b). Evaluations of quality of sleep and of the impact of pain on sleep suggest that OAD morphine will provide the same benefit as twicedaily CR morphine compared with short-acting morphine formulations. Although there were no significant differences between the two treatments in opioid related adverse events, we speculate that the trend for less nausea with OAD morphine compared with twice-daily CR morphine may correlate with the reduction in frequency and magnitude of the plasma concentration fluctuations during OAD morphine treatment. Two other once-daily morphine formulations have been compared to MS Contin, and thus can be indirectly compared to OAD morphine used in the current study. A once daily formulation of morphine, Avinza, has been compared to MS Contin with respect to pharmacokinetics, efficacy and safety. 11,15 Avinza had a significantly reduced C max, and significantly higher C min than MS Contin, as well as fluctuation index of 93%, similar to the findings in the current study. 15 The time that plasma morphine concentration exceeded 0.75 C max for Avinza, however, was 6.51 hours, slightly lower than that of OAD morphine (8 hours). This indirectly suggests that although OAD morphine and Avinza may provide comparable reductions in fluctuations of plasma concentration of morphine as compared to MS Contin, OAD morphine may have a longer duration of action. An earlier once daily morphine formulation (Kadian ), designed to provide the option of 12-hourly or 24-hourly administration, was also compared with MS Contin with respect to pharmacokinetics. 10 Gourlay et al. found no difference in maximum plasma morphine concentration between Kadian and MS Contin, 10 whereas the new OAD morphine formulation evaluated in this study demonstrated a significantly reduced (70%) maximum plasma morphine concentration relative to MS Contin. The fluctuation indices reported for Kadian and MS Contin in the former study were 140% and 160%, respectively, whereas the fluctuation index for OAD morphine was 50% lower than that of MS Contin in the current study. In addition, the time that plasma morphine exceeded 0.75 C max was 8 hours in the case of OAD morphine, compared with only 6 hours, in the case of Kadian. These pharmacokinetic results suggest that OAD morphine may provide more stable plasma levels and potentially more stable pain relief over 24 hours than Kadian. Other long-acting opioid formulations that represent alternatives to controlled-release oral morphine include transdermal formulations, which also have the potential for reduced fluctuations in plasma concentration. The only

10 Vol. 29 No. 1 January 2005 Once-a-Day Morphine in Cancer Pain 89 opioid currently available in a transdermal delivery system is fentanyl (Duragesic ), however, transdermal formulations of buprenorphine providing a longer duration of action (7 days vs. 3 days) are now under clinical investigation. 16 A potential advantage of transdermal formulations is reduced fluctuation in plasma concentrations; interestingly, the fluctuation index calculated for OAD morphine in this study is similar to that reported by Portenoy et al. 17 for transdermal fentanyl in cancer patients. One of the clinical challenges in the use of transdermal fentanyl is the uncertainty surrounding appropriate equianalgesic dose conversions between transdermal fentanyl and oral morphine, which range from 1: to 1:70, 22 as summarized by Grond et al. 23 Alternative long-acting oral morphine formulations may represent a preferred approach to management of cancer pain in patients able to use oral medication who are already receiving benefit from morphine. The results of this randomized double-blind study demonstrate that OAD morphine capsules given once daily provide analgesia that is similar to twice-daily CR morphine tablets. A potential advantage of OAD morphine administration over twice-daily dosing was indicated by the results of a patient questionnaire in which the majority of patients (68%) expressed a preference for OAD morphine for their continuing pain management versus twice-daily dosing of MS Contin. Pharmacokinetic analysis showed equivalent bioavailability of the two formulations and less fluctuation in plasma morphine levels with OAD morphine, in conjunction with more stable pain control. The well-documented clinical advantages of round-the-clock dosing with long-acting opioid analgesics in the management of chronic cancer pain indicate that OAD morphine capsules will provide a valuable therapeutic alternative for this group of patients. Acknowledgments The authors are grateful to the following clinicians for enrollment of patients in this study: Drs. Francis Laberge, Louise Yelle, Dwight Moulin, and Jackie Gardner-Nix. This research was supported by a research grant from Purdue Pharma, Pickering, Ontario. References 1. Walsh TD, Saunders CM. Oral morphine for relief of chronic pain from cancer. N Engl J Med 1981;305: Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer 1987;59: Dickerson D. The 20 essential drugs in palliative care. Eur J Palliat Care 1999;6: Thirlwell MP, Sloan PA, Maroun JA, et al. Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Cancer 1989;63: Goughnour BR, Arkinstall WW, Stewart JH. Analgesic response to single and multiple doses of controlled-release morphine tablets and morphine oral solution in cancer patients. Cancer 1989;63: Ferrell B, Wisdom C, Wenzl C, Brow J. Effects of controlled-release morphine on quality of life for cancer pain. Oncol Nur Forum 1989;16: Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybech TR. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990;150: Gourlay GK. Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine. Clin Pharmacokinet 1998;35: Kerr RO, Tester WJ. A patient preference study comparing two extended-release morphine sulfate formulations (once-daily Kadian versus twice-daily MS Contin) for cancer pain. Clin Drug Invest 2000;19: Gourlay GK, Cherry DA, Onley MM, et al. Pharmacokinetics and pharmacodynamics of twentyfour-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain. Pain 1997;69: Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage 2002;23: Purdue Pharma L.P. A single dose, three-period, randomized, crossover, open label, analytically blind pharmacokinetic/pharmaco-dynamic study of morphine sulfate controlled-release capsule 60 mg (MS Contin XL) in fed versus fasted normal volunteers and MS Contin XL 60 mg capsule versus MS Contin tablet 60 mg in fasted normal volunteers. [Report No.: MS ] Purdue Pharma L.P. A steady-state, pharmacokinetic/pharmacodynamic comparison study of one morphine sulfate controlled-release 60 mg capsule (MS Contin XL) q24h and one MS Contin 30 mg

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