Original Article. 292 Journal of Pain and Symptom Management Vol. 23 No. 4 April 2002

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1 292 Journal of Pain and Symptom Management Vol. 23 No. 4 April 2002 Original Article Steady-State Pharmacokinetic Comparison of a New, Extended-Release, Once-Daily Morphine Formulation, Avinza, and a Twice-Daily Controlled-Release Morphine Formulation in Patients with Chronic Moderate-to-Severe Pain Russell K. Portenoy, MD, Andréa Sciberras, BS, Lise Eliot, PhD, Gordon Loewen, PhD, Jackie Butler, PhD, and John Devane, PhD Department of Pain Medicine and Palliative Care (R.K.P., A.S.), Beth Israel Medical Center, New York, New York; Ligand Pharmaceuticals Inc. (L.E., G.L.), San Diego, California, USA; and Elan Pharmaceutical Technologies ( J.B., J.D.), Athlone, Ireland Abstract Extended-release morphine formulations are widely used in the management of chronic pain. Avinza (morphine sulfate extended-release [MSER, Morphelan ]) is a new, once-a-day, extended-release morphine formulation designed to reach target concentrations rapidly and maintain concentrations throughout a 24-hour period. The primary objective of this study was to compare the 24-hour steady-state pharmacokinetic (PK) profiles of morphine and its metabolites (morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]) following ingestion of MSER once-a-day and MS Contin (controlled-release morphine sulfate [CRM]) twice-a-day in patients with chronic moderate-to-severe pain. Ten patients with chronic moderate-to-severe pain were recruited into an open-label, multiple-dose, nonrandomized, twoperiod, single-center study. All patients were stabilized for a minimum of 7 days on a twicedaily dose of CRM associated with an optimal balance between pain control and side effects. Patients were then switched to the closest equivalent once-daily dose of MSER for a minimum of 10 days. Twenty-four hour steady-state PK profiles were obtained on the last day of each treatment period and additional clinical and safety assessments were performed. PK data were normalized to a 100-mg total daily dose prior to statistical analysis. Nine of the 10 patients completed the entire study. MSER and CRM demonstrated similar bioavailability (AUC) of morphine and its metabolites. Compared to CRM, MSER demonstrated a 19% lower maximum concentration (C max ), a 66% higher minimum concentration (C min ), and a 44% lower peak-to-trough fluctuation (%FI) over the 24-hour period. In addition, MSER maintained concentrations above 50% and 75% of the C max longer than CRM. Clinical Address reprint requests to: Russell K. Portenoy, MD, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, First Avenue at 16th Street, New York, NY 10003, USA. Accepted for publication: January 15, U.S. Cancer Pain Relief Committee, /02/$ see front matter Published by Elsevier, New York, New York PII S (02)

2 Vol. 23 No. 4 April 2002 PK Comparison of Sustained-Released Morphine Formulations 293 efficacy and safety were comparable for MSER and CRM. Once-daily MSER approaches maximum morphine concentration more quickly, approximates maximum concentration longer, and demonstrates less fluctuation in morphine concentration during a 24-hour period than CRM dosed twice daily. The pharmacodynamic implications of this profile deserve further study. J Pain Symptom Manage 2002;23: U.S. Cancer Pain Relief Committee, Key Words Pharmacokinetics, pharmacodynamics, morphine sulfate, chronic pain, sustained-release formulations Introduction In the United States, opioid usage for the treatment of moderate-to-severe pain has increased substantially during the past decade. 1 Long-term opioid therapy is recognized as the mainstay approach for the treatment of chronic pain related to cancer and other serious illnesses. 2 The role of this approach in the management of chronic pain of noncancer origin has been steadily expanding for selected patients. 3 Morphine is considered to be the prototype of all pure mu agonist opioids used for the management of severe pain. Oral morphine is available in both immediate-release and extended-release formulations. Extended-release formulations are preferred for long-term therapy due to the numerous potential advantages, such as convenient dosing schedules, sustained analgesia and uninterrupted sleep. 4,5 Several extended-release oral morphine formulations are commercially available. The dose intervals recommended for these formulations vary from eight or 12 to 24 hours. Longer dosing intervals are usually preferred, and there is some empirical evidence that patients with chronic cancer pain may prefer a formulation of morphine that can be administered once daily. 4 Avinza (morphine sulfate extendedrelease [MSER, Morphelan ]; Elan Pharmaceuticals Research Corp., Gainesville, GA) is a novel extended-release oral morphine formulation designed specifically for once-daily oral administration. MSER contains a mixture of immediaterelease and extended-release beads that release morphine in a distinct time-dependent manner. The immediate-release component provides an initial rapid release of morphine, after which the extended-release component sustains therapeutic concentrations with minimal peak-to-trough fluctuation over a 24-hr dosing interval. 6 The clinical use of MSER will rely on a detailed understanding of its pharmacokinetic (PK) characteristics in clinical populations. The objective of this study was to compare the steady-state PK profiles of morphine and its metabolites in patients with chronic pain following administration of MSER once daily and a commercially available controlled-release formulation, MS Contin (morphine sulfate controlled-release [CRM]; Purdue Frederick, Norwalk, CT), administered twice daily. Methods Subjects Male and female patients of at least 21 years of age were eligible if they were experiencing chronic pain of any type that was severe enough to warrant long-term oral opioid therapy equivalent to a minimum of 60 mg of oral morphine per day. Patients were required to have a documented Karnofsky performance status of at least 70% and an expected survival of at least 3 months. Exclusion criteria included significant comorbid conditions (e.g., significant cardiac, hepatic, renal disease) that could interfere with the assessment of adverse events (AEs); known brain metastasis; a history of active chemical dependency, hepatitis B or C, or human immunodeficiency virus; or gastrointestinal disorders that could affect drug absorption. The study was conducted in accordance with the Declaration of Helsinki. The local Institutional Review Board (IRB) approved the protocol, and all patients provided written informed consent prior to study enrollment.

3 294 Portenoy et al. Vol. 23 No. 4 April 2002 Study Design This was an open-label, nonrandomized, twoperiod, single-center, multiple-dose PK study. During the first phase, patients received CRM twice daily and had access to a short-acting opioid as needed for breakthrough pain (so-called rescue medication). The rescue medication (oxycodone hydrochloride, Roxicodone, Roxane Laboratories Inc., Columbus, OH) was available for administration every 2 hr as needed at a dose approximately equivalent to 10% of the total daily morphine dose. The dose of CRM was adjusted in a routine manner until there was a satisfactory balance between analgesia and side effects and rescue drug use was minimized. Although an effort was made to continue morphine titration until the patient used 4 doses of rescue medication per day, those who took a larger number of doses were allowed to proceed with the study if there was satisfaction with the morphine dose and both the patient and investigator agreed that further morphine titration was unlikely to yield a better outcome. Seven days of stable dosing with CRM was required before the PK study could be performed. Following the CRM treatment period, patients were switched to the closest equivalent dose of MSER, which was administered once daily. Access to the oxycodone rescue medication was continued at the same dose. Dose titration again was allowed, if needed, and stable treatment with MSER was required for at least 10 days before the PK study was done. Adherence to therapy was monitored during visits through active questioning and pill counting. All concomitant medications used during the study were recorded in patient diaries. Clinical Efficacy During both study periods, patients recorded their use of rescue medication on a daily basis. In the morning, worst pain intensity since awakening (8:00 a.m. to 10:00 a.m.) was measured using a 100 mm visual analog scale (VAS), anchored by 0 no pain and 100 excruciating pain. Each evening (8:00 p.m. to 10: 00 p.m.), patients completed the pain intensity items from the Brief Pain Inventory (BPI) Short Form. The BPI measures pain intensity on four 11-point numeric scales that range from 0 (no pain) to 10 (worst pain imaginable). For the purposes of efficacy evaluation, assessments from the last five days of the CRM stabilization period were compared to the last five days of the MSER treatment period. Safety Safety assessments included treatment-emergent adverse event (AE) reporting throughout both periods, and monitoring of clinical laboratory values, physical examinations, and vital signs at baseline, within one week of study drug initiation, and at 24 to 48 hr after study completion or at the time of study withdrawal. Pharmacokinetic Sampling Blood samples were obtained for the purposes of PK analysis on the last day of administration of each study period (CRM and MSER) following an overnight fast. After a minimum of seven days of dosing with CRM, patients were brought into the hospital in the morning. Blood samples were obtained prior to the first dose of CRM and then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 13, 15, 16, 18, 22, and 24 hr after the morning dose. The second daily dose of CRM was administered prior to the 12-hr blood sample. During the MSER treatment period, pre-dose blood samples were obtained from the majority of patients on Days 4, 6, 8, and 10 and at various days thereafter depending upon the length of time the patient remained in the study. After a minimum of 10 days, patients were brought back into the hospital in the morning. Blood samples were obtained prior to the morning dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 13, 15, 16, 18, 22, and 24 hr after the morning dose. Blood samples were collected into lithium heparin blood collection tubes and centrifuged at 3,000 RPM for a period of 15 minutes at 4 C within 1 hr of sample collection. Plasma was transferred into polypropylene tubes and frozen at 20 C prior to analysis. Analytical Procedures Morphine was analyzed with a validated liquid chromatography-mass spectrometry (LC-MS) assay using single MS mode Q1 scan. Morphine and internal standard, deuterated morphine (morphine-d 3 ), were quantitated by monitoring the protonated molecular ions at 286 and 289, respectively. Extraction of morphine and internal standard was carried out using a solid

4 Vol. 23 No. 4 April 2002 PK Comparison of Sustained-Released Morphine Formulations 295 phase extraction process using Oasis HLB extraction cartridges. The calibration curve concentrations ranged from ng/ml for 5 of the analytical runs and ng/ml for nine analytical runs. Quality control samples representative of low, medium and high concentrations of the calibration curve were run in duplicate and differed for the batches. Quality control samples included concentrations of 3, 30, and 80 mg/ml or 3, 30, and 150 mg/ml for analytical batches utilizing calibration curves ranging from ng/ml and ng/ ml, respectively. The mean percent accuracy of morphine ranged from % and precision (%CV) from %. The metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were quantitated using a validated liquid chromatography-mass spectrometry (LC-MS/MS) assay using turbo-ion spray. Internal standards (deuterated metabolites), morphine-d 3-3-glucuronide and morphine-d 3-6-glucuronide, were added to plasma prior to extraction. Solid phase extraction was employed using Oasis HLB extraction cartridges. Multiple reaction monitoring transitions of m/z and 465 Æ289 were used to detect metabolites (M3G and M6G) and internal standards (morphined 3-3-glucuronide and morphine-d 3-6-glucuronide), respectively. The calibration curve concentrations ranged from ng/ml for 11 of the analytical runs and ng/ml for 5 analytical runs. Quality control samples included concentrations of 7, 200, and 1500 mg/ ml, or 7, 200 and 4500 mg/ml for analytical batches utilizing calibration curves ranging from ng/ml and ng/ml, respectively. Accuracy of M6G and M3G batches ranged from % and %, respectively, and the precision (%CV) ranged from % and %, respectively. Assay acceptance specifications required a precision of 15% as measured by the percent coefficient of variation (%CV) and a percent accuracy of %. Batch acceptance was concluded if one or more of the quality control samples at each level were within specification and if no less than four of the total six samples were within specification. Pharmacokinetic Parameters Non-compartmental analysis was performed on morphine and metabolites (M3G and M6G) using WinNonlin Professional Version 2.1 (Pharsight Corporation, CA) to determine the following PK parameters: area under the plasma concentration-time curve from time 0 to 24 hrs (AUC), average plasma concentration (C avg ) throughout the 24-hr period, and percent peak-to-trough fluctuation index (%FI) within the 24-hr period. The maximum plasma concentration (C max ) and minimum plasma concentration (C min ) throughout the 24-hr period were read directly from the plasma concentration-time profiles. In addition, plasma concentration at 30 minutes (C 30min ) post-dose and at the last observation of the 24-hr period (C last ) were read directly from the plasma concentration-time profiles. The duration of time that plasma morphine concentration was 50% of C max (DT50%) or 75% of C max (DT75%) was determined. The time point of intersection between the plasma concentration-time curve and threshold concentrations was calculated by linear interpolation of the two concentration values on either side of the threshold concentration. This process was repeated throughout the 24-hr period and the time interval during which the concentrations was 50% C max or 75% C max, respectively, were calculated and summed to determine DT50% or DT75%. For the purposes of statistical analysis, PK parameters were normalized to a total daily morphine dose of 100 mg. Statistical Analysis An analysis of variance (ANOVA) was conducted on PK parameters using SAS General Linear Models (GLM) procedures. PK variables, except %FI, DT50%, and DT75%, were log-transformed prior to statistical analysis. Time to achieve steady state during the MSER treatment period was determined by employing a linear regression in SAS utilizing the General Linear Model (GLM) procedure with a model response of time on the pre-dose morphine concentrations. The time to achieve steady state was defined as that time at which inclusion of an additional pre-dose value would result in a positive slope and a statistically significant probability (p) value for the slope of the overall regression. Descriptive statistics (mean, standard deviation, median, and range) were used to summarize the efficacy measurements for each treatment period. The Wilcoxon signed rank test

5 296 Portenoy et al. Vol. 23 No. 4 April 2002 was used to assess changes in the average number of rescue medication doses and changes in average scores for each item on the BPI from the last five days of each treatment period. The paired t-test was used to assess the mean change in VAS scores from last five days of each treatment period. Statistical significance was considered at p Results Patient Demographics and Characteristics A total of ten patients (8 females and 2 males) with pain of nonmalignant origin were enrolled into this study. Mean age of patients was 45 years (range 28 65). Mean height and weight were 166 cm (range ) and 79 kg (range ), respectively. Seven of the patients were Caucasian (70%), 2 were African American (20%), and 1 was Asian (10%). Nine patients (7 females and 2 males) completed the study. One patient discontinued the study during the CRM period due to AEs (somnolence and insomnia). For each patient, average daily doses of study drug were similar during the CRM treatment period and the MSER treatment period (Table 1). The average daily dose of MSER and CRM was mg and mg, respectively. Pharmacokinetics Although nine patients completed both treatment periods, eight patients in the CRM treatment period and seven patients in the MSER Table 1 Daily Dose of Morphine During Stabilization and Treatment Periods CRM Stabilization Period Patient No. of Days Average Daily No. Days Number Dosed Dose Dosed MSER Treatment Period Average Daily Dose mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg Data are presented for those patients that completed both periods and were considered evaluabe for PK assessment. CRM controlled release morphine MSER morphine sulfate extended release treatment period were considered evaluable. The data for one patient were not evaluable in both periods due to non-compliance and another patient s concentration data were not evaluable only in the MSER treatment period due to plasma sample analysis difficulties. Following MSER dosing, steady state was demonstrated for the majority of subjects (7/8) by the last day of treatment. Steady state was achieved by one patient at Day 2, by five patients at Day 4, and by one patient at Day 5. Due to the variability in pre-dose morphine concentrations, one patient could not be confirmed to be at steady state by the last day of treatment with the statistical techniques utilized. However, inspection of the pre-dose plasma concentration data suggested that the patient was at steady state and this patient therefore was included in the PK analysis. Mean plasma morphine and metabolite plasma concentration-time profiles are displayed in Figure 1. CRM produced two distinct peakto-trough fluctuations, whereas MSER displayed more of a plateau-like profile with an initial rapid release of morphine. Mean plasma morphine and metabolite PK parameters are listed in Table 2. Total systemic exposure of morphine as measured by AUC was similar following administration of MSER once daily and CRM twice daily. Compared to CRM, MSER demonstrated higher concentrations at 30 minutes and at 24-hr by 55% and 46%, respectively. Throughout the 24-hr period, MSER yielded a 19% lower C max, 66% higher C min, and a 44% lower peak-to-trough fluctuation (%FI) in comparison to CRM. DT50% and DT75% were longer following administration of once-daily MSER by 80% and 86%, respectively. These differences in MSER and CRM steadystate morphine profiles were mirrored by the profiles of M3G and M6G. The one exception was the C last measurement for M3G, which was similar for both formulations. Efficacy and Safety A total of 9 patients were included in the efficacy analysis (Table 3). No differences were apparent between the treatments in any of the efficacy variables analyzed. The number and percentage of patients who required rescue medication during the CRM period were similar to those in the MSER treatment period.

6 Vol. 23 No. 4 April 2002 PK Comparison of Sustained-Released Morphine Formulations 297 Fig. 1. Steady-state mean plasma concentration-time profiles following administration of MSER once daily and CRM twice daily in patients with chronic moderate-to-severe pain. Plasma concentrations were normalized to a total daily dose of 100 mg. The mean number of rescue doses required daily during the last 5 days of the CRM period ( ; range, ) was similar to the mean number required in the MSER period ( ; range, ; p 0.99). The mean values of the VAS, reflecting the average worst pain since rising, and the mean pain intensity values from the BPI were similar in the MSER and CRM treatment periods (Table 3). Treatment-emergent AEs for all patients (n 10) are tabulated in Table 4. A total of five patients in the CRM period and four patients in the MSER period experienced AEs. One patient withdrew from the CRM treatment period due to drowsiness during the morning and insomnia during the evening. No patients withdrew during the MSER treatment period. All AEs were considered to be mild to moderate in severity, with the exception of a severe case of albuminuria observed during the MSER treatment period, which was deemed by the investigator to be unlikely due to study medication. No deaths, serious AEs, or clinically significant AEs were observed. No clinically significant changes in vital signs, physical examinations, or laboratory values were observed for those patients who completed the study (n 9). Discussion This comparative steady-state PK analysis demonstrates that MSER once daily and CRM twice daily provide similar total systemic exposure (as measured by AUC) of morphine and its metabolites throughout a 24-hr period. Nonetheless, these two formulations have distinct PK profiles, which reflect their divergent extended-release technologies. MSER once

7 298 Portenoy et al. Vol. 23 No. 4 April 2002 Parameter Table 2 Pharmacokinetic Parameters CRM twice daily MSER once daily Morphine AUC (ng h/ml) a 312 (121) 323 (154) C max (ng/ml) a 26.1 (7.63) 21.2 (10.6) b C min (ng/ml) a 5.36 (2.86) 8.88 (4.71) b C 30min (ng/ml) a 11.0 (3.32) 17.1 (7.00) b C last (ng/ml) a 8.14 (4.58) 11.9 (6.48) b %FI 167 (43.7) 93.4 (19.6) b DT50% (hr) 10.1 (3.83) 18.8 (4.57) b DT75% (hr) 3.61 (2.10) 6.51 (3.97) Morpine-3-glucuronide AUC (ng h/ml) a (3596) (5372) C max (ng/ml) a 1361 (327) 1086 (356) b C min (ng/ml) a 317 (125) (190.33) b C 30min (ng/ml) a 592 (289) 709 (215) C last (ng/ml) a 527 (184) 559 (177) %FI 136 (25.8) 81.9 (13.0) b DT50% (hr) 14.4 (3.59) 21.9 (1.52) b DT75% (hr) 4.65 (2.22) 7.59 (4.04) Morphine-6-glucuronide AUC (ng h/ml) a 2708 (601) 2759 (969) C max (ng/ml) a 210 (43.2) 168 (42.0) b C min (ng/ml) a 43.1 (13.5) 75.8 (26.7) b C 30min (ng/ml) a 85.8 (42.0) 91.8 (33.6) C last (ng/ml) a 65.8 (22.5) 101 (59.7) b %FI 148 (18.1) 84.8 (21.3) b DT50% (hr) 12.3 (2.25) 20.1 (5.28) b DT75% (hr) 4.76 (1.90) 7.37 (4.88) Data are demonstrated as mean (SD). CRM controlled release morphine, MSER morphine sulfate extended release a indicates that the parameter was normalized to a total daily dose of 100 mg b indicates statistical significance between treatments (p 0.05) daily maintains morphine concentrations at or greater than 50% and 75% of maximum concentrations for a longer duration of time. MSER once daily also yields a lower C max and higher C min, which consequently results in a reduced peak-to-trough fluctuation. The ability of an extended-release formulation to provide stable drug concentrations over time is generally evaluated by the extent of peakto-trough fluctuation over a predefined time interval. This peak-to-trough fluctuation is measured by %FI. Additionally, the extent to which a formulation controls the release rate of morphine can be assessed by the duration of time that drug concentrations equal or exceed a threshold concentration, typically 50% or 75% of the maximum concentration (DT50% or DT75%, respectively). 7 Generally, flatter and more stable concentrationtime profiles correspond to a lower %FI and longer DT50% and DT75% values. Table 3 Efficacy variables CRM twice daily Stabilization Period MSER once daily Treatment Period WPSR VAS Mean (SD) Median (range) 58.2 ( ) 60.6 ( ) BPI Questions Most severe pain a Mean (SD) Median (range) 6.80 ( ) 6.80 ( ) Least severe pain a Mean (SD) Median (range) 3.40 ( ) 3.20 ( ) Average pain a Mean (SD) Median (range) 4.40 ( ) 4.60 ( ) Current pain a Mean (SD) Median (range) 5.00 ( ) 5.00 ( ) WPSR VAS: Worst pain since rising visual analog scale (0 100 mm, 0 no pain and 100 excruciating pain) recorded between 8:00 a.m. and 10:00 a.m. BPI: Brief Pain Inventory short form recorded between 8:00 p.m. and 10:00 p.m. a Pain scale: 0 No pain, 10 Worst pain imaginable CRM controlled release morphine MSER morphine sulfate extended release No significant differences between treatments were observed. In comparison to CRM twice daily, oncedaily MSER produced significantly lower mean values of %FI (93% vs. 167%, respectively) and higher mean values of DT50% (18.8 hr vs hr, respectively). The mean value of DT75% following administration of MSER was approximately two times greater than CRM (6.5 hr and Table 4 Treatment-Emergent Adverse Events a Adverse Event (%) CRM Stabilization Period MSER Treatment Period Number of patients with any event 5 (55%) 4 (44%) Dry mouth 2 (22.2%) 1 (11.1%) Rash 1 (11.1%) 1 (11.1%) Nausea 1 (11.1%) 1 (11.1%) Constipation 1 (11.1%) 0 (0.0%) Albuminuria 0 (0.0%) 1 (11.1%) Somnolence 1 (11.1%) 0 (0.0%) Edema 0 (0.0%) 1 (11.1%) Hyperglycemia 0 (0.0%) 1 (11.1%) Insomnia 1 (11.1%) 0 (0.0%) Pain 0 (0.0%) 1 (11.1%) Flatulence 1 (11.1%) 0 (0.0%) Anorexia 1 (11.1%) 0 (0.0%) Sinusitis 0 (0.0%) 1 (11.1%) a If a patient had more than one of the same type of adverse event, that patient is counted once under that event. CRM controlled release morphine MSER morphine sulfate extended release

8 Vol. 23 No. 4 April 2002 PK Comparison of Sustained-Released Morphine Formulations hr, respectively), which approached statistical significance (p 0.09). These data indicate that MSER dosed once daily provides more stable and consistent morphine concentrations over a 24-hr period than does CRM dosed twice-daily. The %FI following CRM twice daily observed in the present study (167%) is similar to earlier findings (160% and 151%, respectively). 8,9 In comparison to another extended-release morphine sulfate formulation administered once daily (Kadian, Kapanol, F.H. Faulding and Co. Ltd., Adelaide, Australia), MSER appears to provide a smaller peak-to-trough fluctuation (FI% 140% vs. 93%, respectively). 10 The metabolites (M3G and M6G) of morphine are pharmacologically active and presumably contribute to clinical effects. As demonstrated in Figure 1, the shapes of the metabolite concentration-time profiles are similar to those of morphine following administration of both MSER and CRM. In comparison to CRM twice daily, once-daily MSER demonstrated statistically significant differences in all PK parameters for M3G and M6G, with the exception of C last and DT75%. The concentration of M3G at the last observation within the 24-hr period was comparable following administration of MSER once daily and CRM twice daily. Although DT75% was longer for the metabolites following administration of MSER than CRM, no statistically significant differences were observed. Recently, a relationship has been described between steady-state morphine concentrations and pain intensity following administration of both once-daily MSER and twice-daily CRM in patients with chronic moderate-to-severe pain. 10 This relationship suggests that less fluctuation in morphine concentrations may lead to more stable clinical effects. For example, end-of-dose failure, which has been identified as a likely cause of breakthrough pain in the cancer population, 11 may be less likely to occur with delivery systems that produce more stable opioid concentrations throughout the day. Larger controlled studies are warranted to determine whether the type of morphine profile obtained with MSER produces more favorable clinical outcomes than the profiles obtained with other extended-release morphine formulations that are associated with greater fluctuation in morphine concentrations. The open-label design and small sample size of the present PK study preclude conclusions about these pharmacodynamic issues. The similarity between CRM and MSER in the safety and efficacy assessments mirrors other larger studies, which have shown that these products have similar effects at equivalent total daily doses in chronic, moderate-to-severe pain. 12,13 However, more detailed pain assessments than those collected in these trials will be needed to determine whether the different plasma profiles yield reliable clinical distinctions. Conclusion Although similar doses of MSER once daily and CRM twice daily provided similar total systemic exposure of morphine, significant differences were observed for many PK parameters. In comparison to CRM twice daily, once-daily MSER approaches maximum concentration quicker, approximates maximum concentration longer, and has a reduced extent of peak-to-trough fluctuation within a 24-hr period. Similar differences between MSER and CRM were observed with the metabolites M3G and M6G. References 1. Joranson DE, Ryan KM, Gilson AM, Dahl JL. Trends in medical use and abuse of opioid analgesics. JAMA 2000;283: Cherny N. New strategies in opioid therapy for cancer pain. J Oncol Manage 2000;9: Portenoy RK. Opioid therapy for chronic nonmalignant pain: clinician s perspective. J Law Med Ethics 1996;24: 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: 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(11 suppl): Eliot L, Loewen G, Butler J, Tembe E, Devane J. Steady-state pharmacokinetic comparison of Morphelan ROER (Morphine Sulfate Rapid Onset Extended Release) once-a-day and morphine oral solution administered q4h around-the-clock in healthy volunteers [abstract 205]. Presented at American Academy of Pain Medicine 17th Annual Meeting, Miami, FL. February 15 18, 2001.

9 300 Portenoy et al. Vol. 23 No. 4 April Gourlay GK. Sustained relief of chronic pain: pharmacokinetics of sustained release morphine. Clin Pharmacokinet 1998;35: Gourlay GK, Plummer JL, Cherry DA, Onley MM. A comparison of Kapanol (a new sustainedrelease morphine formulation), MST Continus, and morphine solution in cancer patients: pharmacokinetics aspects of morphine and morphine metabolites. In: Gebhart GF, Hammond DL, Jensen TS, eds. Progress in pain research and management. Seattle, WA: IASP Press, 1994: Gourlay GK, Cherry DA, Onley MM, Tordoff SG, Conn DA, Hood GM, Plummer JL. Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain. Pain 1997;69: Gastonguay MR, Jackson K, Rauch R, Kenny P, Lazar JD, Vause EW, Butler J, Devane J, Eliot L. Pharmacokinetic-pharmacodynamic relationship of morphine and metabolites after oral administration of Morphelan or MS Contin in patients with chronic, moderate-to-severe pain of non-malignant origin [abstract 781]. Presented at American Pain Society 20th Annual Meeting, Phoenix, AZ. April 19 22, Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990; 41: Davis JC, Offenberg HL, Marker HW, Caldwell JR, Rapoport RJ, Roth SH. Efficacy of a new oncedaily, rapid-onset, extended-release morphine sulfate formulation (Morphelan ROER ) and a twice-daily morphine sulfate controlled-release formulation (MS Contin ) in patients with chronic moderate-to-severe osteoarthritis pain [abstract 791]. Presented at American Pain Society 20th Annual Meeting, Phoenix, AZ. April 19 22, Rauck RK, Garland WT, Douglas MA, et al. Efficacy and tolerability of once-daily Morphelan and twice-daily MS Contin in patients with chronic, moderate-to-severe pain. Submitted.