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A post hoc pooled data analysis to evaluate the gastrointestinal tolerability profile of tapentadol extended release (ER) versus oxycodone controlled release (CR) in patients ≥75 years of age
P56
Abstracts
The Journal of Pain
(320) A post hoc pooled data analysis to evaluate the gastrointestinal tolerability profile of tapentadol extended release (ER) versus oxycodone controlled release (CR) in patients $75 years of age D Biondi, J Xiang, M Etropolski, and B Moskovitz; Ortho-McNeil Janssen Scientific Affairs LLC, Raritan, NJ This post-hoc analysis evaluated analgesic efficacy and tolerability of tapentadol ER (100-250 mg bid) versus oxycodone HCl CR (20-50 mg bid) in patients $75 years of age (tapentadol ER, n=72; oxycodone CR, n=78) using pooled data from 3 similarly-designed 15-week, randomized, double-blind, placeboand active-controlled, phase 3 studies of tapentadol ER for moderate-to-severe chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain. Analgesic efficacy was determined by the change in pain intensity (11-point numerical rating scale). Times to initial onset of gastrointestinal TEAEs and time to study discontinuation due to these TEAEs were estimated using Kaplan-Meier plots. No significant between-treatment difference in the least-squares mean (SEM) change in pain intensity from baseline to Week 15 was observed (tapentadol ER, 3.66[0.44]; oxycodone CR, 4.02[0.54]; P=0.604). Significantly lower percentages of patients who received tapentadol ER versus oxycodone CR reported gastrointestinal TEAEs (51.4% vs 71.8%; P=0.0119) and study discontinuations due to gastrointestinal TEAEs (16.7% vs 42.3%; P=0.0007). Times to initial onsets of nausea, vomiting, and constipation and times to study discontinuation due to nausea and vomiting occurred later with tapentadol ER versus oxycodone CR (all P#0.0388; time to discontinuation due to constipation, P=0.4685). Patients experienced the following common opioid-related gastrointestinal TEAEs for lower mean percentages of study days with tapentadol ER versus oxycodone CR, respectively: nausea, 10.2% versus 20.2%, P=0.0621; vomiting, 1.6% versus 9.1%, P=0.0008; constipation, 12.0% versus 24.8%, P=0.1144. Severity ratings of the common opioid-related gastrointestinal TEAEs (nausea, vomiting, constipation, and nausea and/or vomiting) were generally lower with tapentadol ER versus oxycodone CR. Tapentadol ER (100-250 mg bid) was associated with comparable analgesia and better gastrointestinal tolerability than oxycodone HCl CR (20-50 mg bid), including lower incidences of gastrointestinal TEAEs and study discontinuation due to gastrointestinal TEAEs, in patients $75 years of age. Ortho-McNeil Janssen Scientific Affairs, LLC, supported this analysis.
(322) A qualitative comparison of diclofenac potassium soft gelatin capsules (DPSGC, Zipsorâ) to other analgesics in the treatment of acute pain following bunionectomy S Daniels, A Rubin, E Kinzler, and G Shangold; Xanodyne Pharmaceuticals Inc., Newport, KY Results of two phase 3 DPSGC (25mg Zipsorâ diclofenac potassium Liquid Filled Capsules) studies were compared with data from other double-blind, placebocontrolled, randomized trials of oral analgesics utilizing the postbunionectomy acute pain model. The validity of this comparative approach is supported by 1) consistent pain associated with bunionectomy, 2) consistent postsurgical anesthetic regimens, and 3) similar pain assessments allowing for at least a qualitative comparison of analgesia for acute pain. Previously published (prior to October 2009) bunionectomy clinical trial data were identified. Eleven trials with similar study designs and analysis were compared. To minimize the impact of rescue medication use and/or variable duration of multi-dose therapy, nearly identical efficacy assessments following the first dose of study medication were evaluated. Patient demographics were comparable across all trials; intensity of baseline pain was somewhat greater in Zipsor studies. Qualitative assessment of placebo-adjusted total pain relief scores over 8 hours (TOTPAR8) suggest that Zipsor’s efficacy was at least comparable to tapentadol 200mg, morphine 60mg, ibuprofen 400mg, and rofecoxib 50mg. Approximately 45% of Zipsortreated patients received rescue medications on Study Day 1; a greater proportion of patients (68% to 94%) reported rescue medication use when receiving other analgesics. Nearly 85% of patients rated Zipsor as ‘‘good/ very good/excellent’’; this satisfaction level is much higher than that reported for most other analgesics. Overall, these evaluations suggest that low-dose Zipsor’s efficacy and patient satisfaction may be considered at least comparable to other commonly-prescribed analgesics for the treatment of mild to moderate acute pain, including both NSAIDs and opioids. Supported by Xanodyne Pharmaceuticals, Inc.
F14 NSAIDS and Acetaminophen
F15 Opioids - Clinical Pharmacology
(321) Pharmacokinetic and pharmacodynamic interaction between furosemide and the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen
(323) Design of a prospective comparative effectiveness research model for interventions used in chronic pain management
D Jacobs, C Paterson, S Rasmussen, S Youngberg, and N McGuinness; King Pharmaceuticals, Bridgewater, NJ
C Inturrisi and S Horn; Weill Cornell Medical College, New York, NY
Nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt anti-hypertensive effects and alter renal-function of loop-diuretics.1,2 An open-label study in healthy volunteers (N=40) compared the pharmacokinetic/pharmacodynamic (PK/PD) profiles of furosemide administered intravenously (IV) alone (20mg/ 2min) vs after oral ibuprofen (800mg TID), oral diclofenac sodium (75mg BID), or topical diclofenac epolamine topical patch 1.3% (DETP) BID.3 Dextrose (5% in water) administered IV at 2mL/2min served as negative control. NSAIDs were administered for 3 days followed by 20mg furosemide IV on day-4. Plasma furosemide and NSAID, and urine furosemide, sodium, potassium, and prostaglandin E2 (PGE2) concentrations were measured at multiple intervals through 24h after furosemide-dose. Interactions between NSAIDs and furosemide vs furosemide alone were concluded if 90% confidence intervals (CIs) for ratios of PK/PD measures fell outside 80%-125%. Ibuprofen yielded greater furosemide systemic-exposure (AUC0-t, % mean ratio 137.2 [CIs 131.7-143.0]; AUCinf, 136.1 [131.2-141.1]), and decreased total body-clearance (CL 73.5 [70.9-76.2]), renalclearance (CLR 76.6 [72.4-81.1]), and maximum excretion-rate (Rmax 81.3 [76.786.1]). Ibuprofen increased urine sodium-excretion (Ae0-24) and decreased Rmax (p<0.01); mean ratios and 90% CI ranges supported an interactive effect with furosemide. Oral diclofenac sodium and DETP had no clinically significant effect on furosemide PK. Oral diclofenac sodium decreased urine-output (14%, p=0.005; Vu0-24 84.7 [76.9-93.2]). DETP did not affect furosemide PD in any clinically significant manner. Urine PGE2 concentrations fell below the level of quantification (30pg/mL) following furosemide-administration. At steadystate, systemic-exposure to diclofenac after DETP was <1% vs oral diclofenac sodium (16.0 vs 2164 ngh/mL). Overall, oral ibuprofen affected furosemide PK and PD; oral diclofenac sodium affected PD; and DETP did not affect PK or PD in healthy subjects. Additional drug-interaction studies between NSAIDs and loop-diuretics are needed to identify interactions and determine clinical significance. Research supported by King Pharmaceuticalsâ, Inc. (1. Brater, € ller, Eur J Clin Pharmacol, 1995; 3. Flector Patch Am J Medicine, 1986; 2. Mu PI, 2009).
Chronic pain is a growing problem of immense proportions in terms of patient suffering and cost. The limited ability of available randomized controlled trials to provide an adequate evidence base for long term management of chronic pain demands the implementation new models for chronic pain research. Comparative effectiveness research (CER) measures outcomes of interventions under ‘‘real world’’ conditions in unselected clinical populations. We describe our approach to the design of a prospective CER study in chronic pain patients at 4 hospital based outpatient pain clinics in NYC (1 each at Weill Cornell Medical College and Hospital for Special Surgery and 2 at the Memorial Sloan-Kettering Cancer Center). The CER model we use is Practice Based Evidence. It requires the acquisition of information on patient Process Factors (eg. Medications and Interventions), and Patient Factors (eg. Diagnoses, Demographics, Medical details, Histories) that can be obtained as discrete elements from electronic medical records or by abstraction by data collectors. Patient Factors include the Comprehensive Severity Index (CSI), which captures each patient’s co-morbidities and severity of illness. CSI is used to adjust the risk associated with each patient’s illness and balance confounding by indication bias that can drive real-life clinical decisions about interventions. The third component of PBE is Outcome Measures (eg. Pain and Other Symptoms, Function, Health Status, Aberrant Behaviors, and Cost Effectiveness) that are used to assess comparative patient benefits and risks. PBE requires input of point of care clinicians at each step, an information systems work plan to capture essential patient, process, and outcome measures, and patient cooperation to complete self report surveys. The analysis uses appropriate statistical methods to decrease biases generally associated with observational research and to determine interventions associated with better outcomes for specific types of patients. Supported by DA028928.
Abstracts
The Journal of Pain
(320) A post hoc pooled data analysis to evaluate the gastrointestinal tolerability profile of tapentadol extended release (ER) versus oxycodone controlled release (CR) in patients $75 years of age D Biondi, J Xiang, M Etropolski, and B Moskovitz; Ortho-McNeil Janssen Scientific Affairs LLC, Raritan, NJ This post-hoc analysis evaluated analgesic efficacy and tolerability of tapentadol ER (100-250 mg bid) versus oxycodone HCl CR (20-50 mg bid) in patients $75 years of age (tapentadol ER, n=72; oxycodone CR, n=78) using pooled data from 3 similarly-designed 15-week, randomized, double-blind, placeboand active-controlled, phase 3 studies of tapentadol ER for moderate-to-severe chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain. Analgesic efficacy was determined by the change in pain intensity (11-point numerical rating scale). Times to initial onset of gastrointestinal TEAEs and time to study discontinuation due to these TEAEs were estimated using Kaplan-Meier plots. No significant between-treatment difference in the least-squares mean (SEM) change in pain intensity from baseline to Week 15 was observed (tapentadol ER, 3.66[0.44]; oxycodone CR, 4.02[0.54]; P=0.604). Significantly lower percentages of patients who received tapentadol ER versus oxycodone CR reported gastrointestinal TEAEs (51.4% vs 71.8%; P=0.0119) and study discontinuations due to gastrointestinal TEAEs (16.7% vs 42.3%; P=0.0007). Times to initial onsets of nausea, vomiting, and constipation and times to study discontinuation due to nausea and vomiting occurred later with tapentadol ER versus oxycodone CR (all P#0.0388; time to discontinuation due to constipation, P=0.4685). Patients experienced the following common opioid-related gastrointestinal TEAEs for lower mean percentages of study days with tapentadol ER versus oxycodone CR, respectively: nausea, 10.2% versus 20.2%, P=0.0621; vomiting, 1.6% versus 9.1%, P=0.0008; constipation, 12.0% versus 24.8%, P=0.1144. Severity ratings of the common opioid-related gastrointestinal TEAEs (nausea, vomiting, constipation, and nausea and/or vomiting) were generally lower with tapentadol ER versus oxycodone CR. Tapentadol ER (100-250 mg bid) was associated with comparable analgesia and better gastrointestinal tolerability than oxycodone HCl CR (20-50 mg bid), including lower incidences of gastrointestinal TEAEs and study discontinuation due to gastrointestinal TEAEs, in patients $75 years of age. Ortho-McNeil Janssen Scientific Affairs, LLC, supported this analysis.
(322) A qualitative comparison of diclofenac potassium soft gelatin capsules (DPSGC, Zipsorâ) to other analgesics in the treatment of acute pain following bunionectomy S Daniels, A Rubin, E Kinzler, and G Shangold; Xanodyne Pharmaceuticals Inc., Newport, KY Results of two phase 3 DPSGC (25mg Zipsorâ diclofenac potassium Liquid Filled Capsules) studies were compared with data from other double-blind, placebocontrolled, randomized trials of oral analgesics utilizing the postbunionectomy acute pain model. The validity of this comparative approach is supported by 1) consistent pain associated with bunionectomy, 2) consistent postsurgical anesthetic regimens, and 3) similar pain assessments allowing for at least a qualitative comparison of analgesia for acute pain. Previously published (prior to October 2009) bunionectomy clinical trial data were identified. Eleven trials with similar study designs and analysis were compared. To minimize the impact of rescue medication use and/or variable duration of multi-dose therapy, nearly identical efficacy assessments following the first dose of study medication were evaluated. Patient demographics were comparable across all trials; intensity of baseline pain was somewhat greater in Zipsor studies. Qualitative assessment of placebo-adjusted total pain relief scores over 8 hours (TOTPAR8) suggest that Zipsor’s efficacy was at least comparable to tapentadol 200mg, morphine 60mg, ibuprofen 400mg, and rofecoxib 50mg. Approximately 45% of Zipsortreated patients received rescue medications on Study Day 1; a greater proportion of patients (68% to 94%) reported rescue medication use when receiving other analgesics. Nearly 85% of patients rated Zipsor as ‘‘good/ very good/excellent’’; this satisfaction level is much higher than that reported for most other analgesics. Overall, these evaluations suggest that low-dose Zipsor’s efficacy and patient satisfaction may be considered at least comparable to other commonly-prescribed analgesics for the treatment of mild to moderate acute pain, including both NSAIDs and opioids. Supported by Xanodyne Pharmaceuticals, Inc.
F14 NSAIDS and Acetaminophen
F15 Opioids - Clinical Pharmacology
(321) Pharmacokinetic and pharmacodynamic interaction between furosemide and the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen
(323) Design of a prospective comparative effectiveness research model for interventions used in chronic pain management
D Jacobs, C Paterson, S Rasmussen, S Youngberg, and N McGuinness; King Pharmaceuticals, Bridgewater, NJ
C Inturrisi and S Horn; Weill Cornell Medical College, New York, NY
Nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt anti-hypertensive effects and alter renal-function of loop-diuretics.1,2 An open-label study in healthy volunteers (N=40) compared the pharmacokinetic/pharmacodynamic (PK/PD) profiles of furosemide administered intravenously (IV) alone (20mg/ 2min) vs after oral ibuprofen (800mg TID), oral diclofenac sodium (75mg BID), or topical diclofenac epolamine topical patch 1.3% (DETP) BID.3 Dextrose (5% in water) administered IV at 2mL/2min served as negative control. NSAIDs were administered for 3 days followed by 20mg furosemide IV on day-4. Plasma furosemide and NSAID, and urine furosemide, sodium, potassium, and prostaglandin E2 (PGE2) concentrations were measured at multiple intervals through 24h after furosemide-dose. Interactions between NSAIDs and furosemide vs furosemide alone were concluded if 90% confidence intervals (CIs) for ratios of PK/PD measures fell outside 80%-125%. Ibuprofen yielded greater furosemide systemic-exposure (AUC0-t, % mean ratio 137.2 [CIs 131.7-143.0]; AUCinf, 136.1 [131.2-141.1]), and decreased total body-clearance (CL 73.5 [70.9-76.2]), renalclearance (CLR 76.6 [72.4-81.1]), and maximum excretion-rate (Rmax 81.3 [76.786.1]). Ibuprofen increased urine sodium-excretion (Ae0-24) and decreased Rmax (p<0.01); mean ratios and 90% CI ranges supported an interactive effect with furosemide. Oral diclofenac sodium and DETP had no clinically significant effect on furosemide PK. Oral diclofenac sodium decreased urine-output (14%, p=0.005; Vu0-24 84.7 [76.9-93.2]). DETP did not affect furosemide PD in any clinically significant manner. Urine PGE2 concentrations fell below the level of quantification (30pg/mL) following furosemide-administration. At steadystate, systemic-exposure to diclofenac after DETP was <1% vs oral diclofenac sodium (16.0 vs 2164 ngh/mL). Overall, oral ibuprofen affected furosemide PK and PD; oral diclofenac sodium affected PD; and DETP did not affect PK or PD in healthy subjects. Additional drug-interaction studies between NSAIDs and loop-diuretics are needed to identify interactions and determine clinical significance. Research supported by King Pharmaceuticalsâ, Inc. (1. Brater, € ller, Eur J Clin Pharmacol, 1995; 3. Flector Patch Am J Medicine, 1986; 2. Mu PI, 2009).
Chronic pain is a growing problem of immense proportions in terms of patient suffering and cost. The limited ability of available randomized controlled trials to provide an adequate evidence base for long term management of chronic pain demands the implementation new models for chronic pain research. Comparative effectiveness research (CER) measures outcomes of interventions under ‘‘real world’’ conditions in unselected clinical populations. We describe our approach to the design of a prospective CER study in chronic pain patients at 4 hospital based outpatient pain clinics in NYC (1 each at Weill Cornell Medical College and Hospital for Special Surgery and 2 at the Memorial Sloan-Kettering Cancer Center). The CER model we use is Practice Based Evidence. It requires the acquisition of information on patient Process Factors (eg. Medications and Interventions), and Patient Factors (eg. Diagnoses, Demographics, Medical details, Histories) that can be obtained as discrete elements from electronic medical records or by abstraction by data collectors. Patient Factors include the Comprehensive Severity Index (CSI), which captures each patient’s co-morbidities and severity of illness. CSI is used to adjust the risk associated with each patient’s illness and balance confounding by indication bias that can drive real-life clinical decisions about interventions. The third component of PBE is Outcome Measures (eg. Pain and Other Symptoms, Function, Health Status, Aberrant Behaviors, and Cost Effectiveness) that are used to assess comparative patient benefits and risks. PBE requires input of point of care clinicians at each step, an information systems work plan to capture essential patient, process, and outcome measures, and patient cooperation to complete self report surveys. The analysis uses appropriate statistical methods to decrease biases generally associated with observational research and to determine interventions associated with better outcomes for specific types of patients. Supported by DA028928.