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A post hoc pooled data analysis to evaluate blood pressure (BP) and heart rate (HR) measurements in patients with a current or prior history of hypertension who received tapentadol ER, oxycodone CR, or placebo in chronic pain studies
Abstracts (316) Antinociceptive sodium channel extended duration of action
The Journal of Pain inhibitors
having
J Mulcahy, D Behera, B Andresen, G Miljanich, D Yeomans, S Biswal, and J Du Bois; SiteOne Therapeutics, Redwood City, CA Existing treatment options for pain, such as the opioids, are not always effective and suffer from a wide range of side effects including potential for addiction. Saxitoxin (STX) is a highly potent naturally occurring sodium channel inhibitor that has been successfully employed in human clinical trials on >100 subjects for pain and certain neurological disorders. We hypothesized that our ability to prepare STX through de novo chemical synthesis would make possible the construction of modified forms of this compound having unique pharmacologic properties. Novel STXs were synthesized, characterized by patch clamp electrophysiology, and administered by local injection to the footpad of male Sprague Dawley rats. Antinociceptive efficacy and duration of action were measured through a variety of behavioral assays. Using this strategy, we have identified a STX derivative that provides up to six days of local analgesia in a rat nociception assay. We continue to evaluate the ADMET properties of our initial STX lead compounds through animal behavioral and radiological studies, and expect that such information will help guide the development of a STX-based therapeutic that offers improved efficacy and reduced side effects compared to existing treatment options for moderate to severe pain.
(317) Efficacy and safety of intravenous tanezumab in osteoarthritis hip and knee pain: comparison to placebo and naproxen in two phase III studies (NCT00830063 & NCT00863304) E Ekman, J Gimbel, A Bello, M Smith, D Keller, K Annis, M Brown, C West, and K Verburg; Pfizer, Inc., New London, CT Two placebo- and naproxen (500mg BID)-controlled multicenter studies evaluated efficacy and safety of tanezumab (5mg or 10mg intravenous, given at Weeks 0 and 8), a monoclonal antibody that inhibits nerve growth factor, in patients with moderate-to-severe knee or hip osteoarthritis. Efficacy was assessed at Week 16 with 3 co-primary endpoints (Western Ontario & McMaster Universities OA Index [WOMAC] Pain, WOMAC Physical Function, and Patient Global Assessment [PGA] of OA). To account for multiple comparisons, fixed sequence testing and Hochberg procedures required that the assessment of superiority for tanezumab 5 mg versus naproxen was dependent on first achieving superiority for all comparisons of tanezumab 5 mg and 10 mg versus placebo and tanezumab 10 mg versus naproxen. Tanezumab 5mg and 10mg provided superior efficacy versus placebo for all co-primary endpoints in both studies (P#0.014). Overall, 9 of 12 contrasts for tanezumab versus naproxen were statistically significant including tanezumab 5mg versus naproxen across all coprimary endpoints in both studies; however, only comparisons in WOMAC Physical Function were declared superior to naproxen with tanezumab 5mg for both studies since tanezumab 10mg failed to show consistent superiority over naproxen in WOMAC Pain & PGA. Adverse events (AEs) and withdrawals due to AEs were more common with active treatments than placebo; rates of serious AEs were similar across treatments. The most frequent AEs ($5% in any active group) were arthralgia, pain in extremity, paresthesia, and peripheral edema. Tanezumab 5mg was better tolerated than tanezumab 10mg in both studies. Six patients (4 placebo, 1 tanezumab 5mg, 1 naproxen) required total joint replacements (TJRs). The tanezumab OA clinical program is currently on clinical hold due to potential AEs leading to TJRs. In conclusion, these studies indicate tanezumab is efficacious in treating osteoarthritis pain and may provide patients greater symptomatic improvement than existing agents such as naproxen.
P55
(318) Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT; EMBEDAâ), when crushed and injected, mitigate morphine-induced respiratory depression L Webster, V Goli, M Lamson, and E Carter; Lifetree Clinical Researchâ and Pain Clinic, Salt Lake City, UT Opioid-induced respiratory depression remains a major public health concern. With half of all drug-related deaths due to prescription drug abuse/misuse, respiratory depression is the leading cause of death following a lethal opioid dose. Morphine can induce respiratory depression which may become fatal within 3 hours of an overdose; however, it may be reversed by the timely administration of an opioid antagonist. Unfortunately, timely intervention is not always available. Morphine is often abused intravenously where respiratory depression can occur in minutes. Tampering with morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT; EMBEDAâ), a unique extended-release morphine formulation with a sequestered naltrexone core, releases both morphine and naltrexone. When both drugs are administered intravenously, naltrexone abates morphine-induced euphoric effects. To our knowledge, the effects on morphine-induced respiratory depression of intravenous administration of morphine and naltrexone in the fixed 25:1 ratio found in MS-sNT have not been previously reported. Results of a singledose, 3-way crossover study in 28 opioid-experienced, non-dependent men indicated that naltrexone HCl 1.2mg administered intravenously in combination with morphine sulfate 30mg significantly diminished morphine-induced respiratory depression compared with intravenous morphine sulfate 30mg administered alone or normal saline (placebo). Exploratory analyses of End-tidal CO2 (EtCO2) detected statistically significant differences in LS means across all treatment groups for Emax and partial AUEs (p<0.0001). No difference was detected between the combination morphine + naltrexone and placebo groups in EtCO2 levels (p=0.3064), which emphasized naltrexone’s pharmacodynamic effect of morphine displacement on the m-opioid receptor. Results suggest that abuse of Embedaâ by extraction and injection may not only abate morphine drug-liking and euphoria but could also mitigate the risk of potentially fatal morphineinduced respiratory depression. The uniqueness of this finding is that the harm reduction potential is already built into the medicine. Supported by King Pharmaceuticalsâ, Inc.
(319) A post hoc pooled data analysis to evaluate blood pressure (BP) and heart rate (HR) measurements in patients with a current or prior history of hypertension who received tapentadol ER, oxycodone CR, or placebo in chronic pain studies D Biondi, J Xiang, M Etropolski, and B Moskovitz; Ortho-McNeil Janssen Scientific Affairs LLC, Raritan, NJ Tapentadol is a centrally-acting analgesic with m-opioid receptor agonist and norepinephrine reuptake inhibitor activity. An analysis of pooled data from 3 similarly-designed 15-week, randomized, double-blind, placebo- and activecontrolled, phase 3 studies of tapentadol ER for moderate-to-severe chronic osteoarthritis knee pain (NCT00421928, NCT00486811) or low back pain (NCT00449176) found no clinically relevant changes in mean BP or HR measurements with placebo (n=946), tapentadol ER (100-250mg bid; n=920), or oxycodone HCl CR (20-50mg bid; n=831). This post-hoc analysis of those pooled data evaluated systolic BP (SBP), diastolic BP (DBP), and HR in 2 cohorts—patients with a medical history of hypertension and patients with a concomitant antihypertensive medication. In patients with a history of hypertension, the least squares mean (LSM [SE]) change from baseline to endpoint in BP and HR with placebo (n=459), tapentadol ER (n=462), and oxycodone CR (n=413), respectively, was SBP, 2.4 (0.64), 2.7 (0.64), and 3.7 (0.67) mmHg; DBP, 1.0 (0.39), 1.3 (0.39), and 2.3 (0.41) mmHg; HR, 0.7 (0.44), 0.2 (0.43), and 0.9 (0.45) beats-per-minute (bpm). In patients with a concomitant anti-hypertensive medication, the LSM (SE) change from baseline to endpoint in BP and HR with placebo (n=429), tapentadol ER (n=434), and oxycodone CR (n=387), respectively, was SBP, 1.8 (0.66), 3.3 (0.65), and 3.7 (0.69) mmHg; DBP, 0.7 (0.40), 1.4 (0.40), and 2.3 (0.42) mmHg; HR, 0.6 (0.45), 0.1 (0.44), and 0.7 (0.47) bpm. There were no significant differences between tapentadol ER and placebo or oxycodone CR in the LSM changes from baseline to endpoint in SBP, DBP, or HR. These results showed no clinically relevant changes in BP or HR with tapentadol ER (100-250mg bid) or oxycodone HCl CR (20-50mg bid) and suggest that tapentadol ER is a reasonable treatment option for chronic pain management in patients with hypertension. Ortho-McNeil Janssen Scientific Affairs, LLC, supported this analysis.
The Journal of Pain inhibitors
having
J Mulcahy, D Behera, B Andresen, G Miljanich, D Yeomans, S Biswal, and J Du Bois; SiteOne Therapeutics, Redwood City, CA Existing treatment options for pain, such as the opioids, are not always effective and suffer from a wide range of side effects including potential for addiction. Saxitoxin (STX) is a highly potent naturally occurring sodium channel inhibitor that has been successfully employed in human clinical trials on >100 subjects for pain and certain neurological disorders. We hypothesized that our ability to prepare STX through de novo chemical synthesis would make possible the construction of modified forms of this compound having unique pharmacologic properties. Novel STXs were synthesized, characterized by patch clamp electrophysiology, and administered by local injection to the footpad of male Sprague Dawley rats. Antinociceptive efficacy and duration of action were measured through a variety of behavioral assays. Using this strategy, we have identified a STX derivative that provides up to six days of local analgesia in a rat nociception assay. We continue to evaluate the ADMET properties of our initial STX lead compounds through animal behavioral and radiological studies, and expect that such information will help guide the development of a STX-based therapeutic that offers improved efficacy and reduced side effects compared to existing treatment options for moderate to severe pain.
(317) Efficacy and safety of intravenous tanezumab in osteoarthritis hip and knee pain: comparison to placebo and naproxen in two phase III studies (NCT00830063 & NCT00863304) E Ekman, J Gimbel, A Bello, M Smith, D Keller, K Annis, M Brown, C West, and K Verburg; Pfizer, Inc., New London, CT Two placebo- and naproxen (500mg BID)-controlled multicenter studies evaluated efficacy and safety of tanezumab (5mg or 10mg intravenous, given at Weeks 0 and 8), a monoclonal antibody that inhibits nerve growth factor, in patients with moderate-to-severe knee or hip osteoarthritis. Efficacy was assessed at Week 16 with 3 co-primary endpoints (Western Ontario & McMaster Universities OA Index [WOMAC] Pain, WOMAC Physical Function, and Patient Global Assessment [PGA] of OA). To account for multiple comparisons, fixed sequence testing and Hochberg procedures required that the assessment of superiority for tanezumab 5 mg versus naproxen was dependent on first achieving superiority for all comparisons of tanezumab 5 mg and 10 mg versus placebo and tanezumab 10 mg versus naproxen. Tanezumab 5mg and 10mg provided superior efficacy versus placebo for all co-primary endpoints in both studies (P#0.014). Overall, 9 of 12 contrasts for tanezumab versus naproxen were statistically significant including tanezumab 5mg versus naproxen across all coprimary endpoints in both studies; however, only comparisons in WOMAC Physical Function were declared superior to naproxen with tanezumab 5mg for both studies since tanezumab 10mg failed to show consistent superiority over naproxen in WOMAC Pain & PGA. Adverse events (AEs) and withdrawals due to AEs were more common with active treatments than placebo; rates of serious AEs were similar across treatments. The most frequent AEs ($5% in any active group) were arthralgia, pain in extremity, paresthesia, and peripheral edema. Tanezumab 5mg was better tolerated than tanezumab 10mg in both studies. Six patients (4 placebo, 1 tanezumab 5mg, 1 naproxen) required total joint replacements (TJRs). The tanezumab OA clinical program is currently on clinical hold due to potential AEs leading to TJRs. In conclusion, these studies indicate tanezumab is efficacious in treating osteoarthritis pain and may provide patients greater symptomatic improvement than existing agents such as naproxen.
P55
(318) Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT; EMBEDAâ), when crushed and injected, mitigate morphine-induced respiratory depression L Webster, V Goli, M Lamson, and E Carter; Lifetree Clinical Researchâ and Pain Clinic, Salt Lake City, UT Opioid-induced respiratory depression remains a major public health concern. With half of all drug-related deaths due to prescription drug abuse/misuse, respiratory depression is the leading cause of death following a lethal opioid dose. Morphine can induce respiratory depression which may become fatal within 3 hours of an overdose; however, it may be reversed by the timely administration of an opioid antagonist. Unfortunately, timely intervention is not always available. Morphine is often abused intravenously where respiratory depression can occur in minutes. Tampering with morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT; EMBEDAâ), a unique extended-release morphine formulation with a sequestered naltrexone core, releases both morphine and naltrexone. When both drugs are administered intravenously, naltrexone abates morphine-induced euphoric effects. To our knowledge, the effects on morphine-induced respiratory depression of intravenous administration of morphine and naltrexone in the fixed 25:1 ratio found in MS-sNT have not been previously reported. Results of a singledose, 3-way crossover study in 28 opioid-experienced, non-dependent men indicated that naltrexone HCl 1.2mg administered intravenously in combination with morphine sulfate 30mg significantly diminished morphine-induced respiratory depression compared with intravenous morphine sulfate 30mg administered alone or normal saline (placebo). Exploratory analyses of End-tidal CO2 (EtCO2) detected statistically significant differences in LS means across all treatment groups for Emax and partial AUEs (p<0.0001). No difference was detected between the combination morphine + naltrexone and placebo groups in EtCO2 levels (p=0.3064), which emphasized naltrexone’s pharmacodynamic effect of morphine displacement on the m-opioid receptor. Results suggest that abuse of Embedaâ by extraction and injection may not only abate morphine drug-liking and euphoria but could also mitigate the risk of potentially fatal morphineinduced respiratory depression. The uniqueness of this finding is that the harm reduction potential is already built into the medicine. Supported by King Pharmaceuticalsâ, Inc.
(319) A post hoc pooled data analysis to evaluate blood pressure (BP) and heart rate (HR) measurements in patients with a current or prior history of hypertension who received tapentadol ER, oxycodone CR, or placebo in chronic pain studies D Biondi, J Xiang, M Etropolski, and B Moskovitz; Ortho-McNeil Janssen Scientific Affairs LLC, Raritan, NJ Tapentadol is a centrally-acting analgesic with m-opioid receptor agonist and norepinephrine reuptake inhibitor activity. An analysis of pooled data from 3 similarly-designed 15-week, randomized, double-blind, placebo- and activecontrolled, phase 3 studies of tapentadol ER for moderate-to-severe chronic osteoarthritis knee pain (NCT00421928, NCT00486811) or low back pain (NCT00449176) found no clinically relevant changes in mean BP or HR measurements with placebo (n=946), tapentadol ER (100-250mg bid; n=920), or oxycodone HCl CR (20-50mg bid; n=831). This post-hoc analysis of those pooled data evaluated systolic BP (SBP), diastolic BP (DBP), and HR in 2 cohorts—patients with a medical history of hypertension and patients with a concomitant antihypertensive medication. In patients with a history of hypertension, the least squares mean (LSM [SE]) change from baseline to endpoint in BP and HR with placebo (n=459), tapentadol ER (n=462), and oxycodone CR (n=413), respectively, was SBP, 2.4 (0.64), 2.7 (0.64), and 3.7 (0.67) mmHg; DBP, 1.0 (0.39), 1.3 (0.39), and 2.3 (0.41) mmHg; HR, 0.7 (0.44), 0.2 (0.43), and 0.9 (0.45) beats-per-minute (bpm). In patients with a concomitant anti-hypertensive medication, the LSM (SE) change from baseline to endpoint in BP and HR with placebo (n=429), tapentadol ER (n=434), and oxycodone CR (n=387), respectively, was SBP, 1.8 (0.66), 3.3 (0.65), and 3.7 (0.69) mmHg; DBP, 0.7 (0.40), 1.4 (0.40), and 2.3 (0.42) mmHg; HR, 0.6 (0.45), 0.1 (0.44), and 0.7 (0.47) bpm. There were no significant differences between tapentadol ER and placebo or oxycodone CR in the LSM changes from baseline to endpoint in SBP, DBP, or HR. These results showed no clinically relevant changes in BP or HR with tapentadol ER (100-250mg bid) or oxycodone HCl CR (20-50mg bid) and suggest that tapentadol ER is a reasonable treatment option for chronic pain management in patients with hypertension. Ortho-McNeil Janssen Scientific Affairs, LLC, supported this analysis.