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The efficacy and safety of buprenorphine transdermal system (BTDS) in subjects with moderate to severe low back pain: a double-blind study
Abstracts (304) Importance of opioid side effects in pain management from patient perspective W Kwong, A Gasik, S Voeller, S Kavanagh, R Gregorian; Johnson and Johnson Pharmaceutical Services, L.L.C., Raritan, NJ Opioids provide efficacious treatment for moderate to severe pain but they are often associated with dose-limiting side effects. This study examined the relative importance of pain relief and opioid side effects in patients’ preferences for pain medication. A total of 618 patients (302 acute pain and 316 chronic pain) who had received scheduled opioids within the past 3 months completed an internet survey related to their experience with opioid medications, including an adaptive conjoint analysis (ACA) experiment. In the ACA experiment, patients reviewed 20 pairs of hypothetical opioid pain medications described by varying levels of two or three of the following attributes: pain relief efficacy (reduction of 1 to 4 points on the 11-point NRS); incidence rates of nausea (15 to 75%), vomiting (5 to 45%), constipation (5 to 35%), drowsiness (5 to 25%) and pruritus (0 to 20%). For each pair of products, patients were asked to state their relative preference for one product over another assuming all other product characteristics were equal. Forty-four percent of patients reported experiencing nausea, 17% for vomiting, 58% for constipation, 76% for drowsiness, and 29% for pruritus from their recent opioid medications. Results of ACA found opioid side effects explained 76% of patient preference and pain relief explained only 24%. Nausea and vomiting were the most important side effects, accounting for 23% and 26% of patient preference, respectively, followed by constipation (12%), pruritus (11%) and drowsiness (4%). Acute and chronic pain patients had similar results. The relative importance of side effects was confirmed in an open-ended question where 51% of patients identified side effect reduction as an unmet need for opioids, with pain relief identified by only 27% patients. Reduction of opioid-related side effects was identified as an important area for the improvement of pain treatment from the patient perspective. (Funded by Johnson & Johnson Pharmaceutical Services, L.L.C.)
(305) The efficacy and safety of buprenorphine transdermal system (BTDS) in subjects with moderate to severe low back pain: a double-blind study D Steiner, C Munera, M Hale, S Ripa, C Landau; Purdue Pharma, L.P., Stamford, CT This multicenter, randomized, double-blind, double-dummy, active comparator, parallel-group study employed an enrichment design. Subjects who demonstrated analgesic benefit and tolerability with BTDS 20 treatment in the run-in period were randomized to receive BTDS 20 q7 days, BTDS 5 q7 days, or OxyIRÒ capsules 40-mg daily (10 mg q6h), and matching placebos in the 12-week double-blind phase. There were 660 male and female adult subjects with chronic low back pain in the full analysis population. Analysis of the primary efficacy variable ‘‘average pain over the last 24 hours’’ scores collected at double-blind weeks 4, 8, and 12 resulted in significant treatment differences for BTDS 20 vs BTDS 5 (P < .001) and for OxyIRÒ vs BTDS 5 (P < .001). Three secondary variables were analyzed using a step-wise gate-keeping approach for multiple comparisons. Subjects randomized to BTDS 20 reported significantly less sleep disturbance (P < .001) and decreased use of supplemental analgesic medication (P = .006) vs BTDS 5. Analyses of OxyIRÒ vs BTDS 5 were not significantly different for any secondary endpoint. 49%, 55%, and 35% of subjects in BTDS 20, OxyIR, Ò and BTDS 5 groups, respectively, demonstrated a 30% improvement in pain. There was 1 death (drowning) in the run-in period, considered unrelated to treatment. The nature and frequency of treatment-emergent adverse events observed (BTDS 5, [58%]; BTDS 20, [77%]; OxyIRÒ, [71%]) were similar for those systemic events expected with opioid agonists and for application site reactions associated with transdermal preparations. Clinical laboratory tests and vital signs did not reveal any apparent safety concerns. This study demonstrated the analgesic efficacy and safety of BTDS 20 for the relief of moderate to severe chronic low back pain. (Funded by Purdue Pharma L.P.)
S51 (306) A randomized, double-blind, placebo- and active-controlled phase III study of tapentadol ER for chronic low back pain: analysis of efficacy endpoint sensitivity M Etropolski, C Rauschkolb-Lo¨ffler, D Shapiro, A Okamoto, C Lange; Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Titusville, NJ This phase III study evaluated the efficacy and safety of tapentadol ER for the relief of moderate-to-severe chronic low back pain over a 3-week titration period and a 12-week maintenance period. Randomized patients received controlled adjustable doses of tapentadol ER (100-250mg), oxycodone HCl CR (20-50mg), or placebo bid. The change from baseline in average pain intensity (PI) at Week 12 of the maintenance period was measured using the last observation carried forward (LOCF) for missing values. Sensitivity analyses to assess the impact of imputation method used baseline observation carried forward (BOCF), worst observation carried forward (WOCF), placebo mean imputation (PMI), and modified BOCF based on the patient’s global impression of change. Of the 981 randomized patients, 965 were evaluable for safety and 958 for efficacy. Compared with placebo, tapentadol ER significantly reduced PI at Week 12 using LOCF (P < 0.001) and all other imputation methods (P = 0.003 or better). Oxycodone CR significantly reduced PI at Week 12 using LOCF (P < 0.001), PMI, and modified BOCF, but not BOCF or WOCF. Significantly higher proportions of patients taking tapentadol ER responded with $30% (P < 0.001) and $50% (P = 0.016) improvements in PI compared with placebo at Week 12. Oxycodone CR did not differ significantly from placebo in the number of patients with $30% or $50% improvements in PI. Oxycodone CR was associated with higher incidences of treatment-emergent adverse events (TEAEs; 84.8%) and discontinuations due to TEAEs (31.7%) than tapentadol ER (75.5% and 16.7%, respectively) or placebo (59.6% and 4.4%). The higher tolerability-related discontinuation rate of oxycodone CR likely impacted sensitivity analyses that more conservatively accounted for discontinuations and the inability to maintain treatment through Week 12. Tapentadol ER effectively relieved chronic low back pain using all imputation methods with an improved tolerability profile. (Study supported by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Gru¨nenthal GmbH.)
(307) An open label study of oxymorphone extended release in patients with chronic neuropathic pain S Nalamachu, A Chhatre, A Reece; International Clinical Research Institute, Overland Park, KS Neuropathic pain (NP), a complex condition with hypoesthesia, allodynia, and hypersensitivity, can develop subsequent to nerve damage and is difficult to treat with substantial negative effects on patient quality of life (QoL). Diabetic neuropathy, postherpetic neuralgia, and neuropathy secondary to chemotherapy are NP conditions. Treatment may require combinations of therapies (antidepressants, antiepileptics, topical anesthetics, opioid analgesics), yet can result in unacceptable adverse events (AEs), including sedation and cognitive dysfunction. A single effective analgesic might decrease the likelihood of AEs and potentially improve QoL. This single-center, open-label, 12-week study is evaluating the efficacy and safety of oxymorphone extended-release (ER) in opioidtolerant NP patients (n = 30). Patients must be aged 18 to 75 years with chronic (>6 months) pain secondary to documented neuropathy; women must use approved birth control. Exclusion criteria include: uncontrolled pain, opioid allergy, alcohol or substance abuse, previous oxymorphone use, medically-significant severe asthma. Breakthrough pain therapies and other medications previously used for NP (excluding long-acting opioids) can continue at the same dose. Oxymorphone ER will be used at the closest lowest dose to patients’ previous opioid therapy. At 2, 4, 8, and 12 weeks, patients complete the Brief Pain Inventory (BPI), Pain Quality Assessment Scale (PQAS), and Sleep Quality Assessment (SQA). Efficacy endpoints are BPI average daily pain intensity (question 5) change from baseline at 12 weeks (primary) and changes from baseline for other questions on the BPI, PQAS, and SQA (secondary). AEs are recorded throughout for onset, severity, outcome, and relationship to treatment. This study is designed to determine if oxymorphone ER will alleviate NP of >6 months duration. Preliminary data suggest that patients tolerated oxymorphone ER well (with no serious AEs), had effective meaningful pain relief, and showed improvement in sleep quality. (Supported by Endo Pharmaceuticals Inc, Chadds Ford, PA.)
(305) The efficacy and safety of buprenorphine transdermal system (BTDS) in subjects with moderate to severe low back pain: a double-blind study D Steiner, C Munera, M Hale, S Ripa, C Landau; Purdue Pharma, L.P., Stamford, CT This multicenter, randomized, double-blind, double-dummy, active comparator, parallel-group study employed an enrichment design. Subjects who demonstrated analgesic benefit and tolerability with BTDS 20 treatment in the run-in period were randomized to receive BTDS 20 q7 days, BTDS 5 q7 days, or OxyIRÒ capsules 40-mg daily (10 mg q6h), and matching placebos in the 12-week double-blind phase. There were 660 male and female adult subjects with chronic low back pain in the full analysis population. Analysis of the primary efficacy variable ‘‘average pain over the last 24 hours’’ scores collected at double-blind weeks 4, 8, and 12 resulted in significant treatment differences for BTDS 20 vs BTDS 5 (P < .001) and for OxyIRÒ vs BTDS 5 (P < .001). Three secondary variables were analyzed using a step-wise gate-keeping approach for multiple comparisons. Subjects randomized to BTDS 20 reported significantly less sleep disturbance (P < .001) and decreased use of supplemental analgesic medication (P = .006) vs BTDS 5. Analyses of OxyIRÒ vs BTDS 5 were not significantly different for any secondary endpoint. 49%, 55%, and 35% of subjects in BTDS 20, OxyIR, Ò and BTDS 5 groups, respectively, demonstrated a 30% improvement in pain. There was 1 death (drowning) in the run-in period, considered unrelated to treatment. The nature and frequency of treatment-emergent adverse events observed (BTDS 5, [58%]; BTDS 20, [77%]; OxyIRÒ, [71%]) were similar for those systemic events expected with opioid agonists and for application site reactions associated with transdermal preparations. Clinical laboratory tests and vital signs did not reveal any apparent safety concerns. This study demonstrated the analgesic efficacy and safety of BTDS 20 for the relief of moderate to severe chronic low back pain. (Funded by Purdue Pharma L.P.)
S51 (306) A randomized, double-blind, placebo- and active-controlled phase III study of tapentadol ER for chronic low back pain: analysis of efficacy endpoint sensitivity M Etropolski, C Rauschkolb-Lo¨ffler, D Shapiro, A Okamoto, C Lange; Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Titusville, NJ This phase III study evaluated the efficacy and safety of tapentadol ER for the relief of moderate-to-severe chronic low back pain over a 3-week titration period and a 12-week maintenance period. Randomized patients received controlled adjustable doses of tapentadol ER (100-250mg), oxycodone HCl CR (20-50mg), or placebo bid. The change from baseline in average pain intensity (PI) at Week 12 of the maintenance period was measured using the last observation carried forward (LOCF) for missing values. Sensitivity analyses to assess the impact of imputation method used baseline observation carried forward (BOCF), worst observation carried forward (WOCF), placebo mean imputation (PMI), and modified BOCF based on the patient’s global impression of change. Of the 981 randomized patients, 965 were evaluable for safety and 958 for efficacy. Compared with placebo, tapentadol ER significantly reduced PI at Week 12 using LOCF (P < 0.001) and all other imputation methods (P = 0.003 or better). Oxycodone CR significantly reduced PI at Week 12 using LOCF (P < 0.001), PMI, and modified BOCF, but not BOCF or WOCF. Significantly higher proportions of patients taking tapentadol ER responded with $30% (P < 0.001) and $50% (P = 0.016) improvements in PI compared with placebo at Week 12. Oxycodone CR did not differ significantly from placebo in the number of patients with $30% or $50% improvements in PI. Oxycodone CR was associated with higher incidences of treatment-emergent adverse events (TEAEs; 84.8%) and discontinuations due to TEAEs (31.7%) than tapentadol ER (75.5% and 16.7%, respectively) or placebo (59.6% and 4.4%). The higher tolerability-related discontinuation rate of oxycodone CR likely impacted sensitivity analyses that more conservatively accounted for discontinuations and the inability to maintain treatment through Week 12. Tapentadol ER effectively relieved chronic low back pain using all imputation methods with an improved tolerability profile. (Study supported by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Gru¨nenthal GmbH.)
(307) An open label study of oxymorphone extended release in patients with chronic neuropathic pain S Nalamachu, A Chhatre, A Reece; International Clinical Research Institute, Overland Park, KS Neuropathic pain (NP), a complex condition with hypoesthesia, allodynia, and hypersensitivity, can develop subsequent to nerve damage and is difficult to treat with substantial negative effects on patient quality of life (QoL). Diabetic neuropathy, postherpetic neuralgia, and neuropathy secondary to chemotherapy are NP conditions. Treatment may require combinations of therapies (antidepressants, antiepileptics, topical anesthetics, opioid analgesics), yet can result in unacceptable adverse events (AEs), including sedation and cognitive dysfunction. A single effective analgesic might decrease the likelihood of AEs and potentially improve QoL. This single-center, open-label, 12-week study is evaluating the efficacy and safety of oxymorphone extended-release (ER) in opioidtolerant NP patients (n = 30). Patients must be aged 18 to 75 years with chronic (>6 months) pain secondary to documented neuropathy; women must use approved birth control. Exclusion criteria include: uncontrolled pain, opioid allergy, alcohol or substance abuse, previous oxymorphone use, medically-significant severe asthma. Breakthrough pain therapies and other medications previously used for NP (excluding long-acting opioids) can continue at the same dose. Oxymorphone ER will be used at the closest lowest dose to patients’ previous opioid therapy. At 2, 4, 8, and 12 weeks, patients complete the Brief Pain Inventory (BPI), Pain Quality Assessment Scale (PQAS), and Sleep Quality Assessment (SQA). Efficacy endpoints are BPI average daily pain intensity (question 5) change from baseline at 12 weeks (primary) and changes from baseline for other questions on the BPI, PQAS, and SQA (secondary). AEs are recorded throughout for onset, severity, outcome, and relationship to treatment. This study is designed to determine if oxymorphone ER will alleviate NP of >6 months duration. Preliminary data suggest that patients tolerated oxymorphone ER well (with no serious AEs), had effective meaningful pain relief, and showed improvement in sleep quality. (Supported by Endo Pharmaceuticals Inc, Chadds Ford, PA.)