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Cancer pain: opioids
48 (756) Duloxetine at doses of 60 mg QD and 60 mg BID is effective in treatment of diabetic neuropathic pain (DNP) J. Wernicke, Y. Lu, D. D‘Souza, A. Waninger, P. Tran; Eli Lilly and Company, Indianapolis, IN Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. This study assessed the efficacy of duloxetine, a potent, selective, and balanced inhibitor of 5-HT and NE reuptake, on the reduction of pain severity, in patients with DNP. Patients with DNP and without comorbid depression were randomized to treatment with duloxetine 60 mg QD, 60 mg BID, or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures included night and 24-hour worst pain severity, Brief Pain Inventory (BPI), Clinical Global Impression of Severity (CGI-Severity), Patient Global Impression of Improvement (PGI-Improvement), Short-form McGill Pain Questionnaire, Dynamic Allodynia, and Average Daily Intake of Acetaminophen. Duloxetine 60 mg QD and 60 mg BID demonstrated significant improvement in the treatment of DNP and showed rapid onset of action, with separation from placebo occurring at week one on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed superiority of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Reduction in 24-hour average pain severity was caused by direct treatment effect. CGI and PGI evaluation also demonstrated greater improvement on duloxetine- versus placebotreated patients. Duloxetine showed no notable interference on diabetic control, and both doses were safely administered and well tolerated. This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is safe and effective in treating DNP.
Abstracts
D04 - Cancer Pain: Opioids (759) Incidence and independent predictors of opiate related central nervous system side effects in cancer pain patients S. Hwang, V. Chang, D. Hoover, C. Zhao, Y. Alejandro, P. Osenenko, S. Srinivas; VA New Jersey Health Care System, East Orange, NJ Opioid Central Nervous System side effects (CNS-SEs) are a major source of distress. We studied the incidence and predictors of CNS-SEs after one week of pain management. Based on a biopsychosocial model, 195 cancer patients with worst pain ⬎ 4/10 completed the Brief Pain Inventory (BPI) and CNS-SEs checklist at baseline and week 1. At baseline, the Geriatric Depression Scale (GDS) was used to assess the risk for depression (RD)(GDS ⬎5) and the laboratory blood results were obtained. The continuous variables were dichotomized into binary variables for multivariate stepwise logistic regression analysis to identify the independent predictors of each CNS-SEs. The median age was 69 years (range 44-87) with KPS 70% (40-80) and creatinine 1.0mg/dl (0.5-9.9). At week 1, there was significant improvement in worst pain (mean 8.4 vs. 6.1,p⬍0.0001) by Wilcoxon matched-pairs test. The percentage of patients on opioids increased from 65% to 96% (p⬍0.0001) with the median morphine equivalent daily dose (MEDD) increasing from 20 mg(03,120) to 90 mg(0-3,120). The CNS-SEs included sedation (31%), difficulty concentrating (18%), myoclonus (15%), confusion (15%), and hallucinations (11%). Multivariate stepwise logistic regression model showed that patients at RD was predictive for all CNS-SEs (p⫽ 0.002-0.005). Larger than 60 mg increase in MEDD was predictive for 4 out of 5 CNS-SEs: sedation (p⫽0.009), hallucination (p⫽0.04), confusion (p⫽0.03) and myoclonous (p⫽0.01). Other significant predictors included ⬎ 4 pain sites at day 1 (p⫽0.009) and poor pain control at week 1 (p⫽0.05) for confusion; creatinine ⬎ 1.5 mg/dl (p⫽0.05) for difficulty concentrating, and baseline difficulty concentrating for sedation (p⫽0.004). The incidence of CNS-SEs ranged from 11 to 31%. RD and larger increases in MEDD were predictive for almost all the CNS-SEs. Serum creatinine was the only laboratory predictor. Easily obtained clinical data can identify high-risk population for opioid related CNS-SEs. VAHSR&D-PCC98068
(757) The safety of duloxetine in the long-term treatment of diabetic neuropathic pain
(760) Long-term treatment of moderate to severe cancer pain: A 2-year study
J. Wernicke, A. Rosen, Y. Lu, T. Lee, S. Iyengar, K. Knopp, D. Goldstein; Eli Lilly and Company, Indianapolis, IN Duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, was found to be safe and effective in the acute treatment of pain associated with diabetic neuropathy (Goldstein et al., 2003). The objective of the study‘s extension phase was to examine the safety of up to 52-weeks exposure to duloxetine in comparison to routine care, and to compare the effect of these treatments on progression of diabetic complications. This was s 52-week, multicenter, open-label study extension of an acute placebo-controlled study, in which 337 patients with diabetic neuropathic pain were re-randomized to either duloxetine 60 mg BID or routine care. Diabetic complications were measured using the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI; neuropathy progression), microalbumin/creatinine ratio (nephropathy progression), and ophthalmologic examination with fundus photograph (retinopathy progression). Treatment effects on QOL were compared using the Short Form-36 and EQ-5D version of the EuroQoL instrument. There were no significant differences between treatment groups regarding neuropathy, nephropathy or retinopathy progression. Discontinuation rates due to adverse events (AEs) were 9.6% and 14.0% for routine care and duloxetine, respectively. Serious adverse events (SAEs) were reported by 19.1% of routine care patients and 14.4% of duloxetine patients. Duloxetine was not significantly greater than routine care regarding the occurrence of SAEs or AEs. There were no significant differences in the number of hypoglycemic events or treatment-emergent abnormal HbA1c or lipids. Duloxetine was significantly better than routine care on the bodily pain subscale of the Short Form 36 Health Survey and the EQ-5D Index. In this study, duloxetine 120 mg/day was safe and well-tolerated in the longterm treatment of diabetic neuropathic pain. Duloxetine was superior to routine care on several measures of quality of life.
N. Slatkin, T. Ma, A. Frailey, H. Ahdieh; City of Hope National Medical Center, Duarte, CA To assess the long-term safety, tolerability, and dosing requirements of oxymorphone extended release (ER) in cancer patients with moderate to severe pain. Patients with moderate to severe chronic cancer pain who completed a randomized controlled trial and met entry criteria were enrolled in this 2-year, open-label, multicenter extension trial of oxymorphone ER q12h. Patients received the oxymorphone ER dose attained in the previous study, titrated to achieve acceptable pain relief. Oxymorphone immediate release was available as rescue medication. Patient pain, use of medication, adverse events, and clinical information were recorded. The median time to discontinuation was 212.5 days (range 1-753 days), with 16/44 patients completing 12 months and 4/12 completing 24 months. The most frequent adverse events were concomitant disease progression (25%), nausea (18%), pyrexia, and exacerbated pain (16% each). No clinically important trends in laboratory test results, vital signs, or EKGs over time were observed. Patient pain was well controlled with dosing q12h of oxymorphone ER (an approximate weekly average score of 30-35 mm on 100-mm Visual Analog Scale). The mean dosage was 125 mg/d during days 0-30, 150 mg/d during days 331-360, and use of rescue medication was low throughout the study (23 mg/d up to day 360; 27.5 mg/d at study end). Oxymorphone ER was safe and well tolerated during long-term use in cancer patients with moderate to severe chronic pain. There was little change in medication utilization during the first year and low use of rescue medication throughout the study. Endo Pharmaceuticals Inc. and Penwest Pharmaceuticals Co. partially supported this study.
(758) WITHDRAWN
Abstracts
D04 - Cancer Pain: Opioids (759) Incidence and independent predictors of opiate related central nervous system side effects in cancer pain patients S. Hwang, V. Chang, D. Hoover, C. Zhao, Y. Alejandro, P. Osenenko, S. Srinivas; VA New Jersey Health Care System, East Orange, NJ Opioid Central Nervous System side effects (CNS-SEs) are a major source of distress. We studied the incidence and predictors of CNS-SEs after one week of pain management. Based on a biopsychosocial model, 195 cancer patients with worst pain ⬎ 4/10 completed the Brief Pain Inventory (BPI) and CNS-SEs checklist at baseline and week 1. At baseline, the Geriatric Depression Scale (GDS) was used to assess the risk for depression (RD)(GDS ⬎5) and the laboratory blood results were obtained. The continuous variables were dichotomized into binary variables for multivariate stepwise logistic regression analysis to identify the independent predictors of each CNS-SEs. The median age was 69 years (range 44-87) with KPS 70% (40-80) and creatinine 1.0mg/dl (0.5-9.9). At week 1, there was significant improvement in worst pain (mean 8.4 vs. 6.1,p⬍0.0001) by Wilcoxon matched-pairs test. The percentage of patients on opioids increased from 65% to 96% (p⬍0.0001) with the median morphine equivalent daily dose (MEDD) increasing from 20 mg(03,120) to 90 mg(0-3,120). The CNS-SEs included sedation (31%), difficulty concentrating (18%), myoclonus (15%), confusion (15%), and hallucinations (11%). Multivariate stepwise logistic regression model showed that patients at RD was predictive for all CNS-SEs (p⫽ 0.002-0.005). Larger than 60 mg increase in MEDD was predictive for 4 out of 5 CNS-SEs: sedation (p⫽0.009), hallucination (p⫽0.04), confusion (p⫽0.03) and myoclonous (p⫽0.01). Other significant predictors included ⬎ 4 pain sites at day 1 (p⫽0.009) and poor pain control at week 1 (p⫽0.05) for confusion; creatinine ⬎ 1.5 mg/dl (p⫽0.05) for difficulty concentrating, and baseline difficulty concentrating for sedation (p⫽0.004). The incidence of CNS-SEs ranged from 11 to 31%. RD and larger increases in MEDD were predictive for almost all the CNS-SEs. Serum creatinine was the only laboratory predictor. Easily obtained clinical data can identify high-risk population for opioid related CNS-SEs. VAHSR&D-PCC98068
(757) The safety of duloxetine in the long-term treatment of diabetic neuropathic pain
(760) Long-term treatment of moderate to severe cancer pain: A 2-year study
J. Wernicke, A. Rosen, Y. Lu, T. Lee, S. Iyengar, K. Knopp, D. Goldstein; Eli Lilly and Company, Indianapolis, IN Duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, was found to be safe and effective in the acute treatment of pain associated with diabetic neuropathy (Goldstein et al., 2003). The objective of the study‘s extension phase was to examine the safety of up to 52-weeks exposure to duloxetine in comparison to routine care, and to compare the effect of these treatments on progression of diabetic complications. This was s 52-week, multicenter, open-label study extension of an acute placebo-controlled study, in which 337 patients with diabetic neuropathic pain were re-randomized to either duloxetine 60 mg BID or routine care. Diabetic complications were measured using the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI; neuropathy progression), microalbumin/creatinine ratio (nephropathy progression), and ophthalmologic examination with fundus photograph (retinopathy progression). Treatment effects on QOL were compared using the Short Form-36 and EQ-5D version of the EuroQoL instrument. There were no significant differences between treatment groups regarding neuropathy, nephropathy or retinopathy progression. Discontinuation rates due to adverse events (AEs) were 9.6% and 14.0% for routine care and duloxetine, respectively. Serious adverse events (SAEs) were reported by 19.1% of routine care patients and 14.4% of duloxetine patients. Duloxetine was not significantly greater than routine care regarding the occurrence of SAEs or AEs. There were no significant differences in the number of hypoglycemic events or treatment-emergent abnormal HbA1c or lipids. Duloxetine was significantly better than routine care on the bodily pain subscale of the Short Form 36 Health Survey and the EQ-5D Index. In this study, duloxetine 120 mg/day was safe and well-tolerated in the longterm treatment of diabetic neuropathic pain. Duloxetine was superior to routine care on several measures of quality of life.
N. Slatkin, T. Ma, A. Frailey, H. Ahdieh; City of Hope National Medical Center, Duarte, CA To assess the long-term safety, tolerability, and dosing requirements of oxymorphone extended release (ER) in cancer patients with moderate to severe pain. Patients with moderate to severe chronic cancer pain who completed a randomized controlled trial and met entry criteria were enrolled in this 2-year, open-label, multicenter extension trial of oxymorphone ER q12h. Patients received the oxymorphone ER dose attained in the previous study, titrated to achieve acceptable pain relief. Oxymorphone immediate release was available as rescue medication. Patient pain, use of medication, adverse events, and clinical information were recorded. The median time to discontinuation was 212.5 days (range 1-753 days), with 16/44 patients completing 12 months and 4/12 completing 24 months. The most frequent adverse events were concomitant disease progression (25%), nausea (18%), pyrexia, and exacerbated pain (16% each). No clinically important trends in laboratory test results, vital signs, or EKGs over time were observed. Patient pain was well controlled with dosing q12h of oxymorphone ER (an approximate weekly average score of 30-35 mm on 100-mm Visual Analog Scale). The mean dosage was 125 mg/d during days 0-30, 150 mg/d during days 331-360, and use of rescue medication was low throughout the study (23 mg/d up to day 360; 27.5 mg/d at study end). Oxymorphone ER was safe and well tolerated during long-term use in cancer patients with moderate to severe chronic pain. There was little change in medication utilization during the first year and low use of rescue medication throughout the study. Endo Pharmaceuticals Inc. and Penwest Pharmaceuticals Co. partially supported this study.
(758) WITHDRAWN