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(250) Oxymorphone extended release in hydrocodone-experienced patients with chronic low back pain: Subgroup analysis of a 12-week, randomized, double-blind, placebo-controlled study
P38 (248) Analgesic efficacy and safety of controlled-release hydrocodone and acetaminophen tablets, dosed twice daily, for moderate to severe mechanical chronic lowback pain: A randomized, double-blind, placebo-controlled withdrawal trial C Codding, D Levinsky, M Hale, J Thomas, E Lockhart, R Jain; Health Research of Oklahoma, Oklahoma City, OK Analgesic efficacy and safety of hydrocodone/acetaminophen extended-release (HC/APAP CR) was assessed in subjects with moderate-to-severe chronic low-back pain (CLBP). Subjects with CLBP (n⫽773) were enrolled at 62 sites; study protocol and informed consent were IRB-approved. Study periods were: Washout/Screening, 3-week Active-Drug Open-Label, 12-week Double-Blind in which subjects were randomized to placebo, 1 or 2 tablets HC/APAP CR twice daily, and Taper/Follow-up. Primary efficacy endpoint was mean change from double-blind baseline to final evaluation in Subject’s Assessment of CLBP Intensity (VAS). Safety was evaluated by adverse-event (AE) assessment. All results reported are from the Double-Blind period. 511 subjects were randomized and received °Y´1 dose of study drug; data for 507 were evaluated for efficacy. Most subjects were women (59%) and white (87%); mean age 48 years. Baseline variables were similar among the 3 groups. Mean change from baseline CLBP intensity was statistically significantly lower in subjects in the HC/APAP CR groups than in the placebo group (8.6, 2-tablet; 13.3, 1-tablet vs 22.2, placebo; p⬍0.05); no statistically significant difference was observed between HC/APAP CR groups. The superiority of treatment with both HC/APAP treatments compared to placebo treatment was consistent across multiple secondary efficacy endpoints. 89/169 (53%) subjects in the HC/APAP CR 2-tablet, 75/170 (44%) in the 1-tablet, and 79/172 (46%) in the placebo group reported °Y´1 AE. AEs in °Y´5% of subjects in any treatment group were nausea, constipation, diarrhea, and headache. Nine subjects reported serious AEs (2 in each HC/APAP CR group; 5 in placebo group); 28 subjects discontinued due to AEs (3% in placebo; 6% in 1-tablet; 7% in 2-tablet group). Both HC/APAP CR doses given twice daily were effective treatment for CLBP over the 12-week period. The safety profile of HC/APAP CR was consistent with known profiles of mu-opioid receptor agonists. Funded by Abbott Laboratories.
(249) Assessment of disability level and sleep interference in moderate to severe chronic low-back pain patients treated with 12-hour extended-release hydrocodone/ acetaminophen tablets: A phase-3 withdrawal trial C Codding, D Levinsky, M Hale, J Thomas, P Vo, S Marx, E Lockhart, R Jain; Health Research of Oklahoma, Oklahoma City, OK Published studies report chronic low-back pain (CLBP) prevalence in the U.S. to be 4-14%. Beyond pain control, assessing disability levels and sleep quality are important aspects of managing patients with CLBP. A phase-3 withdrawal study assessing 12-hour extended-release hydrocodone/acetaminophen (HC/ APAP CR) treatment in subjects with CLBP, consisted of the following phases: Washout/Screening, 3-week Active-Drug Open-Label (OL), 12-week DoubleBlind (DB) in which subjects were randomized to placebo, 1 or 2 tablets HC/ APAP CR twice daily, and Taper/Follow-up. Primary endpoint and study design details are reported elsewhere. Disability level and pain-related sleep interference were assessed and are reported here. To assess disability levels, subjects were given the Roland-Morris Disability Questionnaire (RMDQ), a 24-item selfadministered questionnaire, at OL and DB baselines and final visit. Sleep interference was examined at these time points, with additional assessments at weeks 2, 6, and 12. During the OL period, improvements in randomized subjects’ disability were demonstrated by reductions in RMDQ scores (mean percent change: –52%) from OL-baseline to DB-baseline. Additionally, mean reduction in subject’s assessment of pain-related sleep interference score from OL-baseline to end of the OL-period was 4.0 for all subjects randomized into the DB period. During the DB period, both HC/APAP CR groups demonstrated statistically significantly lower mean percent-change increase in RMDQ scores than the placebo group, from DB-baseline to final visit. More specifically, mean percent increase for RMDQ scores in the 1-tablet HC/APAP CR group was 112% compared to 244% in the placebo group (p⬍0.001). Similarly, statistically significantly lower mean increase in sleep interference was observed for the HC/ APAP CR groups compared with the placebo group at week 2 (p⬍0.001), week 6 (p⬍0.001) and week 12 (p⬍0.003). Twice daily administration of both 1 and 2 tablets of HC/APAP CR improved disability scores and decreased pain-related sleep interference relative to placebo. Funded by Abbott Laboratories.
Abstracts (250) Oxymorphone extended release in hydrocodone-experienced patients with chronic low back pain: Subgroup analysis of a 12-week, randomized, double-blind, placebo-controlled study M Hale, T Ma, H Ahdieh, R Kerwin; Gold Coast Research, LLC, Weston, FL Patients with chronic pain that does not respond to nonopioid medications may switch to agents combining opioid and nonopioid analgesics. However, there is a therapeutic ceiling with such agents because the safe maximum daily dose is limited by the nonopioid component. For example, hydrocodone/acetaminophen induces abnormal liver enzyme elevations at ⱖ4 g/d acetaminophen. In this study we performed a subgroup analysis of hydrocodone-experienced patients who participated in a clinical trial of oxymorphone extended release (OPAN ER) for chronic lower back pain (CLBP). Among the 250 patients with moderate to severe CLBP enrolled in the study, 104 were receiving hydrocodonebased therapy at screening. Of these, 61% (n⫽63) were successfully converted and titrated (for ⱕ1 mo) to a stabilized oxymorphone ER dose (median ⫽ 30 mg every 12 h with ⱕ2 doses per day rescue medication). Median pain on a 100-mm Visual Analog Scale was reduced from 71 mm at screening to 23 mm following titration. After stabilization, 61 patients (59%) began double-blind treatment with oxymorphone ER (n⫽32) or placebo (n⫽29) for up to 12 weeks. Fewer oxymorphone ER patients than placebo patients discontinued treatment owing to lack of efficacy (12% vs 55%). Before titration, a minority (49%) of patients rated their previous hydrocodone-based therapy as Good to Excellent; after titration 99% rated oxymorphone ER Good to Excellent. At final visit, more oxymorphone ER patients than placebo patients rated their medication as Good to Excellent (78% vs 22%; P⬍0.001). Physician ratings followed a similar pattern and favored oxymorphone ER (P⬍0.001). Anxiety, bronchitis, and pain exacerbated were the most frequently reported adverse events during double-blind treatment with oxymorphone ER (2 patients each). In this study, the majority of hydrocodoneexperienced patients with poorly controlled pain were titrated to an effective and well-tolerated dose of oxymorphone ER. This research was supported by Endo Pharmaceuticals Inc.
(251) Decrease of Cold Pain Tolerance Following Opioid Detoxification J Younger, S Parke, P Barelka, I Carroll, L Chu, R Prasad, R Gaeta, S Mackey; Stanford University School of Medicine, Stanford, CA Opioid analgesics are the most commonly prescribed class of medications in the United States. Given evidence that long-term opioid use may lead to hyperalgesic states, the reliance on these medications for chronic pain treatment is concerning. Limited evidence suggests that these hyperalgesic states may be reversed by simple withdrawal of opioids. In this study, we examined the acute effects of opioid detoxification on cold pain tolerance. Participants were 11 chronic pain patients on longterm opioid treatment who were participating in an opioid detoxification and pain rehabilitation program. During their 7- to 14-day stay, participants were withdrawn from their opioid medication using a blinded pain cocktail that consisted of methadone, clonidine and baclofen, mixed in cherry syrup. Participants completed a cold-pressor test at admission and discharge. On each assessment day, cold pain tolerance was assessed by measuring time (in seconds) that participants were able to keep their hand and arm submerged in cold water (0 – 0.5°C). A linear regression was performed to test predictors of change in cold pain tolerance (within-person). Pain tolerance on admission was entered as a control variable and reduction of opioids (in mg morphine equivalence units) was entered as the primary predictor of interest. Reduction of opioid medication significantly predicted change in pain tolerance (t(10) ⫽ 4.07, p ⫽ .004). Greater reductions in opioid medications were associated with greater reductions of cold pain tolerance at discharge. A post-hoc correlation (partialling out admit pain tolerance) found that amount of opioid withdrawal was strongly correlated with change in pain tolerance (r ⫽ .82, p ⫽ .004). These data suggest that opioid detoxification in chronic pain patients may lead to acute reductions of pain tolerance. While this hyperalgesic state may resolve over time, studies are needed to determine the time course of pain sensitivity following tapering of long-term opioid medication.
(249) Assessment of disability level and sleep interference in moderate to severe chronic low-back pain patients treated with 12-hour extended-release hydrocodone/ acetaminophen tablets: A phase-3 withdrawal trial C Codding, D Levinsky, M Hale, J Thomas, P Vo, S Marx, E Lockhart, R Jain; Health Research of Oklahoma, Oklahoma City, OK Published studies report chronic low-back pain (CLBP) prevalence in the U.S. to be 4-14%. Beyond pain control, assessing disability levels and sleep quality are important aspects of managing patients with CLBP. A phase-3 withdrawal study assessing 12-hour extended-release hydrocodone/acetaminophen (HC/ APAP CR) treatment in subjects with CLBP, consisted of the following phases: Washout/Screening, 3-week Active-Drug Open-Label (OL), 12-week DoubleBlind (DB) in which subjects were randomized to placebo, 1 or 2 tablets HC/ APAP CR twice daily, and Taper/Follow-up. Primary endpoint and study design details are reported elsewhere. Disability level and pain-related sleep interference were assessed and are reported here. To assess disability levels, subjects were given the Roland-Morris Disability Questionnaire (RMDQ), a 24-item selfadministered questionnaire, at OL and DB baselines and final visit. Sleep interference was examined at these time points, with additional assessments at weeks 2, 6, and 12. During the OL period, improvements in randomized subjects’ disability were demonstrated by reductions in RMDQ scores (mean percent change: –52%) from OL-baseline to DB-baseline. Additionally, mean reduction in subject’s assessment of pain-related sleep interference score from OL-baseline to end of the OL-period was 4.0 for all subjects randomized into the DB period. During the DB period, both HC/APAP CR groups demonstrated statistically significantly lower mean percent-change increase in RMDQ scores than the placebo group, from DB-baseline to final visit. More specifically, mean percent increase for RMDQ scores in the 1-tablet HC/APAP CR group was 112% compared to 244% in the placebo group (p⬍0.001). Similarly, statistically significantly lower mean increase in sleep interference was observed for the HC/ APAP CR groups compared with the placebo group at week 2 (p⬍0.001), week 6 (p⬍0.001) and week 12 (p⬍0.003). Twice daily administration of both 1 and 2 tablets of HC/APAP CR improved disability scores and decreased pain-related sleep interference relative to placebo. Funded by Abbott Laboratories.
Abstracts (250) Oxymorphone extended release in hydrocodone-experienced patients with chronic low back pain: Subgroup analysis of a 12-week, randomized, double-blind, placebo-controlled study M Hale, T Ma, H Ahdieh, R Kerwin; Gold Coast Research, LLC, Weston, FL Patients with chronic pain that does not respond to nonopioid medications may switch to agents combining opioid and nonopioid analgesics. However, there is a therapeutic ceiling with such agents because the safe maximum daily dose is limited by the nonopioid component. For example, hydrocodone/acetaminophen induces abnormal liver enzyme elevations at ⱖ4 g/d acetaminophen. In this study we performed a subgroup analysis of hydrocodone-experienced patients who participated in a clinical trial of oxymorphone extended release (OPAN ER) for chronic lower back pain (CLBP). Among the 250 patients with moderate to severe CLBP enrolled in the study, 104 were receiving hydrocodonebased therapy at screening. Of these, 61% (n⫽63) were successfully converted and titrated (for ⱕ1 mo) to a stabilized oxymorphone ER dose (median ⫽ 30 mg every 12 h with ⱕ2 doses per day rescue medication). Median pain on a 100-mm Visual Analog Scale was reduced from 71 mm at screening to 23 mm following titration. After stabilization, 61 patients (59%) began double-blind treatment with oxymorphone ER (n⫽32) or placebo (n⫽29) for up to 12 weeks. Fewer oxymorphone ER patients than placebo patients discontinued treatment owing to lack of efficacy (12% vs 55%). Before titration, a minority (49%) of patients rated their previous hydrocodone-based therapy as Good to Excellent; after titration 99% rated oxymorphone ER Good to Excellent. At final visit, more oxymorphone ER patients than placebo patients rated their medication as Good to Excellent (78% vs 22%; P⬍0.001). Physician ratings followed a similar pattern and favored oxymorphone ER (P⬍0.001). Anxiety, bronchitis, and pain exacerbated were the most frequently reported adverse events during double-blind treatment with oxymorphone ER (2 patients each). In this study, the majority of hydrocodoneexperienced patients with poorly controlled pain were titrated to an effective and well-tolerated dose of oxymorphone ER. This research was supported by Endo Pharmaceuticals Inc.
(251) Decrease of Cold Pain Tolerance Following Opioid Detoxification J Younger, S Parke, P Barelka, I Carroll, L Chu, R Prasad, R Gaeta, S Mackey; Stanford University School of Medicine, Stanford, CA Opioid analgesics are the most commonly prescribed class of medications in the United States. Given evidence that long-term opioid use may lead to hyperalgesic states, the reliance on these medications for chronic pain treatment is concerning. Limited evidence suggests that these hyperalgesic states may be reversed by simple withdrawal of opioids. In this study, we examined the acute effects of opioid detoxification on cold pain tolerance. Participants were 11 chronic pain patients on longterm opioid treatment who were participating in an opioid detoxification and pain rehabilitation program. During their 7- to 14-day stay, participants were withdrawn from their opioid medication using a blinded pain cocktail that consisted of methadone, clonidine and baclofen, mixed in cherry syrup. Participants completed a cold-pressor test at admission and discharge. On each assessment day, cold pain tolerance was assessed by measuring time (in seconds) that participants were able to keep their hand and arm submerged in cold water (0 – 0.5°C). A linear regression was performed to test predictors of change in cold pain tolerance (within-person). Pain tolerance on admission was entered as a control variable and reduction of opioids (in mg morphine equivalence units) was entered as the primary predictor of interest. Reduction of opioid medication significantly predicted change in pain tolerance (t(10) ⫽ 4.07, p ⫽ .004). Greater reductions in opioid medications were associated with greater reductions of cold pain tolerance at discharge. A post-hoc correlation (partialling out admit pain tolerance) found that amount of opioid withdrawal was strongly correlated with change in pain tolerance (r ⫽ .82, p ⫽ .004). These data suggest that opioid detoxification in chronic pain patients may lead to acute reductions of pain tolerance. While this hyperalgesic state may resolve over time, studies are needed to determine the time course of pain sensitivity following tapering of long-term opioid medication.