Qinfang Xiang

Comparison of the effectiveness and tolerability of lidocaine patch 5% versus celecoxib for osteoarthritis-related knee pain: Post hoc analysis of a 12 week, prospective, randomized, active-controlled, open-label, parallel-group trial in adults

BACKGROUND Cyclooxygenase-2 (COX-2) selective inhibitors and nonselective NSAIDs are commonly used to treat osteoarthritis (OA) of the knee. OBJECTIVE The aim of this study was to compare the effectiveness of the lidocaine patch 5% with that of celecoxib 200 mg/d in the treatment of OA-related knee pain; however, the study was terminated prematurely by the sponsor because of tolerability concerns regarding the class of COX-2 selective inhibitors. A post hoc analysis of the available data is presented here. METHODS This multicenter, randomized, open-label, active-controlled, parallel-group study included patients >or=18 years of age with unilateral or bilateral moderate to severe OA of the knee. Patients were randomized to receive treatment with either the lidocaine patch 5% or celecoxib 200 mg/d. The primary efficacy end point was change from baseline to 12 weeks in the Western Ontario and McMaster Universities (WOMAC) OA Index pain subscale. Secondary end points included additional WOMAC subscales and Brief Pain Inventory (BPI) measures. Because this trial was prematurely terminated, a post hoc analysis was performed using a random pattern-mixture model of all observed cases of the intent-to-treat population. RESULTS A total of 143 patients were randomized to treatment (lidocaine patch 5%, 69 patients; mean [SD] age, 60.2 [11.4] years; 65.2% female; 66.7% white; weight, 94.1 [23.3] kg) or celecoxib 200 mg/d (74 patients; age, 58.2 [12.1] years; 63.5% female; 68.9% white; weight, 94.3 [22.5] kg). Baseline pain WOMAC OA subscale scores (lidocaine patch 5%, 12.087; celecoxib 200 mg/d, 12.514) and mean rates of change over time (baseline to week 2, -1.5916 vs -1.6513 per week; weeks 2-6, -0.0168 vs -0.119 per week; weeks 6-12, -0.1818 vs -0.1579 per week) were not significantly different between the 2 groups. Improvement in additional WOMAC subscales and in several BPI measures were not significantly different between the 2 groups. Treatment-related adverse events were reported in 8 patients in each treatment group (11.6% in the lidocaine patch 5% group and 10.8% in the celecoxib 200-mg/d group) and were considered mild or moderate in severity. CONCLUSION Statistically significant differences in effectiveness and tolerability were not found between these 2 treatments in these patients with OA knee pain.

The Effects of Ethanol on the Bioavailability of Oxymorphone Extended-Release Tablets and Oxymorphone Crush-Resistant Extended-Release Tablets

UNLABELLED Adverse events may occur with an extended-release (ER) opioid if tampering or coadministration with ethanol causes excessive exposure (dose dumping) to the opioid. The effects of ethanol on the in vitro dissolution and in vivo pharmacokinetics of oxymorphone ER and oxymorphone crush-resistant formulation (CRF) were evaluated. In vitro dissolution rates were measured for oxymorphone ER 40-mg and oxymorphone CRF 40-mg tablets in aqueous solutions of 0 to 40% ethanol. In 2 in vivo, open-label, randomized, crossover studies, fasted healthy volunteers received single oral doses of oxymorphone ER 40 mg or oxymorphone CRF 40 mg with 240 mL of 0 to 40% ethanol. Naltrexone was used to minimize opioid effects. In the in vitro analyses, dissolution rates of oxymorphone ER and CRF were unaffected in aqueous solutions of ≤40% ethanol. Coadministration of oxymorphone ER or oxymorphone CRF with ethanol 20 and 40% increased oxymorphone peak plasma concentrations (C(max)) by 14 to 80% and reduced time to C(max). For both formulations, oxymorphone area under the curve and terminal half-life were largely unaffected, but C(max) increased with ethanol dose. Neither oxymorphone formulation exhibited dose dumping in terms of overall exposure when coingested with ethanol. PERSPECTIVE Administering oxymorphone ER or oxymorphone CRF with 240 mL of ≤40% ethanol increased oxymorphone C(max) without dose dumping in terms of area under the curve. These results provide reassurance about the integrity of oxymorphone ER formulations with ethanol. Nonetheless, alcohol and opioids should never be combined because of the risk of respiratory depression.

Bioequivalence of oxymorphone extended release and crush-resistant oxymorphone extended release

Background A formulation of crush-resistant extended-release opioids may deter abuse. The purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release (Oxy-ER) and a crush-resistant formulation of oxymorphone extended-release (Oxy-CRF). Methods In three open-label, randomized studies, healthy adults at a clinical research center received two single oral doses of Oxy-ER and two single doses of Oxy-CRF, each separated by a ≥7-day washout. Doses were administered under fasted conditions (study 1, 5 mg doses; study 2, 40 mg doses) or after a high-fat breakfast (study 3, 40 mg doses). Subjects administered 40 mg doses also received naltrexone. The primary endpoint was systemic oxymorphone exposure; the bioequivalence criterion was met if the 90% confidence intervals of the geometric mean ratio (Oxy-CRF/Oxy-ER) for oxymorphone area under the curve from time 0 to the last measured concentration (AUC0–t), AUC from time 0 to infinity (AUC0–inf), and maximum plasma concentration (Cmax) were within 0.8–1.25. Safety was assessed by monitoring adverse events. Results In studies 1, 2, and 3, the safety population comprised 30, 37, and 36 subjects and the pharmacokinetics population comprised 27, 30, and 29 subjects, respectively. Oxy-ER and Oxy-CRF produced similar mean ± standard deviation oxymorphone AUC0–t (study 1, 5.05 ± 1.55 versus 5.29 ± 1.52 ng · h/mL; study 2, 31.51 ± 10.95 versus 31.23 ± 10.33 ng · h/mL; study 3, 50.16 ± 14.91 versus 49.01 ± 14.03 ng · h/mL) and Cmax (0.38 ± 0.11 versus 0.37 ± 0.12 ng/mL; 2.37 ± 1.20 versus 2.41 ± 0.94 ng/mL; 5.87 ± 1.99 versus 5.63 ± 2.26 ng/mL) under all conditions. The 90% confidence intervals for plasma oxymorphone AUC0–t, AUC0–inf, and Cmax fulfilled the bioequivalence criterion. Adverse event rates were similar with Oxy-ER and Oxy-CRF (study 1, 25% versus 23%; study 2, 9% versus 16%; study 3, 20% each group). Conclusion Oxy-CRF and Oxy-ER (5 mg and 40 mg) are bioequivalent under fasted and fed conditions, suggesting that Oxy-CRF will have clinical efficacy and safety equivalent to Oxy-ER.

Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers

PURPOSE Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. METHODS Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. FINDINGS In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers. IMPLICATIONS The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms.

Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain

Abstract Objectives: Buprenorphine HCl buccal film has been developed for treating chronic pain utilizing BioErodible MucoAdhesive (BEMA®) delivery technology. Buccal buprenorphine (BBUP; BelbucaTM, Endo Pharmaceuticals) was evaluated for the management of moderate to severe chronic low back pain (CLBP) requiring around-the-clock analgesia in a multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal study in opioid-naive patients. Methods: Patients (n = 749) were titrated to a dose of BBUP (range, 150–450 µg every 12 h) that was generally well tolerated and provided adequate analgesia for ≥14 days, and then randomized to BBUP (n = 229) or placebo (n = 232), respectively. The primary efficacy variable was the change from baseline to week 12 of double-blind treatment in the mean of daily average pain intensity scores (numeric rating scale from 0 [no pain] to 10 [worst pain imaginable]). Results: Patients were experiencing moderate to severe pain at study entry: mean (SD) = 7.15 (1.05). Following titration, pain was reduced to the mild range; 2.81 (1.07). After randomization, mean (SD) pain scores increased from baseline to week 12 more with placebo (1.59 [2.04]) versus BBUP: (0.94 [1.85]) with a significant between-group difference (−0.67 [95% CI: −1.07 to −0.26]; p = 0.0012). A significantly larger percentage of patients receiving BBUP versus placebo had ≥30% pain reduction (63% vs 47%; p = 0.0012). During double-blind treatment, the most frequent adverse events (AEs) with BBUP were nausea (10%), constipation (4%) and vomiting (4%). The most common AEs with placebo were nausea (7%), upper respiratory tract infection (4%), headache (3%) and diarrhea (3%). Conclusions: These findings demonstrate the efficacy and tolerability of BBUP among opioid-naive patients requiring around-the-clock opioid treatment for CLBP.

Factors affecting acceptability of titrated oxymorphone extended release in chronic low back pain - an individual patient analysis.

Abstract Objective: To evaluate the influence of age, sex, and previous opioid experience on the likelihood of successfully titrating opioid-naive and experienced patients with chronic low back pain (CLBP) to an effective and well-tolerated dose of oxymorphone extended release (ER). Methods: Post hoc analysis of open-label titration phases of two enriched-enrollment randomized-withdrawal phase III trials in 575 adults with moderate-to-severe CLBP. Opioid-naive patients (n = 325) initiated oxymorphone ER at 10 mg/day (5 mg q12 h). Opioid-experienced patients (n = 250) initiated at a dose equianalgesic to their previous opioid and were allowed doses of 5 mg oxymorphone immediate-release rescue medication every 4–6 h, as needed. Oxymorphone ER was gradually titrated to a dose that reduced pain to ≤40 mm on a 100 mm visual analog scale. Clinical trial registration: NCT00225797, NCT00226421. Main outcome measures: Number of patients reaching stabilized oxymorphone ER dose, reasons for treatment discontinuation in patients not reaching stabilized dose. Results: Open-label titration was successful in 61% (348/575) of patients, and similar proportions of men (63%) and women (59%) and opioid-naive (63%) and experienced (57%) patients. Patients aged ≥65 years were less likely than patients aged <65 years to complete titration (45 vs. 63%; p = 0.002; 95% CI, −0.30 to −0.06) and more likely to discontinue owing to adverse events (40 vs. 15%; p < 0.001; 95% CI, 0.14–0.36). Oxycodone-experienced patients were less likely than hydrocodone-experienced patients to complete titration (46 vs. 62%, p = 0.03; 95% CI,−0.30 to −0.02). Among successfully titrated patients, pain decreased regardless of prior opioid therapy, sex, or age. Conclusions: Most patients with CLBP were titrated to an effective, generally well-tolerated oxymorphone ER dose. Older patients and those converted from oxycodone may require more gradual titration. A study limitation is that patients initiated oxymorphone ER to comply with protocol, whereas treatment failure typically motivates opioid initiation or switching in clinical practice.

Evaluation of the Tolerability of Switching Patients on Chronic Full μ-Opioid Agonist Therapy to Buccal Buprenorphine

Objective Assess whether patients with chronic pain receiving 80 to 220 mg oral morphine sulfate equivalent of a full μ-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods. A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent by naloxone challenge. Study doses were substituted at the time of the regular dose schedule for each patient. The primary endpoint was the proportion of patients with a maximum Clinical Opiate Withdrawal Scale score ≥ 13 (moderate withdrawal) or use of rescue medication. Results. 35 subjects on ≥ 80 mg morphine sulfate equivalent per day were evaluable for opioid withdrawal. One patient during buccal buprenorphine treatment and two during 50% full μ-opioid agonist treatment experienced opioid withdrawal of at least moderate intensity. The mean maximum Clinical Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There were no significant differences in pain ratings between treatments. The most frequent adverse events with buccal buprenorphine were headache (19%), vomiting (13%), nausea, diarrhea, and drug withdrawal syndrome (each 9%), and with full μ-opioid agonist were headache (16%), drug withdrawal syndrome (13%), and nausea (6%). Conclusions. Chronic pain patients treated with around-the-clock full μ-opioid agonist therapy can be switched to buccal buprenorphine (a partial μ-opioid agonist) at approximately 50% of the full μ-opioid agonist dose without an increased risk of opioid withdrawal or loss of pain control.

Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids.

Background This open-label, single-arm study was conducted to evaluate the long-term safety and efficacy of a novel buprenorphine formulation, buprenorphine buccal film, in the treatment of moderate-to-severe chronic pain requiring around-the-clock opioids. Methods The primary purpose of this study was to evaluate the long-term safety and tolerability of buprenorphine buccal film. Five hundred and six patients who completed previous studies with buprenorphine buccal film (n=445; rollover patients) or were recruited de novo for this study (n=61) were enrolled in this study. All patients underwent a dose titration period of ≤6 weeks, during which doses of buprenorphine buccal film were adjusted to a maximum 900 µg every 12 hours, depending on tolerability and the need for rescue medication. An optimal dose was defined as the dose that the patient found satisfactory for both pain relief and tolerability, without the need for rescue medication or with ≤2 tablets of rescue medication per day. Once the optimal dose was reached, treatment was continued for ≤48 weeks. Pain intensity was measured throughout the study using a 0–10 numerical rating scale. Results Of 435 patients achieving an optimal dose of buprenorphine buccal film who commenced long-term treatment, 158 (36.3%) completed 48 weeks of treatment. Treatment-related adverse events occurred in 116 patients (22.9%) during the titration phase and 61 patients (14.0%) during the long-term treatment phase, and adverse events leading to discontinuation of treatment occurred in 14 (2.8%) and 14 (3.2%) patients, respectively. The most common adverse events were those typically associated with opioids, such as nausea, constipation, and headache. In both rollover and de novo patients, pain intensity scores remained constant at approximately 3–4 during long-term treatment, and the dose of buprenorphine buccal film remained unchanged in 86.2% of patients. Conclusion In appropriate patients, buprenorphine buccal film demonstrated tolerability and efficacy in the long-term management of chronic pain.

Poster 339 Dosage Titration of Oxymorphone Extended Release for Relief of Chronic Low Back Pain in Patients With Comorbidities

Disclosures: R. T. Armendariz, none. Patients or Programs: A 41-year-old man with spastic quadriplegia from cerebral palsy and chronic back pain from scoliosis. Program Description: The patient had history of multiple failed intrathecal pumps due to infection and erosion of overlying soft tissue. He had his intrathecal catheter and pump removed, and was given oral baclofen and diazepam for spasticity management. He then underwent a series of right chest tissue expansions over the course of 4 months to create a stable submuscular pocket. Once the pocket was at appropriate size, a 20-mL baclofen pump was successfully implanted underneath the right pectoralis muscle and an intrathecal catheter was placed intraventricularly via endoscopic insertion. Baclofen concentration of 1900 mcg/mL was placed in the pump at implantation, and dosing was titrated from 115 to 325 mcg/d over the course of weeks, while the patient’s oral medication was titrated down. Five months after implantation, morphine was added for chronic back pain for a new medication concentration of 1900 mcg/mL baclofen and 1170 mcg/mL morphine. Final infusion dose was 356.7 mcg/d baclofen and 220 mcg/d morphine at the time of discharge. Setting: University teaching hospital. Results: At 6 weeks after original pump implantation, the patient demonstrated decreased tone in all 4 extremities and improved hygiene care. At 2 days after the medication change with added morphine, the patient demonstrated improved sleeping and decreased back pain without excessive somnolence. Further developments of his care will be discussed. Discussion: This is an interesting case of using an intraventricular pump with morphine and baclofen in the successful management of back pain and spasticity in an adult patient with cerebral palsy. Conclusions: An intraventricular baclofen pump is a viable delivery system for mixed medication management for spasticity and pain in adults with spastic quadriplegia and scoliosis.

Poster 345 Safety and Efficacy of Oxymorphone Extended Release for Chronic Low Back Pain in Patients With Comorbidities

Disclosures: J. H. Peniston, none. Objective: To establish safety and efficacy of oxymorphone extended release (ER) for chronic low back pain in patients with comorbidities. Design: Post hoc subanalysis of 2 multicenter, randomized-withdrawal trials. Setting: Multiple multidisciplinary pain centers in the United States. Participants: Opioid-naive and opioid-experienced adult patients with chronic low back pain, including subpopulations with comorbid hypertension, diabetes, or cardiovascular disease. Interventions: Open-label oxymorphone ER was initiated at 10 mg/d (5 mg every 12 hours) in opioid-naive and opioid-experienced patients at a dose equianalgesic to their previous opioid plus 5 mg oxymorphone immediate release rescue medication every 4-6 hours, as needed. Oxymorphone ER was titrated to a dose that was tolerated and effectively reduced pain to 40 mm on a 100-mm visual analog scale (VAS). Main Outcome Measures: Safety was assessed from reports of adverse events (AE); efficacy was assessed by pain intensity as recorded on the VAS. Results: During open-label titration of oxymorphone ER, 348 of 575 patients achieved a tolerated, effective dose (median, 40 mg); incidence of 1 AE was similar in patients with and without hypertension (69% versus 69%), diabetes (74% versus 69%), and cardiovascular disease (74% versus 68%). During doubleblind treatment, incidence of 1 AE was similar in patients with and without hypertension (58% versus 49%), diabetes (56% versus 52%), and cardiovascular disease (73% versus 50%). Treatment-related AEs included nausea, constipation, somnolence, headache, and diarrhea. Increases in VAS pain intensity from baseline to final visit were observed for patients taking placebo and with and without hypertension (27.9 versus 28.4), diabetes (26.6 versus 28.4), and cardiovascular disease (30.3 versus 28.0). With oxymorphone ER, a smaller increase in VAS was observed for patients with and without hypertension (9.8 versus 9.6), diabetes (13.3 versus 9.2), and cardiovascular disease (13.0 versus 9.2). Conclusions: Oxymorphone ER was safe and effective in patients with chronic low back pain and with or without comorbidities.