Catherine Munera

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo (“assay sensitivity”). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence‐based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Application site adverse events associated with the buprenorphine transdermal system: a pooled analysis.

Objective: To characterize the profile of application site reactions (ASRs) for patients treated with the buprenorphine transdermal system (BTDS) in chronic pain studies. Methods: The incidences of ASRs during treatment with BTDS were examined using (a) integrated data from 16 controlled and uncontrolled Phase III chronic pain studies (N = 6566), (b) a subset of integrated data that focused on the double-blind phases of five enriched, placebo-controlled studies (n = 1806) and (c) data from an international postmarketing drug safety database. These data were compared with the ASR data reported in the full prescribing information of other transdermal patches marketed in the US. Results: Among the 6566 patients, the overall incidence of ASRs was 23.4%, of which 98.3% were mild to moderate in intensity, none were serious and 4.4% led to treatment discontinuation. Rates of severe and inflammatory ASRs were low. Among the 1806 patients, ASR rates were higher with BTDS (16.6%) than placebo transdermal system (12.7%). Among the 6566 patients, the 1806 patients, and the postmarketing data, the most common ASRs seen were pruritus, erythema and rash. Incidences of most ASRs for other selected transdermal products were 17% or lower. Conclusion: Incidence rates of ASRs in patients treated with BTDS were low and infrequently led to discontinuation. Severe and inflammatory-type ASRs were not common. The ASR profile of BTDS was comparable with those of other transdermal patches.

A randomized, 14-day, double-blind study evaluating conversion from hydrocodone/acetaminophen (Vicodin) to buprenorphine transdermal system 10 μg/h or 20 μg/h in patients with osteoarthritis pain

Objective: The objective of this study was to evaluate continued pain control and tolerability of converting patients from Vicodin® (hydrocodone/acetaminophen; HCD/APAP) to the buprenorphine transdermal system (BTDS). Methods: Adult patients with pain from osteoarthritis receiving a stable dosage of HCD/APAP (i.e., 15 – 30 mg hydrocodone/day) were switched to an equivalent or near-equivalent dosage of open-label Vicodin for 7 days. Patients maintaining acceptable analgesia were stratified based on their Vicodin dosage and randomized to receive either titratable BTDS 10 μg/h or fixed-dose BTDS 20 μg/h. The primary efficacy variable was completion of the 14-day double-blind phase. Tolerability was assessed. Results: A total of 84.3% of patients met the primary end point, completion of the 14-day double-blind phase (167/198 patients, 95% CI 79.3 – 89.4). Adverse events were consistent with those associated with the use of opioid analgesics and transdermal patches. Conclusion: There was a similar analgesic and tolerability profile when patients treated with Vicodin for osteoarthritis pain were switched to 7-day BTDS treatment.

Dose-Dependent Flux of Buprenorphine Following Transdermal Administration in Healthy Subjects.

Buprenorphine transdermal delivery system (BTDS) applied once every 7 days is indicated for the management of pain that is severe enough to require daily, around‐the‐clock, long‐term opioid treatment and for which alternative treatment options are inadequate. The 7‐day flux of buprenorphine from BTDS to systemic circulation was investigated in a phase 1, 2‐period crossover study with 3 randomized groups of healthy subjects receiving BTDS containing buprenorphine 5, 10, or 20 mg for 7 days preceded or followed by intravenous buprenorphine infusion (25 μg/h for 24 hours). Residual and absolute bioavailability methods were used to estimate 7‐day flux of buprenorphine. Following BTDS administration, mean area under the curve of buprenorphine increased proportionally (12.6, 24.3, and 51.1 ng/[mL · h]), maximum mean plasma concentration rose with increasing dose (176, 191, and 471 pg/mL), and absolute bioavailability was 14% to 16%. Mean residual amount of buprenorphine in the BTDS after 7‐day application was 4.50, 8.57, and 17.1 mg. Flux of buprenorphine was approximately 5, 10, and 20 μg/h for BTDS containing 5, 10, and 20 mg buprenorphine, respectively. BTDS was safe and well tolerated following a single 7‐day application in healthy subjects. The results of this study demonstrated dose‐dependent flux of buprenorphine delivered via transdermal system.

A Subgroup Analysis Found no Diminished Response to Buprenorphine Transdermal System Treatment for Chronic Low Back Pain Patients Classified with Depression

Chronic pain (CP) patients with depression typically exhibit worse post‐treatment outcomes than nondepressed CP patients. The cause is often assumed to reflect a differential response to treatment, neglecting other potential explanations, such as the continuation of differences in pretreatment outcomes. This post hoc analysis examines whether worse post‐treatment outcomes for depressed patients with chronic low back pain (CLBP) are driven by reduced treatment efficacy.

Buprenorphine transdermal system compared with placebo reduces interference in functioning for chronic low back pain.

Abstract Objective: This study examines the efficacy of the buprenorphine transdermal system (BTDS) for reducing the interference of pain on physical and emotional functioning associated with chronic low back pain (CLBP). Methods: A post-hoc analysis used data from a randomized, placebo-controlled, double-blind trial of patients with moderate-to-severe CLBP. The Brief Pain Inventory (BPI) measured pain interference at screening, following a run-in period, and during the 12-week double-blind treatment phase. Statistical analyses examined treatment arm differences (BTDS vs placebo) for the following: BPI Interference subscale items and subscale scores at the trial end point (week 12); patterns of change in the Interference subscale scores over time; proportions of patients indicating mild or no interference following treatment; and proportions of patients showing improvement (30%, 50%, 2-point, or 4-point change in score from screening to week 12) for each item and subscale. Results: Mean scores for BPI Interference items and Interference subscale were significantly lower (ie, indicated less interference) for BTDS than for placebo (all P < 0.001). Treatment arm differences in Interference subscale scores emerged within 4 weeks of treatment. The BTDS patients were significantly more likely to indicate mild/no interference on 5 of 7 Interference subscale items following treatment (P < 0.05). For most comparisons, BTDS patients were significantly more likely to show criterion-level improvements in Interference item and subscale scores (P < 0.05 for differences). Discussion: Results indicate the efficacy of BTDS treatment, compared with placebo, for reducing the interference of pain on physical and emotional functioning in patients with moderate-to-severe CLBP. The advantage of BTDS was observed within 4 weeks of treatment, and was maintained throughout the 12-week treatment phase.

Identifying optimal dosage regimes under safety constraints: An application to long term opioid treatment of chronic pain: Identifying Optimal Dosage Regimes Under Safety Constraints

There is growing interest and investment in precision medicine as a means to provide the best possible health care. A treatment regime formalizes precision medicine as a sequence of decision rules, one per clinical intervention period, that specify if, when and how current treatment should be adjusted in response to a patients evolving health status. It is standard to define a regime as optimal if, when applied to a population of interest, it maximizes the mean of some desirable clinical outcome, such as efficacy. However, in many clinical settings, a high-quality treatment regime must balance multiple competing outcomes; eg, when a high dose is associated with substantial symptom reduction but a greater risk of an adverse event. We consider the problem of estimating the most efficacious treatment regime subject to constraints on the risk of adverse events. We combine nonparametric Q-learning with policy-search to estimate a high-quality yet parsimonious treatment regime. This estimator applies to both observational and randomized data, as well as settings with variable, outcome-dependent follow-up, mixed treatment types, and multiple time points. This work is motivated by and framed in the context of dosing for chronic pain; however, the proposed framework can be applied generally to estimate a treatment regime which maximizes the mean of one primary outcome subject to constraints on one or more secondary outcomes. We illustrate the proposed method using data pooled from 5 open-label flexible dosing clinical trials for chronic pain.

Poster 45 Survey of Treatment Satisfaction With Buprenorphine Transdermal Delivery System

Disclosures: W. Wen, Purdue Pharma LP, employment (full or part-time). Objective: The buprenorphine transdermal delivery system (BTDS) uses a matrix system that delivers buprenorphine continuously over a 7-day period at 3 dose strengths: 5, 10, and 20 mcg buprenorphine/h. The objective of this analysis is to evaluate the treatment satisfaction of patients with osteoarthritis pain converted from Vicodin (hydrocodone/APAP) to BTDS by using a Treatment Satisfaction Survey. Design: Adult patients with osteoarthritis who received a stable dosage of hydrocodone 15-30 mg/d with 2 doses/d of supplemental analgesia (either opioids other than hydrocodone/APAP or nonopioid medication) were switched to a near equivalent dosage of open-label Vicodin for 7 days. Patients were stratified based on their hydrocodone dosage (stratum 1, 15-22.5 mg/d; stratum 2, 22.5-30 mg/d) and randomized to receive either BTDS 10 (with an option to titrate up to BTDS 20 for additional analgesia as required) or fixed dose BTDS 20. At the end of the 14-day doubleblind phase, the patients completed a 7-item Treatment Satisfaction Survey. Results: The percentages of patients who responded favorably to treatment for each of the 7 survey items across the 2 treatment groups are as follows: compared with pills, satisfied with using a patch to receive pain medication (extremely/very/satisfied), 85%; easy or difficult to use patch (extremely/very/easy), 93%; compared with pills, the convenience of using patch (extremely/very/convenient), 93%; satisfied with the patch’s ability to manage pain overall (extremely/very/satisfied), 84%; compared with pills, satisfied with the frequency of patch use (extremely/very/satisfied), 92%; willingness to continue using the patch for pain medication (very/willing/ somewhat willing), 87%; would recommend the patch to someone else for pain management (yes), 84%. Conclusions: The patients converted from Vicodin to BTDS showed treatment satisfaction with BTDS treatment.

Poster 46 The Adverse Event Profile of Buprenorphine Transdermal Delivery System in Patients ≥65 and <65 Years of Age

Disclosures: W. Wen, Purdue Pharma LP, employment (full or part-time). Objective: The buprenorphine transdermal delivery system (BTDS) uses a matrix system that delivers buprenorphine continuously over a 7-day period at 3 dose strengths: 5, 10, and 20 mcg buprenorphine/h. The objective of this analysis is to evaluate the treatment satisfaction of patients with osteoarthritis pain converted from Vicodin (hydrocodone/APAP) to BTDS by using a Treatment Satisfaction Survey. Design: Adult patients with osteoarthritis who received a stable dosage of hydrocodone 15-30 mg/d with 2 doses/d of supplemental analgesia (either opioids other than hydrocodone/APAP or nonopioid medication) were switched to a near equivalent dosage of open-label Vicodin for 7 days. Patients were stratified based on their hydrocodone dosage (stratum 1, 15-22.5 mg/d; stratum 2, 22.5-30 mg/d) and randomized to receive either BTDS 10 (with an option to titrate up to BTDS 20 for additional analgesia as required) or fixed dose BTDS 20. At the end of the 14-day doubleblind phase, the patients completed a 7-item Treatment Satisfaction Survey. Results: The percentages of patients who responded favorably to treatment for each of the 7 survey items across the 2 treatment groups are as follows: compared with pills, satisfied with using a patch to receive pain medication (extremely/very/satisfied), 85%; easy or difficult to use patch (extremely/very/easy), 93%; compared with pills, the convenience of using patch (extremely/very/convenient), 93%; satisfied with the patch’s ability to manage pain overall (extremely/very/satisfied), 84%; compared with pills, satisfied with the frequency of patch use (extremely/very/satisfied), 92%; willingness to continue using the patch for pain medication (very/willing/ somewhat willing), 87%; would recommend the patch to someone else for pain management (yes), 84%. Conclusions: The patients converted from Vicodin to BTDS showed treatment satisfaction with BTDS treatment.