Steven R. Ripa

Buprenorphine transdermal system and quality of life in opioid-experienced patients with chronic low back pain

Objectives: To evaluate the impact of 12 weeks of treatment with Butrans® (buprenorphine) transdermal system (BTDS) on the health-related quality of life (HRQoL) for patients with chronic low back pain (CLBP), and the maintenance of effects over 52 weeks. Research design and methods: A multicenter, enriched, double-blind (DB), randomized trial comparing BTDS 20 μg/h (BTDS 20) against 5 μg/h (BTDS 5) for treatment of opioid-experienced patients with moderate-to-severe CLBP, including a 52-week open-label (OL) extension phase. Main outcome measures: QoL was measured with the SF-36v2 survey before and after an OL run-in period with BTDS 20, three times during the DB phase, and seven times over the extension phase. This post hoc analysis tested for SF-36v2 score differences between treatment groups during the DB phase and maintenance of effects over the extension phase. Results: At 12 weeks, BTDS 20 produced larger improvements than BTDS 5 in role limitations due to physical health, bodily pain and overall physical QoL (p < 0.01). Treatment group differences in overall physical QoL were sustained throughout the DB phase. Quality-of-life improvements associated with BTDS 20 persisted through the extension phase. Conclusions: These data suggest that opioid-experienced moderate-to-severe CLBP patients receiving BTDS 20 exhibited better QoL than patients receiving BTDS 5.

12-Month safety and effectiveness of once-daily hydrocodone tablets formulated with abuse-deterrent properties in patients with moderate to severe chronic pain.

OBJECTIVE To characterize the long-term safety and effectiveness of Hysingla™ ER, single-entity, once-daily, extended-release hydrocodone bitartrate tablets formulated with abuse-deterrent properties (HYD), offering a new treatment option for appropriate patients with chronic pain. DESIGN An open-label study with a dose-titration period (up to 45 days) and a maintenance period (12 months). PATIENTS, PARTICIPANTS A total of 922 patients with chronic nonmalignant and non-neuropathic moderate to severe pain received open-label HYD tablets 20-120 mg; 728 of these achieved a stabilized dose of HYD at the end of dose-titration and entered the maintenance period. RESULTS The safety profile was similar to that of other oral opioid analgesics, without new or unexpected safety concerns. The most frequent treatment-emergent adverse events (AEs; ≥ 5 percent) were those commonly associated with the use of systemic µ-opioid analgesics, including nausea, constipation, vomiting, fatigue, dizziness, somnolence, and headache. There were 77 (8 percent) patients with a total of 109 nonfatal treatment-emergent serious AEs. Few patients discontinued due to lack of therapeutic effect overall (6 percent), especially during the 12-month maintenance period (4 percent). Pain relief, sleep, functional health, and activities of daily living all improved at the end of the dose-titration period with HYD. These improvements were maintained through the 12-month maintenance period with stable HYD doses and without increase in concomitant supplemental analgesic medications. CONCLUSIONS This long-term study demonstrated the safety and long-term maintenance of analgesic effect of HYD without continued need for dose increase.

A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain

Objectives: This multicenter, randomized, double-blind, placebo-controlled study with an enriched enrollment, randomized withdrawal design was conducted to evaluate the analgesic efficacy and safety of single-entity, once-daily hydrocodone 20 to 120 mg tablets (HYD) in opioid-naive and opioid-experienced patients with uncontrolled moderate to severe chronic low back pain (CLBP). Research design and methods: The primary endpoint was week 12 pain intensity scores (11-point scale, 0 = no pain) using a mixed effect model with repeated measures incorporating a pattern mixture model framework. Responder analysis was a secondary endpoint. Safety was assessed. Results: Out of 905 patients who were treated with HYD during the open-label titration period, 588 (65%) were randomized to continue to receive HYD (n = 296, 20 – 120 mg taken once daily, average daily dose 57 mg) or a matching placebo (n = 292). HYD demonstrated superior pain reduction (p = 0.0016); this result was supported by sensitivity analyses using different approaches to handling missing data. Proportions of patients achieving ≥ 30 and ≥ 50% improvement in pain from screening to week 12 also favored HYD (p = 0.0033 and 0.0225, respectively). HYD was generally well tolerated. Conclusions: HYD was shown to be an efficacious treatment for CLBP in this study. There were no new or unexpected safety concerns detected.

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.

Buprenorphine Transdermal System Improves Sleep Quality and Reduces Sleep Disturbance in Patients with Moderate-to-Severe Chronic Low Back Pain: Results from Two Randomized Controlled Trials

To evaluate the impact of buprenorphine (Butrans®) transdermal System (BTDS) treatment on sleep outcomes for patients with moderate‐to‐severe chronic low back pain (CLBP).

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.

Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials

ABSTRACT Objectives: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80). Methods: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI). Results: In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively.  Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone. Conclusions: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.

The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low back pain: An application of the international classification of functioning, disability and health

Objectives:The Buprenorphine Transdermal Delivery System (BTDS) is indicated for reduction of pain in moderate to severe chronic low back pain (CLBP), which can affect patients’ ability to perform routine activities of daily living (ADLs). This post hoc analysis of clinical trial data examines the impact of BTDS treatment on CLBP patients’ ability to perform ADLs that relate to functioning with low back pain. Methods:Data are drawn from a multicenter, enriched enrollment, randomized, placebo-controlled, double-blind 12-week trial of BTDS for pain control among opioid-naive patients with moderate to severe CLBP. The 23 selected ADLs are those that (1) appear in the Low Back Pain Core Set of the International Classification of Functioning, Disability and Health and (2) link to the content of 3 patient-reported outcome instruments administered during the trial. Logistic regression models estimated the odds ratios (ORs) of BTDS patients’ ability to perform each ADL at 12 weeks, controlling for baseline ability, relative to placebo. Results:The ORs for 10 ADLs related to sleeping, lifting, bending, and working reached multiplicity-adjusted statistical significance and indicated a greater ability to perform ADLs among BTDS users than among the placebo group. These 10 ORs ranged from 1.9 (no physical health-related restrictions on the kind of work performed) to 2.4 (being able to sleep undisturbed by pain). Discussion:These results suggest that for patients with moderate to severe CLBP, 12 weeks use of BTDS improves the ability to carry out certain ADLs related to sleeping, lifting, bending, and working.

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.