Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics.

PURPOSE: Abuse and misuse of prescription opioids are serious public health problems. Abuse-deterrent formulations are an intervention to balance risk mitigation with appropriate patient access. This study evaluated the effects of physicochemical barriers to crushing and dissolving on safety outcomes associated with extended-release oxycodone (ERO) tablets (OxyContin) using a national surveillance system of poison centers. Other single-entity (SE) oxycodone tablets and heroin were used as comparators and to assess substitution effects. METHODS: The National Poison Data System covering all US poison centers was used to measure changes in exposures in the year before versus the 2 years after introduction of reformulated ERO (7/2009-6/2010 vs 9/2010-9/2012). Outcomes included abuse, therapeutic errors affecting patients, and accidental exposures. RESULTS: After ERO reformulation, abuse exposures decreased 36% for ERO, increased 20% for other SE oxycodone, and increased 42% for heroin. Therapeutic errors affecting patients decreased 20% for ERO and increased 19% for other SE oxycodone. Accidental exposures decreased 39% for ERO, increased 21% for heroin, and remained unchanged for other SE oxycodone. During the study period, other interventions to reduce opioid abuse occurred, for example, educational and prescription monitoring programs. However, these have shown small effects and do not explain a drop for ERO exposures but not for other opioids. CONCLUSIONS: After ERO reformulation, calls to poison centers involving abuse, therapeutic errors affecting patients, and accidental exposures decreased for ERO, but not for comparator opioids. Abuse-deterrent formulations of opioid analgesics can reduce abuse, but switching to other accessible non abuse-deterrent opioids might occur.

Buprenorphine transdermal delivery system in adults with persistent noncancer-related pain syndromes who require opioid therapy: a multicenter, 5-week run-in and randomized, double-blind maintenance-of-analgesia study.

OBJECTIVE: This study compared the efficacy and safety profile of buprenorphine transdermal delivery system (BTDS) and placebo in subjects with persistent noncancer-related pain who required opioid analgesics. METHODS: This was a multicenter, double-blind, parallel-group study in adult subjects (age >/=18 years) with at least a 2-month history of noncancer-related pain for which they received oral opioid combination agents. The study employed a maintenance-of-analgesia, or randomized-withdrawal, design. During a 7- to 21-day open-label run-in phase, all subjects received BTDS, titrated as needed. Subjects who achieved stable pain control and were able to tolerate BTDS in the run-in phase were randomly assigned to continue BTDS at the dose achieved during the run-in phase or to receive placebo for up to 14 days. Acetaminophen 500-mg tablets were provided as escape (rescue) medication. Subjects completed the study on day 14 or when they met predefined criteria for ineffective treatment: requiring >1 g of acetaminophen as escape medication on any day of the double-blind evaluation phase, requiring a change in study drug dose, having difficulty keeping the patch affixed, or discontinuing because of ineffective treatment without meeting any of the first 3 criteria. The primary efficacy variable was the proportion of subjects with ineffective treatment. Secondary efficacy variables were the time to ineffective treatment; the proportion of subjects who reached ineffective treatment or discontinued for any reason other than ineffective treatment; and the amount of escape medication used. Assessment of the safety profile was based on adverse events and changes in vital signs and physical and laboratory findings. RESULTS: Five hundred eighty-eight subjects entered the open-label run-in phase, and 267 (129 BTDS, 138 placebo) were subsequently randomized to doubleblind treatment. Demographic characteristics were similar between the double-blind BTDS and placebo groups (61.2% and 63.8% female, respectively; 99.2% and 98.6% white; mean [SD] age, 56.2 [13.3] and 59.2 [11.5] years). In the primary efficacy analysis, the proportion of subjects with ineffective treatment was lower with BTDS than with placebo (51.2% vs 65.0%; 95% CI, 1.09-2.95); the odds of ineffective treatment were 1.79 times greater for placebo relative to BTDS (P = 0.022). In the secondary efficacy analyses, the median time from the first dose of double-blind study drug to ineffective treatment was significantly longer with BTDS than with placebo (median, 10 vs 3 days; P = 0.011). The proportion of subjects who reached ineffective treatment or discontinued for reasons other than ineffective treatment was lower in the BTDS group compared with the placebo group (55.0% vs 67.9%); the odds of ineffective treatment or discontinuation for a reason other than ineffective treatment was 1.76 times greater with placebo compared with BTDS (P = 0.028). The mean amount of escape medication used was significantly lower in the BTDS group than in the placebo group (1.7 vs 2.2 acetaminophen tablets per day; P = 0.015). The most common adverse events in the open-label run-in or double-blind phase occurring at a higher incidence with BTDS than with placebo were pruritus at the patch application site (9.3% vs 5.1%, respectively), headache (3.9% vs 2.2%), and somnolence (2.3% vs 0.7%). CONCLUSION: In this population of adult subjects with persistent noncancer-related pain who required opioid therapy, BTDS use was associated with analgesic efficacy and was generally well tolerated. Results of this study were presented in part at the annual meeting of the American Pain Society, March 30-April 2, 2005, Boston, Massachusetts.

Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment.

UNLABELLED: Oxycodone hydrochloride controlled-release, also known as extended-release oxycodone (ER oxycodone), was reformulated with physicochemical barriers to crushing and dissolving intended to reduce abuse through nonoral routes of administration (ROAs) that require tampering (eg, injecting and snorting). Manufacturer shipments of original ER oxycodone (OC) stopped on August 5, 2010, and reformulated ER oxycodone (ORF) shipments started August 9, 2010. A sentinel surveillance sample of 140,496 individuals assessed for substance abuse treatment at 357 U.S. centers between June 1, 2009, and March 31, 2012, was examined for prevalence and prescription-adjusted prevalence rates of past-30-day abuse via any route, as well as abuse through oral, nonoral, and specific ROAs for ER oxycodone and comparators (ER morphine and ER oxymorphone) before and after ORF introduction. Significant reductions occurred for 8 outcome measures of ORF versus OC historically. Abuse of ORF was 41% lower (95% CI: -44 to -37) than historical abuse for OC, with oral abuse 17% lower (95% CI: -23 to -10) and nonoral abuse 66% lower (95% CI: -69 to -63). Significant reductions were not observed for comparators. Observations were consistent with the goals of a tamper resistant formulation for an opioid. Further research is needed to determine the persistence and generalizability of these findings. PERSPECTIVE: This article presents preliminary findings indicating that 8 outcome measures of abuse of a reformulated ER oxycodone were lower than that for original ER oxycodone historically, particularly through nonoral ROAs that require tampering (ie, injection, snorting, smoking), in a sentinel sample of individuals assessed for substance use problems for treatment planning.

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.

Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study.

UNLABELLED: In this enriched design study, 1,160 opioid-experienced patients with chronic, moderate to severe low back pain entered an open-label run-in period; 660 demonstrated analgesic benefit from and tolerability to buprenorphine transdermal system 20 mcg/hour (BTDS 20) treatment and were randomized to receive either BTDS 20, BTDS 5 mcg/hour (BTDS 5), or the active control (immediate release oxycodone 40-mg/day) during an 84-day double-blind phase. The primary endpoint, "average pain in the last 24 hours" during double-blind weeks 4, 8, and 12, was significantly lower for patients receiving BTDS 20 compared with patients receiving BTDS 5 (P < .001, treatment difference of -.67). A treatment difference of -.75 in favor of oxycodone 40 mg/day versus BTDS 5 (P < .001) indicated the assay sensitivity of the study. Four sensitivity analyses, secondary, and exploratory analyses supported the results of the primary analysis. Incidences of treatment-emergent adverse events were 56% during the open-label period, and 59, 77, and 73% for the BTDS 5, BTDS 20, and oxycodone 40 mg/day treatment groups, respectively, during the double-blind phase. One death considered unrelated to study treatment occurred in a patient receiving BTDS 10 during the run-in period. BTDS 20 treatment was demonstrated to be efficacious and generally well tolerated. PERSPECTIVE: This article presents results of a pivotal Phase 3 study that assesses a new treatment for the management of chronic low back pain: a transdermal patch containing the opioid buprenorphine (BTDS). In this active controlled, superiority study with an enriched design, BTDS 20 was found to be efficacious and generally well tolerated.

Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study.

CONTEXT: This article presents the results of a pivotal Phase 3 study that assesses a new treatment for the management of chronic low back pain: a transdermal patch containing the opioid buprenorphine. In this randomized, placebo-controlled study with an enriched enrollment design, the buprenorphine transdermal system (BTDS) was found to be efficacious and generally well tolerated. OBJECTIVES: This enriched, multicenter, randomized, double-blind study evaluated the efficacy, tolerability, and safety of BTDS in opioid-naïve patients who had moderate to severe chronic low back pain. METHODS: Patients who tolerated and responded to BTDS (10 or 20 mcg/hour) during an open-label run-in period were randomized to continue BTDS 10 or 20 mcg/hour or receive matching placebo. The primary outcome was "average pain over the last 24 hours" at the end of the 12-week double-blind phase, collected on an 11-point scale (0=no pain, 10=pain as bad as you can imagine). Sleep disturbance (Medical Outcomes Study subscale) and total number of supplemental analgesic tablets used were secondary efficacy variables. RESULTS: Fifty-three percent of patients receiving open-label BTDS (541 of 1024) were randomized to receive BTDS (n=257) or placebo (n=284). Patients receiving BTDS reported statistically significantly lower pain scores at Week 12 compared with placebo (least square mean treatment difference: -0.58, P=0.010). Sensitivity analyses of the primary efficacy variable and results of the analysis of secondary efficacy variables supported the efficacy of BTDS relative to placebo. During the double-blind phase, the incidence of treatment-emergent adverse events was 55% for the BTDS treatment group and 52% for the placebo treatment group. Laboratory, vital sign, and electrocardiogram evaluations did not reveal unanticipated safety findings. CONCLUSION: BTDS was efficacious in the treatment of opioid-naïve patients with moderate to severe chronic low back pain. Most treatment-emergent adverse events observed were consistent with those associated with the use of opioid agonists and transdermal patches.

A randomized, placebo-controlled, double-blinded, parallel-group, 5-week study of buprenorphine transdermal system in adults with osteoarthritis.

BACKGROUND: This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated the analgesic efficacy and safety of buprenorphine transdermal system (BTDS) designed for 7-day wear. METHODS: Patients with OA pain inadequately controlled with nonsteroidal antiinflammatory drugs or patients who had taken opioids for OA pain within the past year entered a 7-day run-in period during which they took ibuprofen only. Patients with pain > or = on a 0-10 scale had their ibuprofen discontinued and were randomized into a 28-day double-blinded period to receive either BTDS at 1 of 3 dose levels (5, 10, or 20 microg/b) or placebo. Doses were titrated to effectiveness over a period of 21 days and maintained for 7 days. No rescue medication was allowed during the study. The primary efficacy measure was the proportion of patients who achieved treatment success, defined as a patient satisfaction score of good, very good, or excellent (on day 28 or at early discontinuation) for those who did not discontinue due to ineffective treatment. RESULTS: More BTDS-treated patients experienced treatment success than placebo TDS-treated patients (44 percent and 32 percent; odds ratio = 1.66, p = 0.036). Fewer patients taking BTDS titrated to the highest dose compared with placebo (p < 0.05). There were two serious adverse events (both in the placebo group) and no deaths. The most common (> or =5 percent) adverse events reported in BTDS-treated patients were nausea, headache, dizziness, somnolence, application site pruritus, and vomiting. CONCLUSION: Compared with placebo, BTDS treatment was effective in treating patients with moderate to severe pain due to OA of the knee or hip. BTDS was well-tolerated.

The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers.

Biodegradable microcapsules containing bupivacaine/dexamethasone produce an anesthetic duration of 7-11 days in animal models. In this investigation, we explored the effect of increasing doses (Part 1) and the effect of including dexamethasone (Part 2) on the onset, density, and duration of analgesia and anesthesia produced by bupivacaine microcapsules. Concentrations ranging from 0.3125% to 5.0% in microcapsules were compared with 0.25% aqueous bupivacaine (bilateral injection, three intercostal nerves, 2 mL per nerve) (Part 1). Part 2 compared 2.5% microcapsules with or without the inclusion of dexamethasone by unilateral blockade. Sensory block was assessed by pinprick, temperature sensation, and subjective numbness (0, not numb; 10, totally numb). Pharmacodynamic assessments and plasma drug concentrations of bupivacaine and dexamethasone were measured for 96 h. The onset time was reduced and the duration of analgesia increased over the 0.3125%-5.0% dose range (P < 0.02). Onset with 2.5% microcapsules approximated that of 0.25% aqueous bupivacaine. Microcapsule block duration increased to at least 96 h and was significantly longer than aqueous bupivacaine (P < 0.001). Inclusion of dexamethasone increased the duration of pinprick anesthesia in 2.5% microcapsules (P = 0.03). We conclude that bupivacaine/dexamethasone microcapsules are well tolerated and demonstrate a dose-related effect in onset and duration of intercostal blockade. Inclusion of dexamethasone increases intercostal block anesthesia.

A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans: bupivacaine-loaded microcapsules.

UNLABELLED: Biodegradable microcapsules produce an ultra-long duration of local anesthesia. We hypothesized that this duration is caused by the sustained-release of bupivacaine from the microcapsules into the surrounding tissue. Previous studies investigated the pharmacokinetics (PKs) of bupivacaine after release from microcapsules and absorption into the systemic circulation. Microdialysis sampling can determine the PKs of any drug at its site of injection. This study was performed to characterize the PKs of bupivacaine and dexamethasone released from microcapsules at a subcutaneous injection site over a 96-h period in volunteers. Bupivacaine concentrations were compared with clinical variables of local anesthetic blockade. This study demonstrates that bupivacaine is released in a sustained manner from microcapsules, that bupivacaine concentrations increase for 24-34 h after microcapsule injection, and that analgesia parallels the tissue bupivacaine concentration obtained by microdialysis. Analgesia was equally rapid in onset with aqueous and microcapsule bupivacaine (P = 0.23). Analgesia was still present at 78% of microcapsule-injected sites after 96 h, significantly longer than for aqueous bupivacaine (P < 0.001). Mild pruritus was the most common side effect, occurring with 56% of the microcapsule injections. Dexamethasone-containing bupivacaine microcapsules are well tolerated and produce a prolonged duration of skin analgesia. Systemic absorption of bupivacaine produces higher peak plasma levels after aqueous injection than after microcapsule injection, despite the injection of a threefold larger load of bupivacaine in the latter. IMPLICATIONS: Microcapsules loaded with bupivacaine and dexamethasone and administered by subcutaneous injection produce prolonged cutaneous anesthesia and analgesia. Determination of local tissue pharmacokinetic variables of bupivacaine by microdialysis confirms that the prolonged duration of anesthesia is caused by the extended release characteristics of the microcapsules.