Extended-release morphine sulfate and naltrexone hydrochloride (EMBEDA): naltrexone-associated withdrawal and abuse-related effects in patients with chronic pain and recreational opioid users.

OBJECTIVE: To review the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across EMBEDA (MSN; extended-release morphine sulfate with sequestered naltrexone) studies. METHODS: Five studies in pain patients and a safety review summarizing AE reports during the first year following approval of MSN were assessed for withdrawal reports. Three of these studies also assessed Clinical Opiate Withdrawal Scale (COWS) scores. Plasma naltrexone concentrations of MSN-treated individuals were summarized. Abuse potential was assessed in four studies in non-dependent recreational opioid users. RESULTS: Withdrawal AEs occurred in 13/1781 patients across five MSN studies, and 25/182 cases involving withdrawal were reported in the safety review. In three of these studies, 11/964 patients experienced moderate withdrawal (COWS score = 13-24) and 1/964 patients experienced moderately severe withdrawal (score = 28); all were either non-compliant with study drug, had undetectable plasma naltrexone concentrations, or were tapering to placebo. In ≥89% of plasma naltrexone concentration samples from patients who took MSN (n = 166), naltrexone was below the limit of quantification (4.0 pg/mL). In four studies with non-dependent recreational opioid users (n = 118), crushed MSN was associated with significantly lower scores of drug liking, high, and take drug again than crushed morphine sulfate (p ≤ 0.005). CONCLUSIONS: When taken intact as directed, naltrexone in MSN does not precipitate withdrawal. However, when MSN is crushed, naltrexone mitigates, but does not eliminate, the euphorigenic effects of crushed morphine sulfate.

Abuse Potential Study of ALO-02 (Extended-Release Oxycodone Surrounding Sequestered Naltrexone) Compared with Immediate-Release Oxycodone Administered Orally to Nondependent Recreational Opioid Users.

Objective: To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. Design: Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases. Subjects: Nondependent, recreational opioid users. Methods: Oral administration of crushed and intact ALO-02, crushed immediate-release (IR) oxycodone, and placebo. Primary endpoints were Drug Liking and High measured on visual analog scales and reported as maximum effect (E max ) and area-under-the-effect-curve from 0 to 2 hours (AUE 0-2h ). Other pharmacodynamic, pharmacokinetic and safety assessments were included. Results: Drug Liking and High (E max ) for crushed oxycodone IR 40 mg were significantly higher compared with placebo, confirming study validity ( P < 0.0001). Drug Liking and High (E max, AUE 0-2h ) for crushed ALO-02 (40 mg/4.8 mg and 60 mg/7.2 mg) were significantly lower compared to corresponding doses of crushed oxycodone IR (40 and 60 mg; P < 0.0001). Likewise, Drug Liking and High (E max and AUE 0-2h ) for intact ALO-02 60 mg/7.2 mg were significantly lower compared with crushed oxycodone IR 60 mg ( P < 0.0001). Secondary pharmacodynamic endpoints and plasma concentrations of oxycodone and naltrexone were consistent with these results. Fewer participants experienced adverse events (AEs) after ALO-02 (crushed or intact: 71.1-91.9%) compared with crushed oxycodone IR (100%). Most common AEs following crushed ALO-02 and oxycodone IR were euphoric mood, pruritus, somnolence, and dizziness. Conclusions: The results suggest that ALO-02 (crushed or intact) has lower abuse potential than crushed oxycodone IR when administered orally in nondependent, recreational opioid users.

Prescription opioid abuse and misuse: gap between primary-care investigator assessment and actual extent of these behaviors among patients with chronic pain.

OBJECTIVES: To compare the results of two open-label primary care-based studies that examined investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion relative to patient self-reports and urine drug tests (UDTs). METHODS: Risk assessment data from two open-label, multicenter, primary care-based US studies in patients with chronic pain were compared. RESULTS: In one study (n = 1487), 54.4% of patients were at moderate, 24.8% at high, and 20.8% at low risk based on patients' self-reports at baseline on the Screener and Opioid Assessment for Patients with Pain®-Revised questionnaire. Investigators assigned 1.3% of patients as high risk despite 5.0% self-reporting prior illicit drug use and 15.3% with positive UDT(s) for an illicit drug at baseline. In the second study (n = 684), few patients were considered by investigators to be at high risk for misuse (1.6%), abuse (1.8%), or diversion (1.0%). However, 10.4% of patients reported prior illicit drug use; 23.4% had at least one abnormal baseline UDT; 60% of 537 patients reported on the Self-Reported Misuse, Abuse, and Diversion questionnaire they took more opioids than prescribed; and 10.9% reported chewing/crushing opioids in the past. Of patients completing the Current Opioid Misuse Measure, 40.6% were classified as having aberrant behaviors. CONCLUSION: A comparison of risk assessment across two studies indicates a tendency for investigators to assess patients as lower risk for opioid-related aberrant behaviors despite a significant proportion self-reporting aberrant behavior and/or presenting with illicit UDTs. These consistent findings underline the importance of appropriate implementation of objective measures and self-reporting tools when evaluating risk in patients. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers: NCT00640042 and NCT01179191.

Intravenous abuse potential study of oxycodone alone or in combination with naltrexone in nondependent recreational opioid users.

BACKGROUND: ALO-02, comprising pellets of extended-release oxycodone surrounding sequestered naltrexone, is intended to deter abuse. OBJECTIVE: Determine the abuse potential of intravenous oxycodone combined with naltrexone, which represents simulated crushed ALO-02 in solution, compared with intravenous oxycodone in nondependent, recreational opioid users. METHODS: A randomized, double-blind, placebo-controlled, three-way crossover study with naloxone challenge, drug discrimination, and treatment phases. Intravenous treatments included oxycodone hydrochloride 20 mg, oxycodone hydrochloride 20 mg plus naltrexone hydrochloride 2.4 mg (simulated crushed ALO-02 20 mg/2.4 mg), or placebo (0.9% sodium chloride for injection). Primary end points were peak effects (Emax) and area under the effects curve within 2 h postdose (AUE0-2h) on drug liking and high visual analog scales. RESULTS: Thirty-three participants were randomized into treatment phase, and 29 completed all treatments. Study validity was confirmed with statistically significant differences in Emax for drug liking and high (p < 0.0001) between intravenous oxycodone and placebo. Intravenous simulated crushed ALO-02 resulted in significantly lower scores than oxycodone on drug liking (Emax: 58.2 vs. 92.4; AUE0-2h: 104.3 vs. 152.4) and high (Emax: 17.2 vs. 93.1; AUE0-2h: 12.0 vs. 133.6), respectively (p < 0.0001, all comparisons). More participants experienced adverse events after intravenous oxycodone (n = 27 [90%]) versus intravenous simulated crushed ALO-02 (n = 4 [12.5%]) or placebo (n = 2 [6.5%]). CONCLUSION: Intravenous administration of simulated crushed ALO-02 resulted in significantly lower abuse potential, as assessed by subjective ratings of drug liking and high, than intravenous oxycodone in nondependent, recreational opioid users. This suggests that injection of ALO-02 may not be as desirable to recreational opioid users compared with oxycodone taken for nonmedical reasons.

A multicenter, primary care-based, open-label study to identify behaviors related to prescription opioid misuse, abuse, and diversion in opioid-experienced patients with chronic moderate-to-severe pain.

OBJECTIVE: To compare the investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion with patient self-reports of these activities in a population with chronic pain. METHODS: As a secondary objective of an open-label, multicenter, primary care-based clinical study to evaluate the success of converting opioid-experienced patients with chronic pain to morphine sulfate with sequestered naltrexone hydrochloride, risk for misuse, abuse, and diversion was assessed using two nonvalidated questionnaires: one was completed by the investigator and another by the patient (Self-Reported Misuse, Abuse, and Diversion [SR-MAD]). In addition, the validated Current Opioid Misuse Measure (COMM) test and urine drug test were used. RESULTS: Of the 684 patients assessed by the investigators, 537 returned the self-assessment, SR-MAD. Most patients were assigned by the investigator as low risk for misuse (84.2%), abuse (89.3%), and diversion (94.3%). Of the patients who returned SR-MAD, 60% indicated having taken more opioids than prescribed and 10.9% reported chewing or crushing their opioids in the past. Of the patients who completed COMM, 40.6% were deemed as having aberrant behaviors. COMM results correlated with the risk levels from the investigator assessment. One-third of patients (33.8%) had at least one abnormal urine drug test result. CONCLUSION: More research is needed to better understand the gap between the investigator assessment of potential risk for misuse, abuse, and diversion and the actual extent of these behaviors among patients with chronic pain.

A multicenter, primary-care-based, open-label study to assess the success of converting opioid-experienced patients with chronic moderate-to-severe pain to morphine sulfate and naltrexone hydrochloride extended-release capsules using a standardized conversion guide.

OBJECTIVE: To evaluate the conversion of opioid-experienced patients with chronic moderate-to-severe pain to extended-release morphine sulfate with sequestered naltrexone hydrochloride (MSN) using a standardized conversion guide. METHODS: This open-label, single-arm study was conducted in 157 primary care centers in the United States. A total of 684 opioid-experienced adults with chronic moderate-to-severe pain were converted to oral administration of MSN from transdermal fentanyl and oral formulations of hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and other morphine products using a standardized conversion guide. The primary endpoint was the percentage of patients achieving a stable MSN dose within a 6-week titration phase. Secondary endpoints included duration of time to stable dose, number of titration steps, safety and efficacy measures, and investigator assessment of conversion guide utility. RESULTS: Of the 684 patients, 51.3% were converted to a stable dose of MSN (95% confidence interval: 47.5%, 55.1%). The mean (standard deviation) number of days to stable dose was 20 (8.94), and number of titration steps to stable dose was 2.4 (1.37). The majority of adverse events were mild/moderate and consistent with opioid therapy. Mean pain scores at stable dose decreased from baseline. Investigators were generally satisfied with the conversion guide and, in 94% of cases, reported they would use it again. CONCLUSION: Conversion to MSN treatment using the standardized MSN conversion guide was an attainable goal in approximately half of the population of opioid-experienced patients with chronic moderate-to-severe pain. Investigators found the guide to be a useful tool to assist conversion of opioid-experienced patients to MSN.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2 h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2 h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2 h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment.

The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

A multicenter, 12-month, open-label, single-arm safety study of oxycodone-hydrochloride/naltrexone-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain.

OBJECTIVE: To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. DESIGN: Open-label, single-arm safety study. SETTING: Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). PATIENTS: Three hundred ninety-five adults (opioid experienced and opioid naïve) with moderate-to-severe chronic noncancer pain (CNCP). INTERVENTIONS: Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. MAIN OUTCOME MEASURES: Number and type of adverse events (AEs) and drugrelated AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). RESULTS: A total of 193 (48.9 percent) patients received ALO-02 for ≥181 days and 105 (26.6 percent) patients for ≥361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug-related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. CONCLUSIONS: Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naïve patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed.

Safety and effectiveness of long-term treatment with diazepam auto-injector administered by caregivers in an outpatient setting for the treatment of acute repetitive seizures.

OBJECTIVE: Part 1 of this phase III study was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study of caregiver administered diazepam auto-injector (AI) in subjects with acute repetitive seizures (ARS) and demonstrated that diazepam AI was well-tolerated and significantly more effective than placebo AI in delaying the time to next seizure or rescue. Part 2 of this study, presented herein, was an open-label continuation to assess the long-term safety and effectiveness of diazepam AI for the treatment of ARS. METHODS: Of the 234 subjects randomized in part 1, 161 continued into part 2 and were provided open-label diazepam AI. Effectiveness measures were time to next seizure or rescue, number of subsequent rescues by type (rescue medication, emergency room visit, or other medical care), and number of subsequent seizures during the 12-h follow-up period. Safety data (adverse events and respirations <8/min) were also collected. RESULTS: During the open-label part 2 study, 129 subjects were administered a total of 1,380 diazepam AI treatments (median 4.5; range 1-118), of which 1,071 (77.6%) were effective with no subsequent seizure or rescue during the 12-h follow-up period. Median number of subsequent seizures experienced by subjects was one (range 0-20). Of the 1,380 administrations, 79 (5.7%) required use of rescue medication, 18 (1.3%) required a visit to an emergency room, and 6 (0.4%) required other rescue medical care. In most (75%) of subjects with treatment-emergent adverse events (TEAEs), TEAEs were mild or moderate in severity. Commonly reported treatment-related TEAEs were injection-site pain (10.9%), injection-site hemorrhage (7%), and injection-site bruising (6.3%). Although three subjects met the predefined respiratory rate threshold, none were considered clinically significant or reported as AEs. SIGNIFICANCE: Long-term treatment with diazepam AI administered by trained caregivers in an outpatient setting to treat ARS is a safe and effective option. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Assessing subjective and physiologic effects following intranasal administration of a new formulation of immediate release oxycodone HCl (Oxecta™) tablets in nondependent recreational opioid users.

OBJECTIVE: To evaluate the pharmacodynamic effects (subjective and physiologic) of a new formulation of immediate release oxycodone HCl (IRO-A; Oxecta™) tablets compared with immediate release oxycodone HCl (IRO; Roxicodone®) tablets when crushed and administered intranasally to nondependent recreational opioid users. DESIGN: Single-center, single-dose, randomized, double-blind, active-controlled two-way crossover study. SETTING: Inpatient Clinical Pharmacology Unit, Toronto, Canada. PARTICIPANTS: Nondependent, recreational opioid users aged 18-55 years. INTERVENTIONS: Subjects able to discriminate intranasally administered crushed IRO from placebo were randomized to receive 15 mg crushed IRO-A and crushed IRO in crossover fashion in treatment phase. MAIN OUTCOME MEASURES: Primary subjective endpoints were maximum effect (E(max)) for Drug Liking and effect at 8 hours (E(8h)) postdose for Take Drug Again and Overall Drug Liking. All were assessed using bipolar 0-100 visual analog scale (VAS; 50 points = neutral). Secondary pharmacodynamic endpoints included other VAS endpoints, pupillometry, and subject-rated scales for nasal effects. RESULTS: Forty subjects were randomized to treatment; 39 were evaluable, one subject was excluded for postdose vomiting. Subjects were mostly male (80 percent) and White (75 percent). Least squares mean Drug Liking VAS E(max) (70.8 vs 93.5), Overall Drug Liking E(8h) (47.8 vs 87.4), and Take Drug Again E(8h) (45.9 vs 91.3) were significantly lower for crushed IRO-A vs IRO (all p < 0.0001). A significant sequence effect was found, but lower liking of IRO-A was observed for both treatment sequence groups. Pupillary responses between treatments were similar overall, but differences were noted for some endpoints/time points. Adverse events common to opioids were observed with both treatments. Subjects experienced more nasal-related symptoms with IRO-A. CONCLUSIONS: Crushed IRO-A tablets demonstrated lower scores on "drug liking," "overall drug liking," and "take drug again" than crushed IRO when administered intranasally to nondependent recreational opioid users.

Dose proportionality and the effects of food on bioavailability of an immediate-release oxycodone hydrochloride tablet designed to discourage tampering and its relative bioavailability compared with a marketed oxycodone tablet under fed conditions: a single-dose, randomized, open-label, 5-way crossover study in healthy volunteers.

BACKGROUND: An immediate-release oxycodone hydrochloride formulation (IRO-A) indicated for moderate to severe pain was designed (by adding functional excipients) to discourage tampering associated with intranasal and intravenous abuse of prescription opioids. OBJECTIVES: The primary objective of this study was to determine the dose proportionality of oxycodone in IRO-A tablets under fasted conditions. Secondary objectives were to assess food effects on the pharmacokinetics of IRO-A tablets, to compare the relative bioavailability of oxycodone in IRO-A tablets versus marketed oxycodone hydrochloride (IRO) tablets under fed conditions and to evaluate the single-dose safety profile of the IRO-A tablets in healthy volunteers pretreated with naltrexone. METHODS: This open-label, single-dose, randomized, 5-way crossover study was conducted in healthy adults who received each of the following treatments, separated by a washout period of ≥7 days: IRO-A 1 × 5 mg, 2 × 5 mg, and 2 × 7.5 mg under fasted conditions, and IRO-A 2 × 7.5 mg and IRO 1 × 15 mg after a high-fat, high-calorie breakfast. Naltrexone was administered to minimize untoward pharmacologic effects of oxycodone. Dose proportionality (IRO-A), food effects (IRO-A), and relative bioavailability in a fed state (IRO-A and IRO) were assessed by using bioequivalence criteria (90% CIs between 80% and 125% for C(max) and AUC). RESULTS: Of the 35 adults enrolled in the study, 33 completed at least 1 dosing period. Most participants were male (54%) and white (69%), with a mean (SD) age of 32.6 (11.1) years and mean weight of 75.5 (12.3) kg. Plasma levels of oxycodone in IRO-A suggested dose-proportional pharmacokinetics; 90% CIs for dose-normalized C(max), AUC(0-last), and AUC(0-∞) fell within the 80% to 125% range. Concomitant food intake with IRO-A resulted in an ~14% reduction in oxycodone C(max) and an ~21% increase in AUC(0-last). The bioavailability of oxycodone from IRO-A tablets in the fed state was comparable with IRO tablets based on AUC parameters, although C(max) was ~16.5% lower. Reported or observed treatment-emergent adverse events were monitored throughout the study and were similar for IRO-A and IRO tablets. Nausea, headache, abdominal pain, and dizziness were the most common and are consistent with known effects of oxycodone after naltrexone blockade. CONCLUSIONS: Plasma levels of oxycodone in IRO-A tablets were compatible with proportional single-dose pharmacokinetics from 5 to 15 mg under fasted conditions. Administration of IRO-A with food suggested increased overall bioavailability relative to fasting conditions and a reduction in peak systemic exposure of oxycodone that is not expected to be clinically significant. When comparing IRO-A tablets with IRO tablets in the fed state, the overall systemic exposure of oxycodone was comparable, and peak systemic exposure was lower.

Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide.

BACKGROUND: Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here. METHODS: Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. RESULTS: Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h). CONCLUSIONS: Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.

Randomized, double-blind, placebo-controlled and active-controlled study to assess the relative abuse potential of oxycodone HCl-niacin tablets compared with oxycodone alone in nondependent, recreational opioid users.

BACKGROUND: Abuse-deterrent formulations attempt to address public health and societal concerns regarding opioid abuse. Oxycodone HCl-niacin tablets combine oxycodone HCl with niacin and functional inactive excipients to create potential barriers to oral, intranasal, and intravenous abuse. This study compared the relative abuse potential of oral immediate-release oxycodone HCl-niacin with that of oral immediate-release oxycodone HCl and placebo in nondependent, recreational opioid users. METHODS: Forty-nine participants received oxycodone HCl-niacin 40/240 mg and 80/480 mg, oxycodone 40 mg and 80 mg, and placebo in a randomized, double-blind, placebo-controlled and active-controlled, five-way crossover study. Primary endpoints based on a bipolar 100 mm visual analog scale for drug liking were area under effect curve (AUE0-1h, AUE0-2h, AUE0-3h), peak disliking, and effect at 0.5 hours post-dose (E0.5h). Other endpoints included take drug again assessment, overall drug liking, and pupillometry. RESULTS: There were statistically significant differences between oxycodone HCl-niacin and oxycodone HCl doses for all primary endpoints (P < 0.0001, all comparisons), suggesting reduced abuse potential with oxycodone HCl-niacin. Take drug again and overall drug liking showed greater liking of oxycodone alone. Oxycodone HCl-niacin 80/480 mg had consistently lower liking assessments than oxycodone HCl-niacin 40/240 mg, suggesting a dose-response to the aversive effects of niacin. Opioid-related adverse events were similar for equivalent oxycodone doses. The treatment-emergent adverse events most specifically associated with oxycodone HCl-niacin (ie, skin-burning sensation, warmth, and flushing) were consistent with the expected vasocutaneous effects of niacin. No serious adverse events were reported. CONCLUSION: Oxycodone HCl-niacin tablets may, in a dose-dependent manner, decrease the potential for oral abuse of oxycodone without unexpected adverse events or clinically signifi-cant differences in safety parameters compared with oxycodone alone. Although statistically powered, the small size of the study sample and the characteristics of its participants may not be generalizable to the population that abuses prescription opioid medications.

Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe.

BACKGROUND: In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients. METHODS: Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered. RESULTS: Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013, <0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses. CONCLUSIONS: This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

Bioequivalence in development of antiepileptic drugs.

Bioequivalence is an important component of the development of AEDs. Development of new formulations after the original testing of any drug requires demonstration that the compounds are therapeutically equivalent and additional efficacy studies may not be required. Extended-release formulations may reduce toxicity with a lower maximum blood concentration (C(max)) and improve efficacy with a higher minimum blood concentration (C(min)). Obtaining an equivalent area under the curve (AUC) while slowing the gastrointestinal transit and avoiding food effects and dose dumping among a population with epilepsy with individual variability requires extensive engineering of the formulation. The development of extended release divalproex (Depakote ER) is used as an example of the challenges of this phase of drug development. Other routes of administration discussed are rectal preparations, nasal formulations, and intravenous infusions. These newer formulations may offer better patient care and more efficient development.

Safety, tolerability, and efficacy of continuous transdermal dopaminergic stimulation with rotigotine patch in early-stage idiopathic Parkinson disease.

Rotigotine is a new dopamine agonist with transdermal patch formulation for the treatment of Parkinson disease. The aim of this study was to investigate safety and efficacy of rotigotine in patients with early-stage Parkinson disease. In this open-label, dose-escalation, safety and efficacy study, 31 patients in the early stages of idiopathic Parkinson disease received rotigotine to a maximum of 18.0 mg/day. Of the 29 patients who completed the 28-day treatment phase, 24 were maintained at the maximum dose level. The drug was well tolerated, and skin reactions were mild. A statistically significant improvement in UPDRS I, II, and III scores was observed from baseline to end of treatment for the 29 subjects who completed the trial. Mean improvement (+/- standard deviation) was -0.41 +/- 0.78 on UPDRS I (P = 0.0078), -2.76 +/- 3.31 on UPDRS II (P = 0.0001), and -4.62 +/- 5.32 on UPDRS III (P < 0.0001). When results were stratified by maximum dose achieved, significant improvements were seen on all 3 subscores for patients achieving the maximum dose. These data suggest that rotigotine is a safe, well-tolerated, and effective treatment for early-stage Parkinson disease.

The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder.

BACKGROUND: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex. METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. RESULTS: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters. CONCLUSION: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

Divalproex in the treatment of impulsive aggression: efficacy in cluster B personality disorders.

Impulsive aggressive behavior is common in psychiatric disorders and accounts for significant morbidity and mortality. However, little systematic treatment data exist from placebo-controlled trials for this symptom domain. This was a multicenter, randomized, double-blind, placebo-controlled study in which outpatients with a score of > or =15 on the Aggression scale of the Overt Aggression Scale-Modified (OAS-M) and who fulfilled DSM-IV criteria for Cluster B personality disorder (n=96), intermittent explosive disorder (n=116), or post-traumatic stress disorder (n=34) were randomized to divalproex sodium or placebo for 12 weeks duration. Based on average OAS-M Aggression scores over the last 4 weeks of treatment, a treatment effect was not observed in the intent-to-treat data set (combined across the three psychiatric disorders), but was observed in both intent-to-treat and evaluable data sets for patients with Cluster B personality disorders. In the Cluster B evaluable data set, statistically significant treatment differences favoring divalproex were also observed for component items of the OAS-M Aggression score, including verbal assault and assault against objects, as well as OAS-M Irritability score, and Clinical Global Impression (CGI)-Severity at multiple time points throughout the study. No treatment group difference was noted for overall premature discontinuation rate; however, across psychiatric diagnoses, 21 (17%) patients in the divalproex group prematurely discontinued because of an adverse event, as compared to 4 (3%) patients in the placebo group (p <0.001). While a treatment effect was not observed when all diagnostic groups were combined, in a large subgroup of patients with Cluster B disorders, divalproex was superior to placebo in the treatment of impulsive aggression, irritability, and global severity.

Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes.

BACKGROUND: Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study. RESULTS: A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88). CONCLUSION: Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects.