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Pain Medicine 2011; 12: 618–631 Wiley Periodicals, Inc. OPIOIDS, SUBSTANCE ABUSE & ADDICTIONS SECTION pme_1093 Beatrice Setnik, PhD,* Carl L. Roland, PharmD,* Jody M. Cleveland, MS,* and Lynn Webster, MD† *Research and Development, King Pharmaceuticals, Inc., Cary, North Carolina (King Pharmaceuticals was acquired by Pfizer Inc in March 2011); † Lifetree Clinical Research and Pain Clinic, Salt Lake City, Utah, USA Reprint requests to: Beatrice Setnik, PhD, Pfizer Inc. 4000 Centre Green Way, Suite 300, Cary, NC 27513, USA. Tel: 919-653-7071; Fax: 919-653-7022; E-mail: [email protected]. Abstract Objectives. Remoxy® is a water-insoluble, highly viscous oral formulation of oxycodone extended release (ER) currently in development. The primary objective was to determine the abuse potential of Remoxy under fed conditions relative to oxycodone ER and immediate release (IR) under fasted conditions and compared with placebo (treatment group X). A secondary objective was to evaluate abuse potential under reversed fed/fasted conditions (treatment group Y). Design. Phase I randomized double-blind tripledummy placebo- and active-controlled 6-way crossover study. Setting. A single US site. Patients. Healthy men and women aged 18–50 years who were nondependent, recreational opioid users. Interventions. Remoxy 40 mg whole and chewed, oxycodone ER 40 mg whole and crushed, oxycodone IR 40 mg crushed, and placebo. 618 618..631 Outcome Measures. The primary endpoint was the drug liking subscale of the drug effects questionnaire assessed by various pharmacodynamic parameters. Secondary endpoints included additional pharmacodynamic measures, chewing duration, and safety measures. Results. In treatment group X, Remoxy whole (fed) and chewed (fed) had a significantly lower abuse potential compared with oxycodone ER (crushed, fasted) and IR (fasted) based on the majority of pharmacodynamic parameters of interest for the primary endpoint (drug liking subscale) as well as secondary endpoints. Treatment group Y showed generally similar results. Conclusions. The abuse potential of Remoxy when taken whole or chewed was significantly lower than two comparators with known abuse potential, including oxycodone IR and crushed oxycodone ER, under the fed/fasted conditions tested. Remoxy may be associated with a reduced risk potential for abuse. Key Words. Abuse; Liability; Oxycodone; Potential; Remoxy Introduction More than one in four American adults experience pain lasting a day or more, and in general, pain affects more Americans than diabetes, heart disease, and cancer combined [1]. Opioids are an important treatment option for the management of moderate to severe chronic pain [2], and their availability and use for acute and chronic pain have increased over the past few decades [3]. Unfortunately, as prescription opioid use has increased so has its abuse, with nearly 12 million persons (4.8%) 12 years of age or older reporting nonmedical use of prescription pain relievers in the past year [4]. Admissions to substance abuse treatment centers for primary abuse of opiates other than heroin has increased from 1% of all admissions Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Original Research Article The Abuse Potential of Remoxy®, an Extended-Release Formulation of Oxycodone, Compared with Immediate- and Extended-Release Oxycodone Abuse Potential of Remoxy (Oxycodone ER) in 1997 to 5% in 2007; however, overall substance abuse admissions increased only 13% during this time [5]. Nearly three quarters (72%) of these admissions reported the route of administration as oral (whole and crushed); however, 16% reported inhalation and 10% reported injection [5]. National results of adolescent drug use found that 1 in 10 twelfth-graders reported recreational use of Vicodin® (Abbott Laboratories, Abbott Park, IL) and 1 in 20 reported use of OxyContin® (Purdue Pharma LP, Stamford, CT) [6]. Remoxy® (King Pharmaceuticals, Inc., Bristol, TN) is an encapsulated, water insoluble, highly viscous ER oral formulation of oxycodone currently in development for the treatment of moderate to severe chronic pain and was designed to limit the release of oxycodone following manipulation or tampering. In previous studies, Remoxy has demonstrated that its formulation limits the release of oxycodone following manipulation, including crushing and extraction in alcohol or water [10]. The true impact that the Remoxy formulation may have on reducing misuse and abuse associated with tampering cannot be established until it is evaluated in the community at large. Abuse potential studies provide a means of predicting the likelihood of abuse by recreational users before larger patient populations are exposed to a drug [14,15]. Generally, a drug’s ability to produce pleasurable effects, such as euphoria, and to become reinforcing may be Methods Study Design and Patients This study was conducted in accordance with Good Clinical Practice requirements as described in the International Conference on Harmonisation guidelines. The protocol was reviewed and approved by the appropriate local institutional review board, and all patients provided written informed consent. This was a phase I randomized double-blind triple-dummy placebo- and active-controlled 6-way crossover study in healthy male and female, nondependent, recreational opioid users aged 18–50 years (inclusive) with a body mass index between 18 and 33 kg/m2. Recreational opioid use was defined as having recreationally abused opioids to achieve a “high” on at least five occasions in the 12 months before screening and at least once in the 90 days before screening (visit 1). Patients who abused multiple drugs were to express a preference for opioids. Urine drug screens and alcohol breath tests were conducted at each clinic admission to confirm compliance with study restrictions. Concomitant medications were not permitted within 14 days before or during the study. Acetaminophen (1000 mg/dose; maximum 4000 mg/day) was permitted to treat an adverse event (AE) provided that the administration was ⱖ8 hours before and/or ⱖ6 hours after any pharmacodynamic (PD) measurement. Figure 1 illustrates the study design. Following the screening visit (visit 1), patient eligibility was confirmed by the naloxone challenge phase (treatment visit 2, day 0) and the drug discrimination phase (treatment visit 2, days 1–2). 619 Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Extended-release (ER) opioid formulations were developed to allow a slow release of the drug to manage chronic pain. Oxycodone ER (e.g., OxyContin) was originally believed to have reduced abuse liability owing to the slow release of oxycodone from the formulation and the resulting lack of an immediate rush or high [7], although no abuse liability studies of the product had been published to support this. Furthermore, oxycodone ER exhibits a biphasic absorption pattern that may lead to an initial immediate release of more than 30% of the oxycodone dose [8]. It was later noted that potency and formulation of oxycodone ER may have actually made it more attractive for abuse. The controlled release formulation is easily compromised, and the original safety warning may have inadvertently provided this information to abusers [7]. Current ER opioid formulations remain a frequent target for drug abusers because the products can be easily compromised to release the full opioid dose [9]. For example, the rate of absorption of oxycodone ER can be increased through various means of tampering such as chewing, crushing and snorting, or dissolving the product in water and injecting the solution [10]. In April 2010, the Food and Drug Administration approved a new formulation of OxyContin that was designed to help discourage misuse and abuse of the medication [11]. In 2009, it was estimated that nearly 1.7 million Americans had used the previous formulation of OxyContin nonmedically in the past year [12]. Whether the new formulation reduces misuse and abuse relative to the previous version will not be known until the results of a required post-market study are available [13]. predictive of abuse and addiction. The primary objective of the current study was to determine the abuse potential of orally administered Remoxy (whole and chewed) under fed conditions relative to oxycodone immediate release (IR) and oxycodone ER (whole and crushed) under fasted conditions, and compared with placebo. Conditions of manipulation (i.e., crushing or chewing) were chosen individually for each drug to include a condition of tampering that was relatively easy to perform, could be applied to the drug based on its physical/chemical properties, and would result in an increased amount of the drug when administered orally. As abuse potential is expected to be greater when the maximum amount of drug is delivered in the shortest amount of time, the comparison between Remoxy administered in the fed state and oxycodone ER and IR in the fasted state was considered most appropriate for this study. Previous studies have shown that oxycodone ER and IR demonstrate a lower bioavailability when administered in a fed relative to a fasted state [16]. In contrast, pharmacokinetic (PK) studies of Remoxy have demonstrated an opposite effect with food (i.e., an increase in bioavailability in the fed vs the fasted state) [10]. Secondary objectives included a comparison of the safety of Remoxy to oxycodone IR and ER and an assessment of the duration and subjective experience of chewing Remoxy. Setnik et al. During the naloxone challenge, 0.2 mg of naloxone HCl was intravenously administered, followed by a second injection of 0.6 mg if no signs of withdrawal were present. Withdrawal symptoms were rated using the clinical opiate withdrawal scale (COWS) following each injection; patients with no withdrawal (COWS score <5 was considered as showing no signs of withdrawal) were eligible to continue in the study. The drug discrimination phase was conducted to confirm that patients could tolerate treatment and discriminate between the effects of oxycodone IR (20 mg) and placebo. Both drugs were administered as single, oral doses in a double-blind randomized order on two consecutive days and were followed by serial PD and safety assessments at pre-dose and up to 5 hours post-dose. Patient eligibility was based on the ability to tolerate study treatments (i.e., no episodes of vomiting within the first 2 hours post-dose), to follow study procedures, and to distinguish oxycodone from placebo on selected PD measures (i.e., ⱖ25-point difference on the visual analog scale [VAS] for drug liking and drug high for oxycodone relative to placebo, at both 0.5 and 1 hour post-dose). In the abuse potential phase 620 (treatment visits 2–5, days 3–24), patients were randomly assigned in a 3:1 ratio to 1 of 2 treatment groups, referred to as treatment groups X and Y (Table 1). Treatment group X was considered the primary analysis group because treatments were administered under the fed/fasted states that produce the highest bioavailability for each drug (i.e., Remoxy administered in the fed state and oxycodone administered in the fasted state). Treatment group Y (Remoxy in the fasted state and oxycodone ER and IR in the fed state) was considered an exploratory analysis implemented to maintain the double-blind nature of the study. Therefore, the results from treatment group Y are not fully detailed. In each group, patients were randomized to one of six treatment sequences and received, in a double-blind fashion, single oral doses of the investigational drug (Remoxy administered whole and chewed), the active comparators oxycodone IR and oxycodone ER (administered whole and crushed), and placebo, as shown in Table 1. Serial PD and safety measures were assessed pre-dose and for up to 24 hours post-dose following each Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Figure 1 Study design. *Discharge following all 24-hour post-dose procedures and † Restudy assessments. admission to clinic on afternoon/ evening prior to next dosing. Abuse Potential of Remoxy (Oxycodone ER) Table 1 Description of treatment groups X and Y Treatment Treatment Group Y (N = 12) Fed Fed Fasted Fasted Fed Fasted Fasted Fed Fasted Fed Fasted Fed Outcomes and Assessments ER = extended release; IR = immediate release. drug administration. Dosing of each treatment was separated by a washout period of at least 92 hours. Study Drugs and Dosing Naloxone HCl was supplied as a 0.4 mg/mL solution for intravenous administration. During the drug discrimination phase, oxycodone IR and placebo were administered orally in solution, as described below. In the abuse potential phase, treatments were administered orally in a tripledummy fashion where patients consumed two different capsules (each blinded for Remoxy and oxycodone ER) and 150 mL of a solution containing active study drug or placebo. Oxycodone IR was sourced as 5-, 15-, and 30-mg tablets and prepared for oral administration of 20and 40-mg doses by crushing the appropriate tablets with a mortar and pestle for 2 minutes. Crushed tablets were then mixed with 150 mL of artificially sweetened, noncarbonated, flavored beverage at room temperature. Oxycodone ER (crushed) was prepared using 40-mg OxyContin tablets, which were crushed with a mortar and pestle and mixed with 150 mL of the previously described beverage. A placebo solution was prepared using the beverage containing aliquoted amounts of inactive ingredients (i.e., glycerol distearate, microcrystalline cellulose, and sodium lauryl sulfate) to mimic the texture of crushed tablets. Oxycodone ER was prepared by overencapsulating OxyContin 40-mg tablets in size #DB AA el Swedish Orange opaque capsules backfilled with microcrystalline cellulose as the diluent. A matching placebo capsule was prepared by filling Swedish Orange capsules with microcrystalline cellulose. During the drug discrimination and abuse potential phases (for fasted treatments only), study drugs were administered orally following an overnight fast of at least 8 hours. For treatments administered in a fed state (abuse potential phase only), patients received a standard breakfast consisting of 8 ounces of orange juice, two fried eggs, and two slices of toast with butter and preserves that was consumed within 30–60 minutes before dosing. No addi- The primary PD endpoint to assess abuse potential was the unipolar 100-mm VAS for drug liking, which ranged from 0 (“none”) to 100 (“extremely”) and is 1 of 9 subscales of the drug effects questionnaire (DEQ). The remaining subscales of the DEQ included assessments for high, any drug effects, good effects, bad effects, feel sick, nausea, sleepy, and dizzy, which were also ranked on a unipolar 100-mm VAS. Several secondary assessments were also performed. The Cole/Addiction Research Center Inventory Morphine Benzedrine Group (Cole/ARCI MBG) scale consists of 16 statements from which the patients rate their answers on a four-point scale (0 = false, 1 = more false than true, 2 = more true than false, and 3 = true) [17,18]. The take drug again assessment is based on a single question “Would you take the drug you just received again, if given the opportunity?” categorized on a bipolar 100-mm VAS scale where 50 is neutral (“do not care”) and the two polar ends are 0 (“definitely would not”) and 100 (“definitely would”). The price value assessment questionnaire (PVAQ) was adapted from the street value assessment questionnaire described by Cole et al. [19] and asked of the patient “What is the most that you would be willing to pay for a single [1] dose of the drug that you have just taken, if it was offered to you on the street?” Responses were provided in increments of $5 amounts, ranging from $0 to $100. This questionnaire has been adjusted to increased values ranging from $0 to $100 rather than the previous range of $0–10. This increase is reflective of the more recent illicit street prices of OxyContin, estimated between $0.50 and $1.00 per milligram [20]. Pupil size was measured by pupillometry (Colvard Pupilometer; OASIS, Glendora, CA) in a dimly lit room with standardized light; the same eye was used for all measurements. Exploratory parameters included the chewing duration of study drug, and subjective ratings of taste and texture (of chewed study drug) using a bipolar 100-mm VAS that was developed for this study and ranged from 0 (“extremely unpleasant”) to 100 (“extremely pleasant”), with a “neutral” anchor at 50. Any patient who chewed for the entire 10-minute duration would be asked to estimate the amount of capsule content remaining in their mouth (% relative to total amount at the start of chewing) and whether they felt that the remaining content was comprised of 1) equal amounts of both gelatin capsule and drug content material, 2) mostly drug content, or 3) mostly gelatin capsule. 621 Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Treatment A: Placebo Treatment B: Remoxy 40 mg (whole) Treatment C: Remoxy 40 mg (chewed) Treatment D: Oxycodone HCl ER 40 mg (whole) Treatment E: Oxycodone HCl ER 40 mg (crushed) Treatment F: Oxycodone HCl IR 40 mg Treatment Group X (N = 36) tional food/water was permitted following all dosing for up to 2 hours post-dose. Dosing during the abuse potential phase was conducted using a triple-dummy paradigm for each treatment; patients swallowed two intact capsules, chewed one capsule, and ingested 150 mL of solution, each containing active drug or placebo. A period of 10 minutes was allotted for chewing, and patients were instructed to vigorously chew the capsule, containing either Remoxy or placebo, for as long as possible. Setnik et al. Safety assessments included AEs, vital signs (i.e., heart rate, respiratory rate, and systolic/diastolic blood pressure), oxygen saturation (SpO2), and end tidal carbon dioxide (CO2). Additional assessments included clinical laboratory tests (i.e., hematology, chemistry, urinalysis, and serology), electrocardiograms, and serum/urine pregnancy tests. Sample Size This study was to screen approximately 90 male and female patients to ensure enrollment of 48 patients into the abuse potential phase. Of these, 36 patients were to be enrolled into treatment group X to allow at least 18 patients to complete the study, and 12 were to be enrolled into treatment group Y to allow at least six patients to complete the study. In total, at least 24 patients were expected to allow the study. The study was not formally powered for any single analysis. However, power calculations for select analyses were performed given the anticipated enrollment and completion sizes provided above. The comparison within treatment group X of Remoxy 40 mg chewed (fed) vs oxycodone IR 40 mg (fasted), of AUE0–2 hours for drug liking, was expected to have at least 80–90% power, assuming a mean difference of 30–35 hours·mm and an SD of the paired differences of 40–45 hours·mm, based on a paired t-test for analysis and a significance level of 5%. Because the mean differences of AUE0–2 hours for drug liking were expected to be larger for the comparison within treatment group X of Remoxy 40 mg whole (fed) vs oxycodone IR 40 mg (fasted), the power was also expected to be larger. Statistical Analyses In general, all statistical testing was two sided and performed at the 0.05 significance level. Multiple comparison adjustments for all pair wise treatment comparisons of the principle parameters for the primary endpoint were made 622 using the Benjamini-Hochberg method [21]. Data are provided as least squares (LS) means for all treatments and LS mean differences for pairwise treatment comparisons with 95% confidence intervals. Linear interpolation was used for missing AUE values in cases where sample collection was not drawn or was invalid. Continuous variables were summarized with descriptive statistics (e.g., means, SDs, medians, minima, and maxima) and categorical values were summarized by count and percentage of patients in corresponding categories. PD parameters for treatment group X were analyzed using an analysis of variance linear mixed model with fixed effects for sequence, period, and treatment, and a random effect for patients nested in sequence to test the hypothesis that there is no difference in abuse potential between Remoxy (whole/chewed, fed) and each of the active comparators separately, compared with the alternative hypothesis that there is a difference. Similar methods were used for treatment group Y, with fixed effects for period and treatment, and a random effect for patients, but not for sequence as the sample size was too small. The primary endpoint, drug liking, was also summarized as a responder analysis based on percent change in drug liking for Remoxy relative to oxycodone IR and ER. The primary population used for PD analyses was the completer population, which included all randomly assigned patients who received all six treatments and who contributed post-dose data for each treatment period in the abuse potential phase. This population was analyzed as randomized. Analyses of the primary PD endpoint (drug liking) and the drug high endpoint were also performed using the per protocol (PP) population. The PP population included all completer population patients who did not have a major protocol violation. Major protocol violations, including deviations related to study drug intake (such as any vomiting occurring within 2 hours post-dose), were defined as those that could potentially affect the PD or safety conclusions of the study. These violations were determined before unblinding the study database. The PP population was also analyzed as randomized. The safety populations were defined by study phase and included all patients who received at least one dose of study drug in the naloxone challenge phase, the drug discrimination phase, and the abuse potential phase, respectively. These populations were analyzed as treated. Results Patient Disposition and Baseline Characteristics Of the 65 patients enrolled in the study, all successfully completed the naloxone challenge phase and proceeded to the drug discrimination phase. During this phase, 20 patients discontinued; 17 patients were not able to distinguish between oxycodone and placebo, two patients vomited within 2 hours post-dose, and one patient voluntarily withdrew consent. A total of 45 patients were Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 To evaluate abuse potential, the following parameters were assessed as the principal parameters for all PD endpoints (with the exception of the take drug again and PVAQ): area under the effect curve (AUE0–1 hour and AUE0–2 hours), maximum effect (Emax), and time to maximum (peak) effect (TEmax) or minimum effect and time to minimum effect (Emin and TEmin, respectively) for pupil size. Emax and TEmax were calculated using all post-dose data, up to 24 hours post-dose. Additional secondary parameters calculated for all PD endpoints (with the exception of the take drug again and PVAQ) were: AUE0–3 hours, AUE0–4 hours, AUE0–8 hours, AUE0–12 hours, AUE0–24 hours, and effects at designated time points (E0.5 hour, E1 hour, E1.5 hours, and E2 hours). For the take drug again assessment and PVAQ, the data were collected and analyzed at 12 and 24 hours postdose and at the maximum (peak) effect (Emax [the maximum effect at either 12 or 24 hours]). Chewing duration and VAS scores for taste and texture were summarized (for Remoxy chewed only) using descriptive statistics (n, arithmetic mean, median, standard deviation [SD], range, and coefficient of variation). Abuse Potential of Remoxy (Oxycodone ER) Enrolled Completed Naloxone Challenge Phase N=65 Completed Drug Discrimination Phase N=65 Enrolled into Abuse Potential Phase (3:1) N=45 Drug Liking Visual Analog Scale Tx: X N=34 Tx: Y N=11 Tx: X N=32 Tx: Y N=11 Figure 2 Patient disposition. Tx = treatment group. enrolled into the abuse potential phase, 34 patients were randomized to treatment group X, and 11 patients were randomized to treatment group Y (Figure 2). During the abuse potential phase, two patients in treatment group X discontinued the study, one upon request and one because of noncompliance. The completer population consisted of the 32 patients in treatment group X and the 11 patients in treatment group Y who completed the study. Three patients had a major protocol violation (i.e., emesis within 2 hours of taking study drug), resulting in their removal from the PP population in treatment group X following administration of oxycodone IR 40 mg or oxycodone ER 40 mg (crushed). Baseline characteristics for completed patients in treatment group X are presented in Table 2. The majority of patients were white (94%) and male (78%), and the mean age was approximately 25 years (range, 18–38 years). Pharmacodynamic Analyses Figures 3A–E present the positive subjective effects PD endpoints and pupillometry endpoint arithmetic mean data across time for each treatment group, demonstrating the time course of effect from time 0 (dosing) to 8 hours post-dose. Figures 4A–D present each treatment’s LS means of the principal parameters for the primary endpoint of drug liking. Study validity was confirmed by the comparison of oxycodone IR 40 mg (fasted) vs placebo (fed). Mean drug liking for oxycodone IR 40 mg (fasted) was statistically For comparisons of Remoxy vs active control on the parameters of Emax and AUE for the primary endpoint, drug liking, a negative difference in the LS means indicates that Remoxy is liked less than the comparator, whereas a positive difference indicates that Remoxy is liked more than the comparator. For TEmax, a positive difference indicates that the time to maximum (peak) drug liking effect is longer for Remoxy. Table 2 Patient characteristics (completer population) Characteristic Age, y Mean (SD) Median Range Gender, N (%) Men Women Ethnicity, N (%) Not Hispanic or Latino Hispanic or Latino Race, N (%) White Asian Native Hawaiian or Pacific Islander Weight, lb Mean (SD) Median Range Height, in Mean (SD) Median Range BMI, kg/m2 Mean (SD) Median Range Treatment Group X (N = 32) 25.2 (4.65) 24.5 18, 38 25 (78) 7 (22) 30 (94) 2 (6) 30 (94) 1 (3) 1 (3) 167.2 (35.03) 167.5 117.0, 251.0 70.0 (3.67) 70.0 62.5, 77.0 23.8 (3.47) 22.8 18.9, 32.7 BMI = body mass index; SD = standard deviation. 623 Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Completed Study significantly greater than that observed with placebo based on the principal parameters of interest (i.e., AUE0–1 hour, AUE0–2 hours, and Emax) (P < 0.0001). Study validity was also supported by the significant differences observed for pupil size, drug high, good effects, Cole/ARCI MBG scale, take drug again assessment, and PVAQ between oxycodone IR 40 mg (fasted) and placebo (fed). Additionally, there were no significant differences observed between active controls, oxycodone IR 40 mg (fasted), and oxycodone ER 40 mg (crushed, fasted) on all principal parameters for drug liking (P ⱖ 0.2665) and on all principal parameters for drug high, good effects, Cole/ARCI MBG scale, take drug again assessment, and PVAQ (P ⱖ 0.0892). N=65 Setnik et al. A. Drug Liking 100 Treatment Placebo fed (n=32) Remoxy® 40 mg (chewed) fed (n=32) Oxycodone HCl ER 40 mg (crushed) fasted (n=32) Remoxy® 40 mg (whole) fed (n=32) Oxycodone HCl ER 40 mg (whole) fasted (n=32) Oxycodone HCl IR 40 mg fasted (n=32) 90 Mean DEQ (mm) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Time (h) Post-Dose B. Drug High 100 Treatment Placebo fed (n=32) Remoxy® 40 mg (chewed) fed (n=32) Oxycodone HCl ER 40 mg (crushed) fasted (n=32) Remoxy® 40 mg (whole) fed (n=32) Oxycodone HCl ER 40 mg (whole) fasted (n=32) Oxycodone HCl IR 40 mg fasted (n=32) 90 Mean DEQ (mm) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Time (h) Post-Dose Note: Visual analog scale from 0 to 100 mm, where 0=’None’ and 100=’Extremely’. At pre-dose, only questions 6–9 were assessed per protocol, question #5 is set to zero for plotting purposes. Figure 3 A–E. Mean visual analog scale (VAS) scores for positive patient effects (drug liking, drug high, and good drug effects subscales of the drug effects questionnaire and the Cole/Addiction Research Center Inventory Morphine Benzedrine Group scale) and pupillometry endpoints for the completer population (treatment group X), demonstrating the time course of effect from dosing through 8 hours post-dose. DEQ = drug effects questionnaire; ER = extended release; IR = immediate release. Table 3 summarizes the analysis of variance results for drug liking in the completer population for treatment group X. All treatments demonstrated a significantly higher abuse potential compared with placebo. The comparisons of interest were Remoxy (whole, fed) and Remoxy (chewed, fed) vs oxycodone IR (fasted) and vs oxycodone ER (whole and crushed, fasted). In general, Remoxy (whole and chewed) had a lower abuse potential than the active comparators of oxycodone IR and crushed oxycodone ER during the time intervals assessed. Mean drug liking was statistically significantly lower for Remoxy 40 mg (whole, fed) and Remoxy 40 mg (chewed, 624 fed) compared with oxycodone IR 40 mg (fasted) and oxycodone ER 40 mg (crushed, fasted) for Emax, AUE0–1 hour, and AUE0–2 hours (P ⱕ 0.0461). In addition, the time to peak drug liking was significantly delayed for Remoxy (whole and chewed) compared with oxycodone IR and oxycodone ER (crushed) (P ⱕ 0.0193). Mean drug liking for Remoxy 40 mg (whole, fed) was also statistically significantly lower than oxycodone ER 40 mg (whole, fasted) for both AUE0–2 hours and Emax (P ⱕ 0.0374). Mean drug liking for Remoxy 40 mg (chewed, fed), however, was statistically significantly higher than oxycodone ER 40 mg (whole, fasted) based on AUE0–1 hour and AUE0–2 hours (P ⱕ 0.0275), but was not significantly different for both Emax and TEmax (P ⱖ 0.3423). Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Note: Visual analog scale from 0 to 100 mm, where 0=’None’ and 100=’Extremely’. At pre-dose, only questions 6–9 were assessed per protocol, question #4 is set to zero for plotting purposes. Abuse Potential of Remoxy (Oxycodone ER) C. Good Drug Effects 100 Treatment Placebo fed (n=32) Remoxy® 40 mg (chewed) fed (n=32) Oxycodone HCl ER 40 mg (crushed) fasted (n=32) Remoxy® 40 mg (whole) fed (n=32) Oxycodone HCl ER 40 mg (whole) fasted (n=32) Oxycodone HCl IR 40 mg fasted (n=32) 90 Mean DEQ (mm) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Time (h) Post-Dose Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Note: Visual analog scale from 0 to 100 mm, where 0=’None’ and 100=’Extremely’. At pre-dose, only questions 6–9 were assessed per protocol, question #2 is set to zero for plotting purposes D. Cole/Addiction Research Center MBG Scale 100 Placebo fed (n=32) Remoxy® 40 mg (chewed) fed (n=32) Oxycodone HCl ER 40 mg (crushed) fasted (n=32) Remoxy® 40 mg (whole) fed (n=32) Oxycodone HCl ER 40 mg (whole) fasted (n=32) Oxycodone HCl IR 40 mg fasted (n=32) 90 80 Mean Total Score Treatment 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Time (h) Post-Dose E. Pupillometry Endpoints 100 Treatment Placebo fed (n=32) Remoxy® 40 mg (chewed) fed (n=32) Oxycodone HCl ER 40 mg (crushed) fasted (n=32) Remoxy® 40 mg (whole) fed (n=32) Oxycodone HCl ER 40 mg (whole) fasted (n=32) Oxycodone HCl IR 40 mg fasted (n=32) 90 Mean Pupil Size (mm) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Time (h) Post-Dose Figure 3 Continued. The LS mean values for each of the principal parameters are graphically depicted in Figure 4A–D for drug liking and demonstrate general consistency in the overall abuse potential of Remoxy (whole and chewed, fed) relative to the oxycodone comparators (fasted). For all of the principal PD parameters, Remoxy (whole and chewed, fed) was liked less compared with the oxycodone comparators (fasted), except for Remoxy (chewed, fed) vs oxycodone 625 ** * ** * * ** * ** * ** D. Drug Liking TEmax * ** * ** ** * ** * ** * ** * ** Figure 4 A–D. Least squares means of the principal parameters of drug liking (primary endpoint) for the completer population (treatment group X), demonstrating general consistency in the overall abuse potential of Remoxy (whole and chewed, fed) relative to the oxycodone comparators (fasted). * P < 0.05 vs Remoxy (chewed). ** P < 0.05 vs Remoxy (whole). ER = extended release; IR = immediate release; LS = least squares. * ** * B. Drug Liking AUE0−2 hours * ** * ** * ** C. Drug Liking Emax Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 626 * A. Drug Liking AUE0−1 hour Setnik et al. 12.8 (1.2, 24.5) 0.0372 30.7 (22.5, 38.8) <0.0001 3.4 (2.4, 4.4) <0.0001 AUE0–1 hour (h·mm) LS mean difference* 95% CI* Adjusted P value† AUE0–2 hours (h·mm) LS mean difference* 95% CI* Adjusted P value† Emax (mm) LS mean difference* 95% CI* Adjusted P value† TEmax (h) LS mean difference* 95% CI* Adjusted P value† 2.2 (1.2, 3.1) <0.0001 -26.4 (-34.6, -18.3) <0.0001 -71.6 (-83.2, -60.0) <0.0001 -32.2 (-38.1, -26.3) <0.0001 2.0 (1.1, 3.0) <0.0001 -21.6 (-29.8, -13.4) <0.0001 -65.9 (-77.6, -54.3) <0.0001 -28.8 (-34.7, -22.9) <0.0001 Oxycodone ER 40 mg (Crushed, Fasted) (N = 32) 0.9 (-0.1, 1.8) 0.0836 -8.9 (-17.1, -0.8) 0.0374 -21.2 (-32.8, -9.6) 0.0007 -2.8 (-8.6, 3.1) 0.3718 Oxycodone ER 40 mg (Whole, Fasted) (N = 32) 2.6 (1.6, 3.5) <0.0001 43.7 (35.6, 51.8) <0.0001 49.8 (38.2, 61.5) <0.0001 13.7 (7.9, 19.6) <0.0001 Placebo (Fed) (N = 32) 1.4 (0.4, 2.3) 0.0089 -13.4 (-21.5, -5.2) 0.0022 -34.6 (-46.3, -23.0) <0.0001 -22.6 (-28.5, -16.7) <0.0001 Oxycodone IR 40 mg (Fasted) (N = 32) 1.2 (0.2, 2.2) 0.0193 -8.6 (-16.7, -0.4) 0.0461 -28.9 (-40.6, -17.3) <0.0001 -19.1 (-25.0, -13.3) <0.0001 Oxycodone ER 40 mg (Crushed, Fasted) (N = 32) Remoxy 40 mg (Chewed, Fed) Vs Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 0.1 (-0.9, 1.0) 0.9033 4.1 (-4.0, 12.3) 0.3423 15.8 (4.2, 27.5) 0.0109 6.9 (1.0, 12.8) 0.0275 Oxycodone ER 40 mg (Whole, Fasted) (N = 32) AUE = area under the effect curve; CI = confidence interval; Emax = maximum effect; ER = extended release; IR = immediate release; LS = least squares; PD = pharmacodynamics; TEmax = time to maximum effect; VAS = visual analog scale. * LS means, 95% CIs, and unadjusted P values were from a linear mixed model with fixed effects for sequence, period, and treatment, and a random effect for patients nested in sequence. † P values for the primary endpoint only were based on the Benjamini–Hochberg adjustment for multiplicity. 4.1 (-1.8, 10.0) 0.1879 PD Parameter Oxycodone IR 40 mg (Fasted) (N = 32) Remoxy 40 mg (Whole, Fed) Vs LS mean difference in VAS score for drug liking in treatment group X (completer population) Placebo (Fed) (N = 32) Table 3 Abuse Potential of Remoxy (Oxycodone ER) 627 Setnik et al. ER (whole, fasted). Of note, Figure 4D illustrates that the difference in the time to maximum drug liking was smallest for the Remoxy (chewed, fed) vs oxycodone ER (whole, fasted) and Remoxy (whole, fed) vs Remoxy (chewed, fed) comparisons. Remoxy (chewed, fed) demonstrated a statistically significantly larger mean pupil size compared with oxycodone IR (fasted) for AUE0–1 hour (P = 0.0027) and oxycodone ER (crushed, fasted) for AUE0–1 hour and AUE0–2 hours (P ⱕ 0.0384). Compared with oxycodone ER (whole, fasted), Remoxy (chewed, fed) had a statistically significantly smaller mean pupil size for AUE0–1 hour and AUE0–2 hours (P ⱕ 0.0136). Other Endpoints Secondary PD Endpoints In general, among patients in treatment group X, the LS mean differences in the principal parameters for the drug high and good effects subscales of the DEQ and the Cole/ARCI MBG scale supported the trends identified with the drug liking subscale. The means for drug high, good effects, and Cole/ARCI MBG scale were statistically significantly lower (greater for TEmax; no significant difference in TEmax on the Cole/ARCI MBG Scale) for Remoxy (whole, fed) compared with oxycodone IR (fasted) and oxycodone ER (crushed, fasted) based on the principal parameters of interest (P ⱕ 0.0130). In addition, the means for drug high and good effects were significantly lower (greater for TEmax) for Remoxy (chewed, fed) compared with oxycodone IR (fasted) and oxycodone ER (crushed, fasted) for all principal parameters (P ⱕ 0.0347). The means for the Cole/ ARCI MBG scale were statistically significantly lower for Remoxy (chewed, fed) compared with oxycodone IR (fasted) and oxycodone ER (crushed, fasted) based on AUE0–1 hour and AUE0–2 hours (P ⱕ 0.0183). Figure 3 demonstrates the consistency of effect across the various positive subjective endpoints. The results of any drug effect and the negative subjective effect endpoints showed similar trends as the primary PD endpoint of drug liking and the other positive subjective effect endpoints (e.g., Remoxy [whole, fed] had lower mean negative subjective effects than oxycodone IR [fasted] and oxycodone ER [crushed, fasted]). However, mean differences between treatments were not as great as those observed for positive subjective effect endpoints. 628 No patient was able to chew the capsules for the allotted 10 minutes. The mean chewing time for Remoxy was <1 minute (0.8 minutes), with a maximum reported chewing time of 1.5 minutes. The VAS for assessing pleasantness of chewing found that the majority of patients reported the taste (mean VAS score = 17.7) and texture (mean VAS score = 21.6) of Remoxy as unpleasant. Treatment Group Y Results In brief, results from treatment group Y were similar to those for treatment group X. Even under conditions of lesser bioavailability (fasted for Remoxy and fed for oxycodone IR and ER), the trends in treatment group Y were consistent with those seen in treatment group X, demonstrating lower abuse potential for Remoxy (whole) and Remoxy (crushed) relative to oxycodone IR and oxycodone ER (crushed) during the time intervals assessed. Safety The AEs associated with Remoxy and oxycodone IR and ER were typical of those that occur with any opioidcontaining drug, with the most common (occurred in ⱖ10% of patients) being pruritus, dizziness, somnolence, nausea, and vomiting during the abuse potential phase. Most AEs were considered mild in intensity. There were no serious AEs, deaths, or discontinuations due to AEs during the study. There were no clinically important changes from baseline in vital signs or laboratory values. Mean end tidal CO2 demonstrated an opioid treatment effect in the active treatment groups relative to placebo; however, mean SpO2 and end tidal CO2 remained within normal ranges. Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 The responder analysis based on percent change in Emax for drug liking demonstrated that 88% and 75% of patients had some degree of reduced drug liking after receiving Remoxy 40 mg (whole, fed) and Remoxy 40 mg (chewed, fed), respectively, compared with oxycodone IR 40 mg (fasted). Of the 9% and 19% with any increase (nine patients), only three patients had increases greater than 10% and all three were in the Remoxy 40 mg (chewed, fed) treatment group. From the responder analysis, relative to oxycodone ER (crushed, fasted), 78% and 66% of patients had some degree of reduced drug liking after receiving Remoxy 40 mg (whole, fed) and Remoxy 40 mg (chewed, fed), respectively. Of the 19% and 28% with any increase (14 patients), respectively, half (seven patients) had increases greater than 10%, two from the Remoxy 40 mg (whole, fed) group and five from the Remoxy 40 mg (chewed, fed) group. For treatment group X, LS mean values for the take drug again assessment and PVAQ for Remoxy whole and chewed (fed) were generally lower (indicating less willingness to take the drug again or pay more for the drug) compared with the other active treatments; however, the majority of these comparisons were not statistically significant. For assessments of pupil size, larger values indicate less pupil constriction (i.e., a lesser drug effect). The mean pupil size was statistically significantly larger for Remoxy 40 mg (whole, fed) compared with oxycodone IR 40 mg (fasted) and oxycodone ER 40 mg (crushed, fasted) (P ⱕ 0.0371) based on the principal PD parameters, and for AUE0–2 hours when compared with oxycodone ER (whole, fasted) (P = 0.0303). Abuse Potential of Remoxy (Oxycodone ER) Discussion Study validity was confirmed by demonstrating statistically significant increases in drug liking, as well as other positive subjective effect endpoints (i.e., drug high, good effects, Cole/ARCI MBG scale) and significant decreases in pupil size, following administration of oxycodone IR 40 mg relative to placebo. In general, all active treatments containing oxycodone showed, on the majority of parameters, significantly higher ratings on drug liking and the positive subjective drug effects, and significant decreases in pupil size compared with placebo. With respect to the active controls, the results of this study demonstrated that when crushed, oxycodone ER showed a similar abuse potential to oxycodone IR. Remoxy 40 mg, administered either whole or chewed, had statistically significantly lower ratings on all principal parameters assessed for drug liking and for the majority of secondary endpoints and parameters assessed, compared with both oxycodone IR and oxycodone ER (crushed), indicating a relative decrease in abuse potential. A responder analysis also demonstrated that the majority of patients showed some degree of reduced drug liking following Remoxy whole and chewed treatments, compared with oxycodone IR and oxycodone ER (crushed). Hence, even under conditions of tampering, Remoxy demonstrated decreased abuse potential compared with a manipulated oxycodone ER tablet. Under conditions of intact administration, Remoxy whole had significantly decreased maximum (peak) effect and In general, the trends observed in the PD analyses were similar to those noted in pupillometric response, in that peak pupil constriction showed a similar trend to peak positive subjective response across treatments. Overall, based on the primary endpoint analyses and supported by the secondary endpoint analyses, the key findings are: 1) Remoxy whole or chewed has significantly less abuse potential than oxycodone IR and oxycodone ER crushed, 2) Remoxy whole has a slight trend toward less abuse potential than oxycodone ER whole, and 3) Remoxy chewed has a slight trend toward greater abuse potential than oxycodone ER whole. These results suggest that Remoxy whole or chewed is less likely to be abused than oxycodone IR and ER when it is manipulated. Owing to the highly viscous nature of the liquid formulation of Remoxy, previous studies have not explored the chewing duration or analyzed the taste or texture of Remoxy capsules. Remoxy contains sucrose acetate isobutyrate; therefore, this study assessed chewing duration and pleasantness of taste/texture. Although the formulation is highly viscous, no patient was able to chew Remoxy for more than 1.5 minutes, and the taste and texture of Remoxy were rated as unpleasant or neutral by all of the patients. No unexpected safety findings were observed in this study. The majority of AEs reported were those commonly associated with opioid use and were mild in severity. There were no deaths or other serious AEs. No patient discontinued owing to an AE during the study. Vital signs and laboratory safety test results during the study do not suggest a safety concern for treatment with Remoxy 40 mg whole or chewed. Conclusions Abuse potential studies provide a means to anticipate the likelihood of abuse of a drug before exposure to the 629 Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016 Remoxy is a water-insoluble, highly viscous ER oral formulation of oxycodone developed to resist physical and chemical challenges. To date, the integrity of the Remoxy formulation has only been studied nonclinically and in human PK studies following a variety of challenges. Because the Remoxy formulation is highly viscous and therefore is not easily injected and/or crushed, the most likely method of misuse/abuse is anticipated to be chewing in an attempt to extract an immediate release of the oxycodone. To evaluate the abuse potential of Remoxy when taken whole and when chewed, this study was designed as a placebo- and active-controlled six-way crossover study in recreational opioid users using various PD measures to assess subjective drug effects. To assess each treatment under conditions that led to the greatest bioavailability, a condition that would be sought after by recreational drug users, the study focused on conditions where Remoxy was administered in a fed condition and the active comparators oxycodone IR and ER were administered under fasted conditions. Assessment of abuse potential was based on the primary endpoint of drug liking and supported by other subjective endpoints (i.e., high, good effects, Cole/ARCI MBG scale, take drug again, and PVAQ) that indicate pleasurable drug effects and/or reinforcing properties. Furthermore, assessments of Emax, TEmax, and AUE curves within the first 2 hours, to demonstrate the magnitude of effect over time, were selected as the principal parameters of interest to assess potential for abuse. area under the effect curve (within 2 hours post-dose) for drug liking and showed decreases in secondary endpoints, the majority of which, however, were not statistically significant when compared with intact oxycodone ER (whole). A trend toward reduced abuse potential was apparent; however, it was not as pronounced compared with the active oxycodone IR and oxycodone ER controls. Remoxy crushed, compared with intact oxycodone ER, showed significant increases in the area under the effect curves within 1 and 2 hours post-dosing; however, it did not show significant changes for peak drug liking and time to peak drug liking. The majority of secondary endpoints and parameters did not show statistically significant differences between Remoxy chewed and oxycodone ER (whole), although there was a trend for slightly higher ratings on measures for Remoxy chewed, indicating a trend toward slightly higher abuse potential. Similar findings were also observed for all treatment comparisons under reverse fed/fasted states (treatment group Y). Setnik et al. general population [14]. The results of this trial confirm that Remoxy is associated with a reduced potential for abuse, including conditions in which the product is manipulated, compared with oxycodone products with known abuse potential. Although the impact of the novel formulation of Remoxy will not be established until it has had ample time in the marketplace for a complete assessment, further analysis in the real world setting will confirm if the reduced abuse potential observed translates to lower rates of actual abuse and misuse. 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