Intranasal Abuse Potential Research Articles

Intranasal Pharmacokinetics of Morphine ARER, a Novel Abuse-Deterrent Formulation: Results from a Randomized, Double-Blind, Four-Way Crossover Study in Nondependent, Opioid-Experienced Subjects.

Objective To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.

Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users

To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose. Single site in Canada (INC Research Toronto). Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30mg/3mg). Peak effect (Emax) for bipolar Drug Liking (0-100 point visual analog scale). Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking Emax relative to placebo. Significant reductions (p<0.001) in median Drug Liking [Emax] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower Emax for IN ELI-200 (p<0.001) compared to IN oxycodone IR. IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.

Relative Bioavailability, Intranasal Abuse Potential, and Safety of Benzhydrocodone/Acetaminophen Compared with Hydrocodone Bitartrate/Acetaminophen in Recreational Drug Abusers.

ObjectivesBenzhydrocodone is a hydrocodone prodrug that has been combined with acetaminophen (APAP) in a novel immediate-release analgesic. This study evaluated the relative bioavailability, intranasal abuse potential, and safety of benzhydrocodone/APAP compared with commercially available hydrocodone bitartrate (HB)/APAP.DesignSingle-center, randomized, double-blind, double-dummy, two-part study comprising a Dose Selection (Part A) phase and a Main Study (Part B) phase.SettingClinical research site.SubjectsHealthy adult, nondependent, recreational opioid users with a history of intranasal abuse.MethodsSubjects (N = 42) in Part B received five in-clinic treatments consisting of intranasal and oral benzhydrocodone/APAP (13.34/650 mg), intranasal and oral hydrocodone/APAP (15/650 mg), and placebo, with four or more days of washout between treatments. Pharmacodynamic assessments included subjective effects of Drug Liking, Overall Drug Liking, and Take Drug Again (assessed on visual analog scale [VAS]), as well as nasal irritation. Pharmacokinetics and safety were also assessed.ResultsHydrocodone Cmax was 11% lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P = 0.0027). Early cumulative hydrocodone exposures for intranasal benzhydrocodone/APAP through 0.5, 1, and 2 hours were reduced by approximately 50%, 29%, and 15%, respectively (P ≤ 0.0024). Correspondingly, Drug Liking VAS values up to two hours postdose were significantly lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P ≤ 0.0079), although peak Drug Liking VAS (Emax) scores were not different (P = 0.2814). Adverse nasal effects were more frequent for intranasal benzhydrocodone/APAP vs intranasal HB/APAP.ConclusionsReduced hydrocodone exposure and drug liking at early time intervals, coupled with adverse nasal effects, can be expected to provide a level of deterrence to the intranasal route of abuse for benzhydrocodone/APAP.

Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

ObjectiveTo assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]).DesignSingle-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study.SettingOne US site.SubjectsHealthy, adult, nondependent, recreational opioid users.MethodsSubjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on “at the moment” Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed.ResultsMean maximum effect for “at the moment” Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled “at the moment” Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF.ConclusionsThe statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Abuse Potential and Pharmacodynamic Characteristics of Oral and Intranasal Eluxadoline, a Mixed μ- and κ-Opioid Receptor Agonist and δ-Opioid Receptor Antagonist.

Drugs with μ-opioid receptor (OR) activity can be associated with abuse and misuse. The peripherally acting mixed μ-OR and κ-OR agonist and δ-OR antagonist eluxadoline is approved in the United States for the treatment of irritable bowel syndrome with diarrhea. In two separate crossover studies, we evaluated the oral and intranasal abuse potential of eluxadoline versus placebo and the active control oxycodone. Healthy recreational opioid users received eluxadoline 100, 300, and 1000 mg, oxycodone 30 and 60 mg, and placebo (oral study), or eluxadoline 100 and 200 mg, oxycodone 15 and 30 mg, and placebos matched to eluxadoline and oxycodone (intranasal study). In the oral study, Drug Liking Visual Analog Scale (VAS) peak (maximum) effect (Emax) score (primary endpoint) was significantly greater with eluxadoline 300 and 1000 mg versus placebo, but scores were significantly lower versus oxycodone. Following intranasal insufflation of eluxadoline, Drug Liking VAS Emax scores were not statistically different versus placebo, and were significantly lower versus oxycodone. Across other subjective measures, eluxadoline was generally similar to or disliked versus placebo. Pupillometry indicated no or minimal central effects with oral and intranasal eluxadoline, respectively. Adverse events of euphoric mood were reported with oral and intranasal eluxadoline but at a far lower frequency versus oxycodone. These data demonstrate that eluxadoline has less abuse potential than oxycodone in recreational opioid users.

Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo.Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study.Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse.Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics.Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists.Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

Evaluation of relative intranasal abuse potential of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in nondependent, recreational opioid users

Evaluation of relative intranasal abuse potential of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in nondependent, recreational opioid users

(425) Evaluation of the relative intranasal abuse potential of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in nondependent, recreational opioid users

Misuse and abuse of opioids pose serious public health and safety risks. A hydrocodone bitartrate extended-release (ER) tablet, formulated with CIMA® Abuse-Deterrence Technology, provides resistance against rapid release of hydrocodone when tablets are manipulated or taken with alcohol, potentially reducing abuse liability when misused or abused. This study examined the relative abuse potential of manipulated intranasal hydrocodone ER in healthy nondependent adults with a history of recreational and intranasal opioid use. Subjects able to tolerate a 45-mg intranasal dose of hydrocodone active pharmaceutical ingredient (API) powder and discriminate effects of hydrocodone from placebo were randomized into a double-blind, 5-period crossover, treatment phase to assess abuse potential. Subjects received each of the following: intranasal manipulated hydrocodone ER 45 mg, intranasal hydrocodone API 45 mg, intact oral hydrocodone ER 45 mg, intranasal manipulated Zohydro 45 mg (commercially available hydrocodone ER capsule), and placebo. Forty-five subjects were enrolled; 34 were evaluable for pharmacodynamic assessments performed through 48 hours after administration of study drug. Maximum effect (Emax) of “at this moment” drug liking based on a bipolar Visual Analog Scale (VAS; primary endpoint) was significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (72.8 vs. 80.2 and 83.2, respectively) and significantly (P<0.001) higher vs. oral hydrocodone ER (57.3) and placebo (58.6). Emax of end-of-day/next-day Overall Drug Liking VAS (co-primary endpoint) was also significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (68.5 vs. 77.1 and 79.8, respectively) and significantly (P≤0.001) higher vs. oral hydrocodone ER (57.8) and placebo (57.7). No new safety signals were observed. Abuse potential via the intranasal route, one of the two most common routes of abuse, was significantly lower with hydrocodone ER compared with non–abuse-deterrent opioid products, including Zohydro. When administered as intended (intact orally), liking scores for hydrocodone ER were similar to placebo. Misuse and abuse of opioids pose serious public health and safety risks. A hydrocodone bitartrate extended-release (ER) tablet, formulated with CIMA® Abuse-Deterrence Technology, provides resistance against rapid release of hydrocodone when tablets are manipulated or taken with alcohol, potentially reducing abuse liability when misused or abused. This study examined the relative abuse potential of manipulated intranasal hydrocodone ER in healthy nondependent adults with a history of recreational and intranasal opioid use. Subjects able to tolerate a 45-mg intranasal dose of hydrocodone active pharmaceutical ingredient (API) powder and discriminate effects of hydrocodone from placebo were randomized into a double-blind, 5-period crossover, treatment phase to assess abuse potential. Subjects received each of the following: intranasal manipulated hydrocodone ER 45 mg, intranasal hydrocodone API 45 mg, intact oral hydrocodone ER 45 mg, intranasal manipulated Zohydro 45 mg (commercially available hydrocodone ER capsule), and placebo. Forty-five subjects were enrolled; 34 were evaluable for pharmacodynamic assessments performed through 48 hours after administration of study drug. Maximum effect (Emax) of “at this moment” drug liking based on a bipolar Visual Analog Scale (VAS; primary endpoint) was significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (72.8 vs. 80.2 and 83.2, respectively) and significantly (P<0.001) higher vs. oral hydrocodone ER (57.3) and placebo (58.6). Emax of end-of-day/next-day Overall Drug Liking VAS (co-primary endpoint) was also significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (68.5 vs. 77.1 and 79.8, respectively) and significantly (P≤0.001) higher vs. oral hydrocodone ER (57.8) and placebo (57.7). No new safety signals were observed. Abuse potential via the intranasal route, one of the two most common routes of abuse, was significantly lower with hydrocodone ER compared with non–abuse-deterrent opioid products, including Zohydro. When administered as intended (intact orally), liking scores for hydrocodone ER were similar to placebo.

(441) A single-center, randomized, double-blind crossover study to evaluate the abuse potential, pharmacokinetics, and safety of milled and intranasally administered extended-release hydrocodone (HYD) in recreational opioid users

HYD is a once-daily, extended-release hydrocodone bitartrate tablet formulated with polyethylene oxide to control the hydrocodone release rate and to confer abuse deterrent physicochemical properties. The intranasal abuse potential of fine-milled and coarse-milled HYD (using an industrial mill and razor blade, respectively) were compared to hydrocodone powder and placebo. Study design, conduct, analysis and interpretation followed FDA’s Jan-2013 draft abuse-deterrent opioid guidance. Healthy subjects with a history of recreational opioid use who were not physically dependent on opioids were enrolled.

Pharmacokinetics, Tolerability, and Safety of Intranasal Administration of Reformulated OxyContin® Tablets Compared with Original OxyContin® Tablets in Healthy Adults

Background and ObjectiveReformulated OxyContin® (oxycodone-HCl controlled release) tablets (ORF) became available in the United States in August 2010. The original formulation of OxyContin® (oxycodone-HCl controlled release) tablets (OC) used a delivery system that did not provide inherent resistance to crushing and dissolving. The objective of this study was to compare the pharmacokinetics, tolerability, and safety of finely crushed ORF tablets, coarsely crushed ORF tablets, and finely crushed OC tablets.MethodsThis randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study enrolled eligible healthy adults (aged 18–55 years inclusive). The study evaluated the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed and coarsely crushed, as well as finely crushed OC tablets. Plasma oxycodone concentrations were quantified and analyzed to determine the maximum observed plasma concentration (C max), time to maximum plasma concentration (t max), area under the plasma concentration–time curve from hour 0 to the last measurable plasma concentration (AUClast), and area under the plasma concentration–time curve extrapolated to infinity (AUC∞). The abuse quotient (AQ), calculated as C max/t max, served as an index of the average rate of increase in drug concentration from dosing to t max. Intranasal tolerability rating scales (discomfort, itching, burning, pain, runny nose, and stuffiness) and intranasal endoscopy were conducted. Safety assessments included adverse events, vital signs, pulse oximetry (SpO2), and electrocardiograms.ResultsOf 83 subjects screened and enrolled, 30 were randomized to period 1, with 1 subject subsequently discontinuing due to the subject’s choice. Mean C max values for finely crushed ORF (17.1 ng/mL) and coarsely crushed ORF (15.5 ng/mL) were lower than that for finely crushed OC (22.2 ng/mL). Median t max for finely crushed OC (1.0 h) was shorter than that for either finely crushed ORF (2.0 h) or coarsely crushed ORF (3.0 h). Mean AQ values were approximately 66 and 80 % lower, respectively, for finely crushed ORF and coarsely crushed ORF than that for finely crushed OC. Finely crushed ORF, coarsely crushed ORF, and finely crushed OC demonstrated similar total oxycodone exposures (AUC∞). Insufflation of ORF produced greater nasal discomfort and stuffiness than finely crushed OC, although the latter produced higher runny nose scores. No significant difference was found in other nasal tolerability measures. The overall safety profile was as expected following opioid administration in healthy subjects.ConclusionsIn contrast to OC, both finely and coarsely crushed ORF retained some control of oxycodone release. Reduced C max and increased t max for ORF resulted in lower AQ scores for ORF compared with OC. ORF was associated with greater intranasal irritation than OC. These data suggest that ORF has a lower intranasal abuse potential than OC.