scholarly journals 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

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Lynn R. Webster ◽  
Carmela Pantaleon ◽  
Matthew Iverson ◽  
Michael D. Smith ◽  
Eric R. Kinzler ◽  
...  
Keyword(s):  
Crossover Study ◽  
Intranasal Administration ◽  
Extended Release ◽  
Oral Morphine ◽  
Abuse Potential ◽  
Maximum Effect ◽  
Double Blind ◽  
Opioid Users ◽  
Physical Manipulation ◽  
Drug Liking

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.

scholarly journals Evaluation of the oral human abuse potential of Oxycodone DETERx® formulation (Xtampza® ER)

2018 ◽  
Vol 14 (5) ◽  
pp. 359-372 ◽  
Author(s):  
Diana Meske, PhD ◽  
Ernest A. Kopecky, PhD ◽  
Steven Passik, PhD ◽  
Megan J. Shram, PhD
Keyword(s):  
Immediate Release ◽  
Oral Route ◽  
Abuse Potential ◽  
Maximum Effect ◽  
Double Blind ◽  
Visual Analog Scales ◽  
The Mean ◽  
Opioid Users ◽  
Primary Measure ◽  
Drug Liking

Objective: To further characterize the human abuse potential and pharmacokinetics (PK) of Oxycodone DETERx (Xtampza® ER) after intact and chewed oral administration.Design: Randomized, double-blind, triple-dummy, active- and placebo-controlled, single-dose, six-period, crossover comparison study.Setting: Clinical research unit.Subjects: Adult, nondependent recreational opioid users who liked the effects of crushed immediate-release (IR) oxycodone in solution and were able to differentiate the effects from placebo solution.Interventions: Oral administration of intact Oxycodone DETERx (fasted and fed), chewed Oxycodone DETERx (fasted and fed), crushed IR oxycodone (fasted), and placebo (fed).Main Outcome Measures: Subject ratings (100-point visual analog scales) of Drug Liking (primary measure) and Take Drug Again (key secondary measure).Results: The pharmacodynamic (PD) analysis included 52 subjects who completed the study; the PK analysis included 71 subjects. Compared with crushed IR oxycodone fasted, the least-squares mean maximum effect (Emax) was statistically significant (p 0.01) for Drug Liking and Take Drug Again, respectively, for chewed Oxycodone DETERx fasted (LS mean difference ± standard error of the mean: 13.1 ± 2.2 and 10.0 ± 3.2 points) and fed (10.9 ± 2.2 and 9.7 ± 3.3 points) and intact Oxycodone DETERx fasted (12.2 ± 2.2 and 9.3 ± 3.3 points) and fed (10.3 ± 2.2 and 9.2 ± 3.3 points). Results were consistent for other PD measures (Good Effects, Feeling High). Chewed Oxycodone DETERx fasted and fed treatments were bioequivalent to the respective intact treatments based on PK parameters. Conclusions: This study showed that when chewed or swallowed intact, under fasted or fed conditions, Oxycodone DETERx had statistically significantly lower abuse potential via the oral route compared with IR oxycodone.

A nasal abuse potential randomized clinical trial of REMOXY® ER, a high-viscosity extended-release oxycodone formulation

2018 ◽  
Vol 14 (6) ◽  
pp. 437-443 ◽  
Author(s):  
Nadav Friedmann, PhD, MD ◽  
Michael R. Marsman, PharmD ◽  
Annelies W. De Kater, PhD ◽  
Lindsay H. Burns, PhD ◽  
Lynn R. Webster, MD
Keyword(s):  
Clinical Trial ◽  
Extended Release ◽  
High Viscosity ◽  
Abuse Potential ◽  
Maximum Effect ◽  
Self Administration ◽  
Open Label ◽  
Secondary Endpoints ◽  
Opioid Users ◽  
Drug Liking

Objective: This study examined the nasal abuse deterrence of REMOXY ER, a novel high-viscosity extended-release oxycodone formulation.Design: An Institutional Review Board-approved, single-center, randomized, double-blind, placebo, and active-controlled, four-way crossover study of intranasal REMOXY ER gel, manipulated or intact, and ground oxycodone immediate-release (IR). An open label extension examined pharmacokinetics of OxyContin® ER in the first 20 subjects.Participants: Healthy, adult nondependent recreational opioid users with a history of intranasal abuse. Thirty-eight subjects enrolled; 36 completed.Setting: A clinical research in-patient unit.Interventions: Cross-over arms included nasal self-administration of the entire contents of REMOXY ER 40 mg capsules (manipulated or intact), ground oxycodone IR 40 mg tablets, and placebo. The open-label arm was ground OxyContin ER.Main outcome measures: The primary endpoint was the maximum effect (Emax) of visual analog scale ratings of Drug Liking. Secondary endpoints included Take Drug Again (12 and 24 hours), Drug High Emax, area under effect curves through 12 hours, pupillometry, peak oxycodone concentrations (Cmax), time to maximum concentration (Tmax), and Abuse Quotient (Cmax/Tmax).Results: Intranasal REMOXY ER (manipulated or intact) elicited lower Drug Liking and Drug High compared to ground oxycodone IR. Secondary endpoints also reflected reduced Abuse Potential. Intranasal REMOXY ER (manipulated or intact) led to fourfold lower Cmax, a 57 to 128 percent longer Tmax, a 10-fold lower Abuse Quotient and lower Take Drug Again scores compared to both OxyContin ER and oxycodone IR.Conclusion: In this study, REMOXY ER demonstrated significantly lower nasal abuse potential compared to oxycodone IR or OxyContin ER.Perspective: Abuse-deterrent drugs are intended to help fight opioid abuse. Yet the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are needed. A new, high-viscosity, extended-release oxycodone formulation showed robust abuse-deterrence against the nasal route of abuse in an Food and Drug Administration-advised clinical trial in recreational opioid users.

scholarly journals Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy

SLEEP ◽  
2019 ◽  
Vol 43 (4) ◽  
Author(s):  
Beatrice Setnik ◽  
Michael McDonnell ◽  
Catherine Mills ◽  
Catherine Scart-Grès ◽  
Philippe Robert ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Inverse Agonist ◽  
Mean Difference ◽  
Abuse Potential ◽  
Adult Patients ◽  
Maximum Effect ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
H3 Receptor ◽  
Drug Liking

Abstract Objectives To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. Methods Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking (“at this moment”) visual analog scale. Results In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. Conclusions In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. Clinical Trial Registration ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.

scholarly journals Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study

Pain Medicine ◽  
2019 ◽  
Author(s):  
Xue Ge ◽  
Jack E Henningfield ◽  
Suresh Siddhanti ◽  
Janet Jobes ◽  
Lin Lu ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Subjective Effects ◽  
Mu Opioid Receptor ◽  
Primary Objective ◽  
Abuse Potential ◽  
Double Blind ◽  
Mu Opioid ◽  
Opioid Users ◽  
Oral Doses ◽  
Drug Liking

Abstract Objective To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone. Design This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non–physically dependent recreational opioid users. Setting Inpatient clinical research site. Subjects Seventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years). Methods The primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking “at this moment” (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo. Results Compared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone. Conclusions NKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone.

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

2017 ◽  
Vol 13 (6) ◽  
pp. 449 ◽  
Author(s):  
Beatrice Setnik, PhD ◽  
Kerri Schoedel, PhD ◽  
Cindy Bartlett, MMath ◽  
Chris Dick, MS, MBA ◽  
Nasrat Hakim, MS, LLM ◽  
...  
Keyword(s):  
Drug Effects ◽  
Immediate Release ◽  
Peak Effect ◽  
Abuse Potential ◽  
Double Blind ◽  
Nasal Irritation ◽  
Pupil Constriction ◽  
Oxycodone Hydrochloride ◽  
Opioid Users ◽  
Drug Liking

Objective: To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone.Design: 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.Setting: Single site in Canada (INC Research Toronto).Participants: Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test.Intervention: 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 (30 mg/3 mg).Main Outcome Measure: Peak effect (E max) for bipolar Drug Liking (0-100 point visual analog scale).Results: Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p < 0.001) median Drug Liking E max relative to placebo. Significant reductions (p < 0.001) in median Drug Liking [E max ] 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 E max for IN ELI-200 (p < 0.001) compared to IN oxycodone IR.Conclusions: 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.

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