A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Human Abuse Potential Study of Oxycodone ARIR, a Novel, Immediate-Release, Abuse-Deterrent Formulation

Abstract Objective Prescription opioid abuse continues to be a public health concern. Oxycodone ARIR is an immediate-release (IR) oxycodone tablet composed of multiple overlapping barriers that deter manipulation of the tablet for non-oral abuse. Design This randomized, double-blind, double-dummy, active- and placebo-controlled, four-way crossover, intranasal human abuse potential study assessed the pharmacodynamics and pharmacokinetics of crushed intranasal oxycodone ARIR compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. Outcome Measures Pharmacodynamic end points included mean maximum drug liking (Emax), as measured by subjects on a bipolar 100-mm visual analog scale (primary), and desire to take the drug again, overall drug liking, drug high, and good effects (secondary). Pharmacokinetic assessments included peak concentration and time to peak concentration. Results Twenty-nine subjects completed the treatment phase. Crushed intranasal oxycodone ARIR demonstrated a significant reduction of 46.9% and 23.4% in drug liking Emax compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR, respectively (P < 0.0001 for both). Significant reductions also were observed in desire to take the drug again, drug high, overall drug liking, and good effects when comparing crushed intranasal oxycodone ARIR with crushed intranasal IR oxycodone and intact oral oxycodone ARIR (P < 0.001 for all). Crushed intranasal oxycodone ARIR exhibited lower peak oxycodone plasma concentrations and slower time to peak concentration compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. All treatments were well tolerated; adverse effects were typical of opioids or intranasal administration. Conclusions These data indicate that oxycodone ARIR has the potential to reduce abuse via the intranasal route.

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10 Pharmacodynamics and Tolerability of Intranasally Administered Immediate-Release Amphetamine Sulfate Among Recreational Intranasal StimulantUsers

CNS Spectrums ◽

10.1017/s1092852919000063 ◽

2019 ◽

Vol 24 (1) ◽

pp. 178-178

Author(s):

Beatrice Setnik ◽

Steve Caras ◽

Terrilyn Sharpe ◽

Stephen V. Faraone

Keyword(s):

Active Drug ◽

Immediate Release ◽

Abuse Potential ◽

Post Dose ◽

Dose Escalation Study ◽

Double Blind ◽

Study Objective ◽

Amphetamine Sulfate ◽

Drug Liking ◽

Intranasal Dose

AbstractStudy ObjectiveDespite increased nonmedical use of ADHD prescription stimulants, there are limited data to inform selection of intranasal doses for abuse-potential evaluations. This study determined a dose of amphetamine sulfate that is tolerable and distinguishable from placebo on pharmacodynamic (PD) measures.MethodsIn this randomized, double-blind, placebo-controlled, dose-escalation study, healthy, nondependent, recreational stimulant users received a single intranasal dose of amphetamine sulfate (20, 30, or 40mg ; n=6 per group) or placebo (n=2 per group). PD and safety were assessed pre-dose and ≤24hours post-dose. Drug Liking was measured using a bipolar Visual Analogue Scale (VAS; 0–100). Dose selection criteria were complete dose insufflation (≥95%); demonstration of peak Drug Liking ≥75 points, and ≥15 points greater than placebo in ≥3 participants receiving active drug; and tolerability.ResultsPeak Drug Liking criteria were met in the 20-, 30-, and 40-mg groups by 2, 0, and 6 participants, respectively. Mean (SD) peak Drug Liking was 62 (13.0), 71 (17.8), and 93 (8.7) for amphetamine sulfate versus 54 (3.5), 76 (34.6), and 51 (0) for placebo in the 20-, 30-, and 40-mg groups, respectively. Thirteen participants experienced mild AEs (n=1, 4, 6, and 1 in 20-, 30-, 40-mg, and placebo groups, respectively), there were no serious or clinically significant AEs. The most common AE was nostril burning sensation (active drug, n=7). There were no instances of an incompletely insufflateddose.ConclusionA 40-mg intranasal dose produced distinguishable PD effects and was well tolerated. This dose has been selected for further abuse-potential evaluations.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

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Pharmacokinetics and Abuse Potential of Asalhydromorphone, a Novel Prodrug of Hydromorphone, After Intranasal Administration in Recreational Drug Users

Pain Medicine ◽

10.1093/pm/pnz066 ◽

2019 ◽

Vol 21 (3) ◽

pp. 511-520

Author(s):

Sven Guenther ◽

Travis C Mickle ◽

Andrew C Barrett ◽

Adam Smith ◽

Rene Braeckman ◽

...

Keyword(s):

Drug Users ◽

Area Under The Curve ◽

Immediate Release ◽

Abuse Potential ◽

Double Blind ◽

End Points ◽

Molecular Features ◽

Nasal Irritation ◽

The Moment ◽

Drug Liking

Abstract Objectives Hydromorphone (HM) is a potent μ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM. Design Single-center, randomized, double-blind, crossover study. Setting Clinical research site. Subjects Healthy adult, nondependent recreational opioid users. Methods Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed. Results Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on “at-the-moment” (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence. Conclusions The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products.

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

Journal of Opioid Management ◽

10.5055/jom.2018.0468 ◽

2018 ◽

Vol 14 (5) ◽

pp. 359-372 ◽

Cited By ~ 2

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.

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

Journal of Opioid Management ◽

10.5055/jom.2017.0421 ◽

2017 ◽

Vol 13 (6) ◽

pp. 449 ◽

Cited By ~ 4

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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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 ◽

10.1093/sleep/zsz252 ◽

2019 ◽

Vol 43 (4) ◽

Cited By ~ 7

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.

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A randomized, double-blind, placebo-controlled, crossover study to evaluate the human abuse liability of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor

Journal of Psychopharmacology ◽

10.1177/0269881118796814 ◽

2018 ◽

Vol 32 (12) ◽

pp. 1351-1361 ◽

Cited By ~ 8

Author(s):

Lawrence P Carter ◽

Jack E Henningfield ◽

Y Grace Wang ◽

Yuan Lu ◽

Debra Kelsh ◽

...

Keyword(s):

Reuptake Inhibitor ◽

Subjective Effects ◽

Test Phase ◽

Abuse Potential ◽

Double Blind ◽

Norepinephrine Reuptake Inhibitor ◽

The Moment ◽

Selective Dopamine ◽

Drug Liking ◽

Norepinephrine Reuptake

Background: This study evaluated the human abuse potential of solriamfetol (formerly JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects. Methods: Adults with a recent history of recreational polydrug use, including stimulants, and who met criteria in a Qualification Phase were randomized to one of six sequences in a Test Phase. Each Test Phase sequence included a single administration of placebo, solriamfetol (300, 600, and 1200 mg), and phentermine (45 and 90 mg), with a two-day washout between periods. The primary endpoint was peak rating ( Emax) of Liking at the Moment across the first 12 h on a liking/disliking visual analog scale; key secondary endpoints were Next Day Overall Drug Liking, how much the participant would like to Take the Drug Again, and positive and negative subjective effects. Safety was also assessed throughout the study. Results: Of 43 participants (74.4% male; mean age 29.3 years), 37 completed the study. Peak Emax Liking at the Moment for all solriamfetol doses was significantly greater than placebo and significantly less than phentermine 90 mg ( p < 0.05). Overall Next Day Drug Liking was greater than placebo for solriamfetol 300 mg and phentermine 45 and 90 mg ( p < 0.05). Willingness to Take the Drug Again was significantly greater than placebo and significantly less than both doses of phentermine for all doses of solriamfetol ( p < 0.05). Ratings of negative subjective effects (bad effects, disliking, anxiety, agitation) were higher with solriamfetol 600 and 1200 mg relative to phentermine. The most common treatment-emergent adverse events with solriamfetol were hypervigilance, elevated mood, dry mouth, hyperhidrosis, and insomnia. Conclusion: Solriamfetol appears to have abuse potential similar to or lower than phentermine.

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81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

CNS Spectrums ◽

10.1017/s1092852919000609 ◽

2019 ◽

Vol 24 (1) ◽

pp. 216-216

Author(s):

Steve Caras ◽

Terrilyn Sharpe

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Peak Concentration ◽

Immediate Release ◽

Open Label ◽

Time Curve ◽

Time To Peak ◽

Amphetamine Sulfate ◽

Quantifiable Concentration ◽

Funding Acknowledgements

AbstractStudy ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

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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

Pain Research and Management ◽

10.1155/2018/7276021 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 5

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.

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Pharmacodynamics of Orally Administered Sustained- release Hydromorphone in Humans

Anesthesiology ◽

10.1097/00000542-200101000-00014 ◽

2001 ◽

Vol 94 (1) ◽

pp. 63-73 ◽

Cited By ~ 65

Author(s):

Martin S. Angst ◽

David R. Drover ◽

Jörn Lötsch ◽

Bhamini Ramaswamy ◽

Sujata Naidu ◽

...

Keyword(s):

Plasma Concentration ◽

Sustained Release ◽

Analgesic Effect ◽

Time Course ◽

Plasma Concentrations ◽

Experimental Pain ◽

Immediate Release ◽

Double Blind ◽

Sustained Release Formulation ◽

Analgesic Effects

Background The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. Methods Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. Results The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. Conclusion A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

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