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

Abstract

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.

A Review of the Opioid Analgesic Benzhydrocodone-Acetaminophen

“…Another key randomized, double-blind, double dummy, two-part study, evaluated the bioavailability, safety and IN abuse potential of benzhydrocodone/APAP when compared to hydrocodone bitartrate/APAP in 42 healthy adults, with a history of non-dependent, recreational IN opioid abuse [ 4 ].…”

“…Patients from a dose selection phase (Part A) were randomized in the main study (Part B) to receive five doses of IN and oral benzhydrocodone/APAP (13.4 mg/650 mg), hydrocodone bitartrate/APAP (15 mg/650 mg) and placebo in one of 10 crossover sequences, separated by a minimum of a 96-hour washout period between treatments [ 4 ]. Assessments included the drug’s primary pharmacodynamics endpoint, drug liking peak effect (E max ), assessed on a visual analog scale (VAS), as well as time to peak effect (TE max ) and area under the drug liking effect curve (AUE) at five different time intervals.…”

“…Assessments included the drug’s primary pharmacodynamics endpoint, drug liking peak effect (E max ), assessed on a visual analog scale (VAS), as well as time to peak effect (TE max ) and area under the drug liking effect curve (AUE) at five different time intervals. Safety and nasal effects assessments as well as ease of insufflation were also determined in each dosing period [ 4 ].…”

“…There were no significant differences in the primary pharmacodynamic endpoints of peak E max and TE max at different time intervals, but there was a significantly lower systemic hydrocodone exposure at early time intervals by approximately 50% (AUC 0-0.5 hrs ), 29% (AUC 0-1 hrs ), and 15% (AUC 0-2 hrs ) for IN benzhydrocodone/APAP compared to IN hydrocodone/APAP (p < 0.01, 90% CI for all comparisons) [ 4 ]. Unlike hydrocodone/APAP, the prodrug benzhydrocodone/APAP showed similar bioavailability for oral and intranasal routes of administration with an approximate 11% decrease in the intranasal C max (mean = 34.7 ng/ml vs 39.1 ng/ml, p = 0.0027).…”

“…Despite the manufacturer’s effort to create a diversion from the opioid crisis, benzhydrocodone/APAP is not classified as an abuse-deterrent drug. The potential benefits of benzhydrocodone/APAP are due to its prodrug approach where absorption is best achieved with oral administration as opposed to non-oral administration routes such as insufflation or injection [ 4 ]. Herein, we provide an overview of benzhydrocodone/APAP as well as its role in clinical practice.…”