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

Mickle, Travis; Guenther, Sven; Barrett, Andrew C.; Roupe, Kathryn A.; Zhou, Jing; Dickerson, Daniel; Webster, Lynn R.

doi:10.1093/pm/pnx247

Cited by 4 publications

(10 citation statements)

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“…Consistent with this interpretation are findings from a study in which pure benzhydrocodone and hydrocodone active pharmaceutical ingredient (API) were administered intranasally. Under these conditions, there were marked reductions in all indices of hydrocodone exposure and Drug Liking for IN benzhydrocodone API relative to IN hydrocodone API [30]. These collective findings confirm that benzhydrocodone retains its prodrug properties when absorbed via the nasal mucosa, regardless of whether it is derived from crushed tablets or the pure API.…”

Section: Discussionmentioning

confidence: 64%

“…Eligible subjects in either Part A or Part B underwent an in-clinic naloxone challenge (to confirm the absence of physical opioid dependence) [30] and a Drug Discrimination Test (to ensure that the subject could identify active drug effects). In the Drug Discrimination Test, subjects received double-blind single IN doses of active drug and placebo, separated by at least 24 hours.…”

Section: Methodsmentioning

confidence: 99%

“…The pharmacologically inactive prodrug benzhydrocodone is designed to quickly and effectively release its active hydrocodone component through esterase metabolism in the intestinal tract following oral administration. However, in vitro stability and human pharmacokinetic studies indicate that bypassing presystemic metabolism, as occurs with nonoral administration, results in significantly reduced conversion to hydrocodone [30,31]. While this means that benzhydrocodone is still susceptible to oral abuse, it may be a poor candidate for nonoral routes of abuse.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…A critical double-blinded, randomized crossover trial in 51 healthy adults, who identified as non-dependent recreational opioid abusers, demonstrated the pharmacokinetics and abuse potential of intranasal (IN) benzhydrocodone [ 6 ].…”

Section: Reviewmentioning

confidence: 99%

“…Blood samples were collected and peak plasma hydrocodone levels as well as total hydrocodone exposures were measured. Drug liking scores, safety and nasal assessments, along with ease of insufflation were assessed throughout each dosing interval [ 6 ].…”

Section: Reviewmentioning

confidence: 99%

A Review of the Opioid Analgesic Benzhydrocodone-Acetaminophen

Mustafa¹,

Rajan²,

Suárez³

et al. 2018

Cureus

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There is an undeniable opioid crisis in the United States that has caused significant negative consequences including many lives lost due to opioid overdoses. Currently, researchers are searching for alternatives for pain management as well as developing abuse-deterrent agents. In February 2018, the Food and Drug Administration (FDA) approved benzhydrocodone and acetaminophen (Apadaz™) for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and where alternative treatments are inadequate. This article looks further into this oral opioid prodrug and assesses its clinical pharmacology, pharmacokinetics, clinical trials and safety considerations that led to approval. Even though this prodrug provides a novel approach to analgesia, it was not classified as an abuse-deterrent agent and therefore still has the potential for abuse and misuse. This new agent potentially runs a higher risk of augmenting the opioid crisis rather than curtailing it. Innovative approaches to discover opioid alternatives are warranted.

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Degradable polyprodrugs: design and therapeutic efficiency

et al. 2022

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

Abstract: Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.

Cited by 4 publications

References 19 publications

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

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

A Review of the Opioid Analgesic Benzhydrocodone-Acetaminophen

Degradable polyprodrugs: design and therapeutic efficiency

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