Intranasal asalhydromorphone (ASAL-HM), a hydromorphone prodrug, was found to reduce opioid abuse-related effects and hydromorphone exposure when compared with intranasal hydromorphone, according to a study published in Pain Medicine.
As a 𝜇-opioid agonist with a potency 2- to 4-fold greater than that of hydrocodone or oxycodone, hydromorphone has high abuse potential, particularly in nonoral forms. ASAL-HM was developed to deter nonoral abuse by reducing hydromorphone bioavailability, exposure, and peak concentrations.
In this single-center phase 1 randomized double-blind crossover study, a total of 26 healthy recreational opioid users (mean age, 31.2 years; 92.3% men; mean drug abuse frequency, 62.6 times over 12 months) who were deemed nondependent and had experience with insufflation were enrolled. After an initial screening phase and a naloxone challenge test, there was a 2-part treatment phase during which participants received intranasal hydromorphone 8 mg or intranasal ASAL-HM (16.1 mg, a molar equivalent to the ASAL-HM dose), followed by the other formulation, with a washout period ≥48 hours between administrations. A follow-up phase occurred 5 to 8 days after discharge.
The study’s primary outcome was the drug’s pharmacokinetic profile (ie, peak concentration, Cmax; time to peak concentration, Tmax; and area under the curve [AUC], AUC0-last and AUC0-Inf), assessed in blood samples taken at regular intervals over 24 hours after each dose. The study’s secondary outcome was the exploratory pharmacodynamic profile, established to evaluate abuse potential using questions regarding “drug liking,” intensity of the high, and other personal preferences, and recorded over 8 hours after each dose. The safety profile of each drug, including nasal irritation, was also assessed.
There was a ≥50% reduction in the rate and extent of hydromorphone exposure with intranasal ASAL-HM compared with intranasal hydromorphone. More specifically, mean Cmax was 3.45 ng/mL with ASAL-HM vs 9.3 ng/mL with hydromorphone, and mean Tmax was longer with ASAL-HM vs hydromorphone (1.2 hour vs 0.75 hour, respectively; P <.001). Mean overall exposure to hydromorphone was lower after intranasal ASAL-HM compared with intranasal hydromorphone (AUC0-last, 14.5 h x ng/mL vs 34.7 h x ng/mL, respectively; AUC0-Inf, 20.0 h x ng/mL vs 38.8 h x ng/mL, respectively). Relative bioavailability, expressed as geometric least square means, was markedly lower with ASAL-HM vs hydromorphone (Cmax, 3.2 ng/mL vs 8.9 ng/mL, respectively; AUC0-last, 13.9 h x ng/mL vs 34.4 h x ng/mL, respectively).
The exploratory pharmacodynamic end points — maximum effect for feeling high and drug liking, and ratings for overall drug liking and desire to take the drug again — evaluated on a 0 to 100 visual analog scale, were lower for ASAL-HM vs hydromorphone. Mean differences for maximum effect and related parameters ranged from -25.0 to -11.4 (P =.0017 to P <.001).
Nasal irritation (P <.001) and facial pain (P =.007) were worse after intranasal ASAL-HM compared with intranasal hydromorphone. However, ASAL-HM resulted in fewer of the typical adverse events (AEs) seen with opioids, with a lower incidence of somnolence, pruritus, and euphoria compared with hydromorphone. Treatment-emergent AEs were mostly mild in both groups, and there were no serious AEs reported.
Study limitations include lack of a drug discrimination phase, the lack of a placebo group, and the use of a single dose for each drug.
“ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products,” concluded the authors. They recommended that the final drug product undergo formal abuse potential studies that incorporate placebo control and a drug discrimination phase.
Funding and Conflicts of Interest Disclosures:
KemPharm, Inc., funded this study.
Sven Guenther, Travis Mickle, Andrew Barrett, Adam Smith, and Rene Braeckman are employees and stockholders of KemPharm, Inc. Debra Kelsh and Bradley Vince are employees of Vince & Associates.
Guenther S, Mickle TC, Barrett AC, et al. Pharmacokinetics and abuse potential of asalhydromorphone, a novel prodrug of hydromorphone, after intranasal administration in recreational drug users [published online April 15, 2019]. Pain Med. doi:10.1093/pm/pnz066