Pharmacokinetics and Pharmacodynamics of Intranasal Diacetylmorphine in Heroin-Assisted Treatment for Severe Opioid Use Disorder

Abstract

Background: Intranasal diacetylmorphine (IN DAM) represents a promising new route of administration, which is currently under investigation as a novel treatment approach for opioid use disorder in Switzerland. This study characterized the pharmacokinetics and pharmacodynamics of therapeutically relevant intranasal doses of DAM and its metabolites in patients with severe opioid use disorder.

Methods: In this prospective observational study, patients on intranasal heroin-assisted treatment (HAT) in Basel, Switzerland, self-administered their usual dose of IN DAM before receiving their daily maintenance dose. Inclusion criteria were age ≥ 18 years and current participation in IN HAT. Plasma concentrations of diacetylmorphine, 6-monoacetylmorphine (6-MAM), morphine, morphine-6-glucuronide, and morphine-3-glucuronide were measured using liquid chromatography-tandem mass spectrometry at baseline and at 2, 5, 10, 15, 20, 30, 40, 50, 60, 120, and 180 min. Acute subjective effects and cravings were assessed repeatedly using visual analog scales, withdrawal symptoms were measured using the Short Opiate Withdrawal Scale, and autonomic responses were recorded over the 3 h after IN DAM administration.

Results: In total, 14 patients were included in the study. The mean self-administered IN DAM dose was 346 mg (range 190-700 mg) delivered over a mean time of 3.8 min (range 1-9 min). IN DAM elicited moderate-to-strong peak drug effects, with marked reductions in heroin craving and withdrawal symptoms. No clinically relevant respiratory depression or decrease in oxygenation saturation was observed. Subjective effects occurred rapidly within the first 2 min after the start of administration. These effects gradually increased and peaked at 30-35 min, which paralleled the rising plasma concentrations of DAM and 6-MAM, while the sustained heroin-like effects best correlated with morphine and morphine-6-glucuronide plasma concentrations. Plasma half-lives of diacetylmorphine and 6-monoacetylmorphine were longer, and time to maximal plasma concentration was later than previously reported, suggesting saturated absorption at high intranasal doses and volumes.

Conclusions: IN DAM has a good safety profile and should be considered as an effective alternative for patients in HAT, offering rapid onset of effects without significant side effects. Optimization of intranasal delivery may further improve absorption and clinical utility.

Fig. 1

Plasma concentrations of diacetylmorphine and 6-monoacetylmorphine (A), morphine and morphine-6-glucuronide (B), and visual analog scale scores of drug effects (C) and craving (D) over time. Mean intranasal diacetylmorphine doses of 346 mg (range 190–700 mg) were self-administered by the patients over a mean time of 3.8 min (range of 1–9 min). A Plasma concentrations of diacetylmorphine and 6-monoacetylmorphine peaked at 10 and 15 min and decreased with a mean elimination half-life of 17 and 47 min respectively. B Morphine and 6-monoacetylmorphine concentrations peaked at 30 and 120 min, respectively, and morphine decreased with a mean elimination of 154 min. C Rush and heroin-typical effects peaked within 30 min and remained stable until 60 min. From 60 to 180 min, “rush” and “herointypical effect” slowly decreased. “Bad drug effect” remained constantly low during the 180 min. The data are expressed as the mean ± standard error of the mean (SEM) of 14 patients. The corresponding maximal responses are shown in Table 1. Individual concentrations are shown in Supplementary Fig. 3

Fig. 2

Correlation of the administered diacetylmorphine dose with the maximum plasma concentration (C_max) (A), and correlation of the duration of administration with the time of maximum plasma concentration (t_max) of diacetylmorphine (B). Higher doses resulted in a higher C_max whereas the duration of administration only mildly influenced the t_max of diacetylmorphine.

Fig. 3

Plasma concentration–effect relationship of diacetylmorphine (DAM), 6-monoacetylmorphine (6-MAM), morphine, and morphine-6-glucuronide (M6G). Plasma concentration values and “heroin-typical effect” on the visual analog scale are means. The time of sampling (in min) is indicated next to each data point. Counterclockwise hysteresis was observed for DAM and 6-MAM and clockwise hysteresis for morphine and M6G, indicating that the active metabolites morphine and M6G may prolong the effects of DAM and 6-MAM.

Fig. 4

Acute autonomic effects of intranasal diacetylmorphine over time. Intranasal diacetylmorphine slightly reduced heart rate, blood pressure, and oxygenation within the first 60 min after administration. The breathing rate remained unchanged. The data are expressed as mean and SEM in 14 patients. Exact values are displayed in Supplementary Table S4.