Opioid challenge evaluation of blockade by extended-release naltrexone in opioid-abusing adults: dose-effects and time-course

Abstract

Background: Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans.

Methods: Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade.

Results: Blockade of the VAS "any drug effect" response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing.

Conclusions: These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.

Copyright © 2011. Published by Elsevier Ireland Ltd.

Figures

Figure 1

The percent of subjects tolerating and receiving the maximum available 13.5 mg cumulative hydromorphone in the within-session, 4-injection ascending dose sequence is shown for each XR-NTX dose group for each time point. The Placebo Challenge data show the percent of subjects receiving the full 4-injection sequence when all injections were placebo instead of hydromorphone. Days are number of days after XR-NTX administration. BL is the baseline session preceding XR-NTX administration.

Figure 2

The median slope of the hydromorphone time-action function is shown for each XR-NTX dose group at each challenge session. Slopes are based on the time course of response to 3 mg hydromorphone. Top panel shows response to the VAS questions “Do you feel any drug effect?” Bottom panel shows pupil diameter response. Days are number of days after XR-NTX administration. BL is the baseline session preceding XR-NTX administration. Asterisks indicate points for which there is not even a trend (p>0.20) for the slope of the hydromorphone time-action function to differ from zero.

Figure 3

The median slope of the hydromorphone time-action function is shown for each XR-NTX dose group at each challenge session. Slopes are based on the time course of response to the full cumulative hydromorphone dose actually received by each volunteer (maximum possible = 13.5 mg). Top panel shows response to the VAS questions “Do you feel any drug effect?” Bottom panel shows pupil diameter response. Days are number of days after XR-NTX administration. BL is the baseline session preceding XR-NTX administration. Asterisks indicate points for which there is not even a trend (p>0.20) for the slope of the hydromorphone time-action function to differ from zero.

Figure 4

Top panel shows the median peak score for the VAS question “Do you feel any drug effect?” for each dose group for each challenge session. Bottom panel shows median peak pupil constriction for each session (median change from each subject's within-session pre-hydromorphone pupil diameter). BL is the baseline session preceding XR-NTX administration.

Figure 5

Top panel shows the median naltrexone plasma concentrations over time for each XR-NTX dose group. Bottom panel shows the median 6-beta-naltrexol concentrations over time.