3.1. Subject Characteristics, Retention and Adherence
The sample was predominately male and non-white (). Subjects had used opioids non-medically for an average of 11.6 years. Their qualifying opioid use histories were primarily with heroin. Alcohol use and cocaine use were also prevalent. Routes of administration were not recorded. There were no significant differences between the treatment groups on baseline characteristics, with the exception of age (the 150 mg group was older than the other two groups; p=0.026).
Demographic and Baseline Clinical Characteristics of Participants
Of the 27 randomized subjects, 21 completed the study: 8 of 9 in the 75 mg group, 6 of 8 in the 150 mg group, and 7 of 10 in the 300 mg group. Non-completions were for personal or scheduling reasons unrelated to the study, except for one subject who discontinued due to leg pain judged possibly related to the XR-NTX injection procedure (not to the drug itself). During the sponsor's close-out visits to the study sites, it was discovered that 2 subjects had enrolled at both sites (sequentially, not concurrently). One completed the study twice, first in the 300 mg condition and then later in the 75 mg condition; the second, who completed the study in the 75 mg condition, was later randomized again to that same condition and received the XR-NTX injection, but then dropped out due to incarceration, so the second enrollment contributed only the pre-treatment Baseline session data. Due to the study's small samples, and the fact that bias risk was mitigated by no individual's contributing multiply to the outcomes of a single dose condition, it was judged better to include all available data, and these enrollments were treated as independent cases in the analyses.
There was infrequent evidence of illicit opioid use during study participation. Urine samples collected at study days 7, 14, 21, 28 (the days of intended opioid blockade) were opioid positive on 19%, 17%, and 0% of occasions for the 75, 150, and 300 mg XR-NTX dose groups, respectively, with at least one opioid-positive urine provided by 50%, 12%, and 0% of subjects, respectively. No samples were methadone-positive; buprenorphine was not tested.
Session cancellation or rescheduling due to intoxication were rare. Schedule variation due to subject availability was more common. Study results are reported according to their nominal time point (e.g., Days 7, 14, 28, etc.), but actual session times could vary slightly. Of 131 total session 56% were on the nominal day and 95% were within two days of the nominal day number. The means (and standard deviations) for the actual session times were 6.8 (1.0), 14.0 (1.3), 21.0 (1.2), 28.3 (2.4), 42.0 (1.1), and 55.8 (1.1) days.
3.2. Hydromorphone Dose Escalation Tolerability
One index of the extent of opioid blockade by XR-NTX is whether subjects received the full sequence of ascending hydromorphone challenge doses without its being interrupted by the on-site medical monitor. shows, for each XR-NTX dose, the percent of subjects who received the full 4-injection sequence, totaling 13.5 mg hydromorphone, at each study time point. In the 22 randomly selected double blind sessions, when all placebo injections were substituted for hydromorphone, the full 4-injection sequence was tolerated without interruption on 95% of sessions. At the BL sessions, prior to XR-NTX administration, only 30% of subjects received the full injection sequence. After XR-NTX administration, this percentage rose to higher levels through day 28 (56-100% for all XR-NTX groups combined), and then declined to low levels (6-17%) at days 42-56. All three XR-NTX doses had time points with percent above 80%; for the 300mg dose the percent was 80% or above at every time point from day 7 through day 28. The data show a clear XR-NTX effect in increasing tolerability of escalating opioid agonist doses, and are suggestive of a dose-effect relationship, but not a pronounced one. At no time-point, including BL, was the difference between XR-NTX dose conditions statistically significant on this measure. shows the mean total cumulative hydromorphome dose administered on each test day for each XR-NTX group.
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 (more ...)
Mean Total Hydromorphone Mg Given on Each Test Day
3.3. Blockade of Hydromorphone 3mg Effects
and show data for XR-NTX blockade of 3mg hydromorphone. This is the highest hydromorphone dose uniformly present in every challenge session, and so provides a constant metric for evaluating opioid effects and opioid blockade. shows the median slope of the 3mg hydromorphone time-action (dose) functions for each XR-NTX dose at each assessment time point for each of the two pre-specified primary outcome variables, VAS Drug Effect, and pupil diameter. shows the median slopes for these two primary measures and also for each of three other measures reflective of opioid agonist effects, VAS High, VAS Good Effects, and VAS Liking – and, in addition, shows the results of the statistical analysis of each slope. Major features in the data are:
- Sensitivity to opioid agonist effects: Statistically significant opioid agonist effects in the expected directions are present at the pre-XR-NTX BL assessment for every measure for every XR-NTX dose group.
- Opioid blockade by XR-NTX: Throughout the month following XR-NTX administration there is a high prevalence of zero or near-zero slopes, indicating complete or near-complete blockade of hydromorphone's opioid agonist effects.
- Duration of blockade: The slopes of the opioid agonist measures were substantially reduced (zero or near zero) for about one month, especially the VAS measures, and returned toward BL values at the later time points (days 42 and 56).
Blockade of 3 mg hydromorphone: Entries are slopes of the time-action regression lines
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 (more ...)
VAS subjective effect measures were more completely blocked than the pupil diameter measure, though the pupil measure also shows substantial blockade by XR-NTX. Blockade of the VAS subjective “any drug effect” measure was complete (i.e., zero slope) for 28 days with 300 mg XR-NTX, for 21 days with 150 mg, and for 14 days with 75mg. Similar dose x duration of blockade relationships are seen with each of the other VAS opioid agonist effect measures. The data show a clear and sustained blockade of opioid agonist effects by XR-NTX and suggest a dose-effect relationship, with more complete and/or longer duration opioid blockade with higher XR-NTX doses.
3.4. Blockade of Escalating-Dose Hydromorphone Effects
and show data analogous to that above, but with the slopes based on the full cumulative hydromorphone dose sequence actually administered in each session, i.e., with the total hydromorphone dose varying somewhat across subjects and across time points, but often totaling 13.5 mg per session during the month after XR-NTX administration. This provides an assessment of how readily opioid blockade by XR-NTX can be surmounted by higher opioid agonist doses. In general, despite this administration of substantially higher hydromorphone doses, the relationships in the data are similar to those described for 3 mg hydromorphone challenges:
- Substantial and often complete blockade of opioid agonist effects (i.e., zero slopes), especially on the VAS subjective effect measures, but also evident on the pupil diameter measure;
- Blockade duration of approximately one month; and
- An apparent dose-effect relationship, with more complete and/or longer duration opioid blockade with higher XR-NTX doses.
Blockade of ascending-dose hydromorphone: Entries are slopes of the time-action regression lines
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 (more ...)
As in the 3 mg analysis, there were statistically significant opioid agonist effects for every measure and every XR-NTX dose group at BL assessment, a high-prevalence of zero or near-zero slopes during the month following XR-NTX administration, and return of slopes toward BL values at the later time points (days 42 and 56). In comparison to the 3 mg analysis, there are fewer zero slopes with the escalating-dose hydromorphone challenges, and there are more statistically significant opioid agonist effects, especially at the lowest XR-NTX dose of 75 mg. As before, VAS subjective effect measures were more completely blocked than the pupil diameter measure. The VAS “any drug effect” measure was completely blocked (i.e., zero slope) for 14 days, and was substantially blocked (i.e., not even a trend toward a significant slope) for 28 days after 300 mg XR-NTX. Extent and duration of blockade were somewhat less with the lower XR-NTX doses.
3.5. Absolute Magnitudes of Effects
Two examples illustrate the absolute magnitudes of effects represented by the above slope data and analyses. Peak scores on the VAS “any drug effect” measure at BL, 28 days, and 56 days were summarized for the subset of subjects with data available at all 3 timepoints; the two higher XR-NTX doses (150 and 300 mg), combined, provided an N of 7 such subjects. The summary used peak scores from the full cumulative dose given, which was usually higher on day 28 than on the other days. Mean peak scores were 54.3, 10.4, and 39 for BL, day 28, and day 56, respectively. Six of these 7 subjects also had data from all-placebo challenge sessions, and all had peak scores of 0 in those sessions. In addition, median peak VAS scores and median peak pupil constriction for all available subjects are presented in (sample sizes vary over time from 9 to 7 for the 75 mg group, 8 to 5 for the 150 mg group, and 10 to 5 for the 300 mg group). These data show reduced subjective response and reduced hydromorphone-produced pupil constriction as a function of XR-NTX administration.
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 (more ...)
3.6. Effects on Respiratory Depression
The opioid effects and opioid blockade effects seen with subjective effects measures and pupil constriction were also seen on physiological parameters related to opioid safety. Respiratory rate and blood oxygen saturation were both significantly depressed during the Baseline (unblocked) hydromorphone challenge sessions. Respiratory rate was reduced by a mean of 4.8 breaths per minute (95% CI: 3.7 to 5.9); oxygen saturation was reduced by a mean of 3.3% (95% CI: 2.1 to 4.6%). Mean respiratory depression (for both these measures) fell well outside these 95% confidence intervals during sessions in which placebo was substituted for hydromorphone (mean respiratory rate change -1.3 bpm; mean oxygen saturation change -0.6%), and for XR-NTX blocked sessions (mean respiratory rate change -1.6 bpm; mean oxygen saturation change -0.5%). These means XR-NTX-blocked sessions are based on the earliest post XR-NTX active hydromorphone challenge session (typically Day 7) for each subject across all XR-NTX doses combined, and are quite similar to the mean changes in placebo challenge sessions.
3.7. Naltrexone Plasma Concentrations
Median plasma concentrations of naltrexone and 6-beta-naltrexol are shown in for each XR-NTX dose at each time point. Concentrations were dose-related and declined over time, reaching levels below the limits of quantification by day 56. Concentrations of naltrexone's major metabolite 6-beta-naltrexol were initially about twice those of naltrexone itself, but fell below detectable levels sooner. Hydromorphone's pharmacodynamic effects were moderately correlated with these plasma concentrations; the critical plasma concentration for achieving opioid blockade was approximately 1 ng/mL for naltrexone and approximately 3 ng/mL for 6-beta-naltrexol.
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.
3.8. Adverse Events and Injection Site Reactions
One subject in each dose group reported adverse events of mild severity that were considered possibly related to the study drug. These were: increased heart rate, increased sweating, and tremors in the arms (75 mg), myalgia (150 mg), and dizziness and nausea (300 mg). The subject who reported myalgia in the right lower leg (after receiving the study injection in the right buttock) received extensive multi-specialty evaluation without determination of pathology or etiology; the event was rated as possibly related to study procedures and the subject was discontinued from the study.
Twelve of 27 subjects (44%) experienced at least one injection site reaction (4 in the 75 mg group; 5 in the 150 mg group; 3 in the 300 mg group). These included tenderness and induration and there was one instance of slight bruising at the injection site. None of the injection site reactions were considered clinically significant.