There are two comparisons of interest in these analyses: 1) for a given formulation, how effects differed by route of administration (IM vs. SL), and 2) for a given route of administration, how presence versus absence of naloxone affected the abuse liability profile of buprenorphine. Results are presented to illustrate the IM and SL comparisons (, ), and the presence versus absence of naloxone comparisons (). Comparisons are addressed in more detail below.
Peak Change from Baseline Analysis
Visual Analog Scale Items at Three Different Time Points for Each Drug Condition
Figure 1 Peak change from baseline means (±SEM) for visual analog item Drug Effect, observer rated Agonist, and pupil diameter for doses of hydromorphone (2, 4 mg), buprenorphine (4, 8, and 16 mg), and buprenorphine/naloxone (4/2, 8/4, and 16/8 mg). * (more ...)
Route of Administration Comparisons
A significant main effect was shown for VAS ratings of Drug Effect, Liking, High, and Good Effects (p<0.05; ). There were no significant differences between placebo and the two doses of hydromorphone for these four VAS measures. Pairwise comparisons did not reveal statistically significant differences between routes of administration for any dose of buprenorphine and buprenorphine/naloxone. No overall significant effects were found for VAS ratings of Bad Effects or Sick (data not shown)
There were four adjective scale scores: Agonist scores and Withdrawal scores, from subject ratings and from observer ratings (, Withdrawal scores not shown). There was a significant main effect for observer adjective Agonist scale scores, but there were no other significant main effects for the other adjective scale scores (subject or observer; ). Pairwise comparisons failed to reveal statistical significance between placebo and either dose of hydromorphone for any of the four scales (). Subject rated and observer rated Agonist and Withdrawal scores were generally of low magnitude and did not significantly differ between routes of administration ().
Outcomes on physiological measures are shown in . For pupil diameter, both hydromorphone doses decreased pupil diameter (by about 1 mm), although these decreases were not significantly different from placebo. In contrast, the 8 mg SL dose of buprenorphine administered alone, the 8/2 mg and 16/4 mg SL doses of buprenorphine/naloxone, and the 16/4 mg IM buprenorphine/naloxone dose significantly decreased pupil diameter compared to placebo (p<0.05). There were no significant differences in pupil diameter by route of administration for a given dose of buprenorphine or buprenorphine/naloxone (). No significant differences were found between drug conditions for all other physiological measures.
Presence versus Absence of Naloxone Comparisons
Pairwise comparisons within a given route of administration, and within a given dose of buprenorphine found no statistically significant differences as a function of the presence versus absence of naloxone. provides an illustrative example of a subject-rated VAS item (Drug Effect), an observer rated adjective scale (Agonist), and a physiological measure (pupil diameter). For the IM route of administration (squares), there was no evidence that the inclusion of naloxone (filled squares) significantly affected these measures compared to buprenorphine alone (open squares).
Time Course Analysis
In addition to peak change from baseline analyses, the time dependent changes for each VAS measure were examined in order to determine onset differences by route of administration (IM vs. SL) or differences resulting from the addition of naloxone (i.e., buprenorphine alone vs. buprenorphine in combination with naloxone). Statistical differences were found for both main effects (Condition and Time) for Drug Effect [F(14,98)=2.16, p<.05; F(12,84)=18.05, p<0.0001], Liking [F(14,98)=1.84, p<0.05; F(12,84)=16.94, p<0.0001], High [F(14,98)=2.1, p<.05; F(12,84)=19.24, p<0.0001], and Good Effects [F(14,98)=1.91, p<0.05; F(12,84)=18.01, p<0.0001]. No differences were found for Bad Effects or Sick (data not shown). provides an illustrative example of these time course results for VAS ratings of Liking, highlighting differences as a function of route of administration. Overall, there was a pattern of generally higher ratings of Liking associated with IM compared to SL administration for a given dose of buprenorphine and buprenorphine/naloxone, with the magnitude of this difference greatest for the 4/1 and 16/4 mg buprenorphine/naloxone conditions ().
Figure 2 Visual Analog Scale for Liking following administration of each dose condition. Filled symbols indicate significant difference between routes of administration within dose condition. * p≤0.05 versus placebo, ** p≤0.05 versus 4 mg hydromorphone. (more ...)
Pairwise comparisons were performed for early time points (15, 30, 45 min) to capture differences in the onset of effects and are summarized in . Overall, the SL route of administration for both buprenorphine alone and in combination with naloxone did not significantly increase subjective ratings on VAS items when compared to placebo or hydromorphone during the first 45 minutes after administration. Generally, IM buprenorphine alone did not significantly alter subjective ratings compared to placebo or hydromorphone (4 mg). The combination of buprenorphine/naloxone (4/1 and 16/4 mg) administered intramuscularly significantly increased ratings on some VAS items (, ). These increases occurred earlier for the 16/4 versus 4/1 mg dose of buprenorphine/naloxone, suggesting the higher dose combination (16/4 mg) produced a quicker onset of action for these subjective measures.
The SL and IM routes of administration for buprenorphine and buprenorphine/naloxone also were compared within each dose. Generally, IM administration was associated with increased positive subject ratings (e.g., Drug Effect, Liking, High, Good Effects) compared to SL dosing () with a statistically significant difference found for the intermediate dose of buprenorphine alone (8 mg).
In contrast to these buprenorphine alone findings, buprenorphine/naloxone (4/1 and 16/4 mg) administered intramuscularly increased ratings of Drug Effect, Liking, High, and Good Effects compared to the SL preparation (p<0.05). The addition of naloxone to buprenorphine (4/1 and 16/4) increased positive ratings following IM administration compared to placebo and hydromorphone (4 mg); however, there were no statistically significant differences between buprenorphine and buprenorphine/naloxone within a given dose or route of administration.