Intranasal buprenorphine alone and in combination with naloxone: Abuse liability and reinforcing efficacy in physically dependent opioid abusers

Abstract

Background: Buprenorphine can be abused by the intranasal route. This study sought to examine the relative abuse liability and reinforcing efficacy of intranasal buprenorphine compared to intranasal buprenorphine/naloxone in opioid-dependent individuals.

Methods: Eleven healthy male and female volunteers physically dependent on short-acting opioids resided as inpatients during participation in this double blind, within subject, placebo-controlled study. Participants were maintained on oxycodone (30 mg/q.i.d., p.o.) throughout the 6-week study. Eight pairs of experimental sessions were conducted at ≥48 h intervals to examine the pharmacodynamic profile (Sample) and reinforcing efficacy (Self-administration the following day) of intranasal placebo, oxycodone (60 mg), buprenorphine (2, 8 & 16 mg) and buprenorphine/naloxone (2/0.5, 8/2 & 16/4 mg). Subjective, observer-rated and physiological measures were collected to assess the magnitude of opioid agonist and antagonist effects. A progressive ratio self-administration procedure assessed choices for drug versus money.

Results: All active doses produced opioid agonist-like effects (e.g., increased ratings of "liking," and miosis) compared to placebo. The effects of buprenorphine and buprenorphine/naloxone were not reliably dose-dependent. Intranasal buprenorphine/naloxone elicited modest and transient opioid withdrawal-like effects in the first hour post-drug administration, while simultaneously blunting or blocking the early onset of agonist effects seen with buprenorphine alone. All active doses of buprenorphine were self-administered more than placebo, but buprenorphine/naloxone doses were not.

Conclusions: These data confirm that intranasal buprenorphine/naloxone has deterrent properties related to transient withdrawal effects that likely decrease its desirability for misuse compared to buprenorphine in opioid-dependent individuals maintained on short-acting opioids.

Keywords: Abuse; Buprenorphine; Misuse; Mu agonist; Opioid; Opioid withdrawal.

Figure 1

Mean peak data (n=11; ± 1 SEM) are shown for four measures of opioid withdrawal comparing placebo (white bars) versus naloxone (0.2 mg, i.m.; black bars). Significant main effects of drug condition (placebo vs. naloxone; designated by the asterisk *) were found for all four measures (df=10) as follows: “Bad Effects” (t=3.43; p=.006), Opiate Withdrawal (t= −2.74; p =.021), OOWS Score (t= −3.3; p=.008) and pupil diameter (t= −5.47; p<.001).

Figure 2

Mean peak data (n=11; ± 1 SEM) are shown for six measures reflecting opioid agonist effects, abuse potential and opioid withdrawal from the subjects and observers after intranasal administration of placebo (diamond), oxycodone (triangle), BUP alone (square) and BUP/NX (circles). For all measures, there were statistically significant main effects of dose as follows: Subject-rated Agonist Scale (upper left; F [7, 70] = 5.43; p<.0001), Observer-rated Agonist Scale (upper right; F=3.86; p=.001), the VAS “How much do you LIKE the drug?” (center left; F=3.48; p=.003), the VAS “Do you feel any DRUG EFFECT?” (center right; F=3.81; p=.002), Subject-rated Withdrawal Scale (lower left; F=2.45; p=.027) and the observer-rated Himmelsbach Scale (lower right; F=3.41; p=.003). Filled symbols indicate significant post-hoc differences between active doses and placebo; asterisks (*) indicate significant difference between matched doses of BUP vs. BUP/NX (Fisher’s LSD test, p<.05).

Figure 3

Data shown depict the time-action curves for mean data (n=11; error bars omitted for clarity) collected during the 6.5 hour Sample sessions for two visual analog scales: Does the drug have any GOOD EFFECTS? (upper panels) and Does the drug have any BAD EFFECTS? (lower panels). On the left side, data are shown for the control conditions (placebo & 60 mg oxycodone) and the BUP doses while, on the right side, data are repeated for the control conditions and shown with the BUP/NX doses. For ratings of “good effects” there was a significant main effect of dose (F[7,70]=4.12; p=.001) and dose×time interaction (F[126, 160]=2.22; p<.0001). For ratings of bad effects, there was a significant main effect of dose (F=2.46; p=.026) and dose×time interaction (F=1.8; p<.0001). For both outcomes, there were significant main effects of time (p<.05). Filled symbols indicate significant differences between matched BUP vs. BUP/NX doses (e.g., 8 versus 8/2 at that time; Fisher’s LSD test; p<.05).

Figure 4

Shown for mean (n=11) data for VAS ratings of “How HIGH are you?” (upper panel), pupil diameter (middle panel) and VAS ratings of “How severe is your OPIOID WITHDRAWAL?” for baseline (BL) and the first hour after intranasal placebo (triangles) or matched doses of BUP (circles) and BUP/NX (squares). For each outcome, there was a significant main effect of dose as follows: (“High?” (F[7,70]=6.61; p<.0001); pupil diameter (F[7,70]=17.43; p<.0001), “Opioid Withdrawal” (F[7,70]=3.01; p=.008). Filled symbols indicate a significant difference at that time point between the matched dose of BUP and BUP/NX (Fisher’s LSD test, p<.05).

Figure 5

Data are shown for the mean (n=11) number of trials completed (± 1 SEM) to earn the study drug during the progressive ratio sessions (upper panel) and number of trials not worked (lower panel). Significant main effects of dose were found for both outcomes (F[7,70]=4.71; p<.001 trials completed for drug and (F [7, 70] =2.9; p = .010) trials not worked, respectively. Asterisk (*) indicates significant difference from placebo, while hash (#) indicates significant difference between matched BUP and BUP/NX doses (Fisher’s LSD; p<.05). Number of trials worked for money can be derived by adding trials worked for drug with trials not worked for a given condition and subtracting that total from 7 (the total possible trials within a session).