As part of its program to evaluate new treatments, the section is studying the clinical pharmacology of drug of abuse and potential treatment medications. Buprenorphine is a partial mu opioid agonist under development for agonist maintenance therapy. Although buprenorphine will be marketed as a sublingual tablet, it has the potential for diversion for use by the intravenous (IV) route. We examined the safety of IV administration of buprenorphine doses in the range of those used for maintenance, evaluated buprenorphine's abuse liability by the IV route, and determined whether a ceiling occurs on the effects of IV buprenorphine in experienced opioid abusers. Buprenorphine 12 mg SL, IV/SL placebo, and escalating IV BUP doses (2, 4, 8, 12, and 16 mg) were tested in separate sessions in 6 non-dependent opioid abusers living on a research unit. Physiological and subjective measures were collected for up to 72 hours post drug administration. Buprenorphine significantly increased systolic blood pressure with no other statistically significant changes in heart rate or oxygen (02) saturation among the 7 drug conditions. The mean maximum decrease in 02 saturation from baseline was greatest for the 8 mg IV dose. Buprenorphine produced positive mood effects, though with substantial inter-subject variability. Onset of effects occurred earlier following IV than SL administration. Peak IV effects occurred between 0.25 and 3 hrs; peak SL effects occurred at 3 to 7 hrs. Duration of effects varied among the outcome measures. The dose-response curves were flat for most measures, particularly subjective measures. Side effects were mild except in one participant who was discontinued after the 12-mg IV dose because of severe nausea. Buprenorphine administered IV in doses ranging from 2 mg to 16 mg produced substantial subjective and physiological effects, but a ceiling effect was clearly apparent on a range of measures across the doses tested. Nausea and vomiting were the most common adverse effects and were clinically significant in severity and duration, possibly decreasing the abuse potential by the IV route. Sedation was also common, though participants were easily roused. Respiratory depression occurred but was relatively short lasting and not medically significant. Though participants reported subjective effects consistent with abuse potential, their responses were quite variable and included reports of effects that were not consistently positive. Overall, buprenorphine appears to have a ceiling for subjective and cardio-respiratory effects and a high safety margin when administered by the IV route.
| Hughes, John R (2010) Craving among long-abstinent smokers: an Internet survey. Nicotine Tob Res 12:459-62 |
| Huestis, M A; Gorelick, D A; Heishman, S J et al. (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58:322-8 |
| Preston, K L; Bigelow, G E (2000) Effects of agonist-antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination. J Pharmacol Exp Ther 295:114-24 |
| Epstein, D H; Silverman, K; Henningfield, J E et al. (1999) Low-dose oral cocaine in humans: acquisition of discrimination and time-course of effects. Behav Pharmacol 10:531-42 |
| Jones, H E; Bigelow, G E; Preston, K L (1999) Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure. J Pharmacol Exp Ther 289:1350-61 |
