Fig 1.
BUP, buprenorphine; PD, pharmacodynamic; PK, pharmacokinetic. aRandomised sequences for Part A were Placebo:BUP N = 5, BUP:Placebo N = 3 for the 0.2 ng/mL group and Placebo:BUP N = 2, BUP:Placebo N = 4 for the 0.5 ng/mL group. bOne volunteer in the lower dose group received the incorrect buprenorphine dose and was excluded from the PD analyses. Data were available for six healthy volunteers in each treatment (placebo and buprenorphine) for the PD analyses in the lower dose group due to two volunteers in the lower dose group who completed only one study period.
Table 1.
Participant demographic and clinical characteristics.
Fig 2.
Mean buprenorphine plasma concentration-time curves.
Upper panel: Part A, healthy volunteers; Lower panel: Part B, opioid-tolerant patients. In both healthy volunteers and opioid-tolerant patients, a 10-fold higher infusion rate was used over the first 15 minutes to speed attainment of steady-state buprenorphine concentrations at the site of action. Infusions were stopped at 360 min. Steady-state buprenorphine infusion rates are labelled in the graphs.
Fig 3.
Mean fentanyl plasma concentration-time curves.
Upper panel: Part A, healthy volunteers; Lower panel: Part B, opioid-tolerant patients. At 120, 180, 240, and 300 minutes after the start of the buprenorphine or placebo infusion, escalating intravenous fentanyl doses were administered over 90 seconds. Planned fentanyl bolus doses are labelled in the graphs. Higher doses were not administered to participants if they did not tolerate lower fentanyl doses.
Table 2.
Number and percentage of participants who experienced apnea that required stimulation (i.e. persistent apnea).
Fig 4.
Example graphs showing the effect of fentanyl on minute ventilation in three opioid-tolerant patients during placebo infusion and buprenorphine infusion.
(1) Placebo infusion (A, C and E) and buprenorphine infusion (B, D, F) at target plasma concentrations of 1 ng/mL (top row), 2 ng/mL (middle row) and 5 ng/mL (lower row). (2) Open spaces in the beginning of graphs A, C, D and E relate to concurrent clinical events such as temporary removal of the facemask. (3) Grey dots are stimulated breaths in case of an apnea episode. (4) The time on the x-axis in the graphs is related to the start time of the ventilation experiment, not the timing of the buprenorphine/placebo infusion and fentanyl injections.
Table 3.
Maximum decreases in minute ventilation after fentanyl bolus administration (%).
Table 4.
Maximum change from pre-fentanyl baseline in oxygen saturation (%) in opioid-tolerant patients.