Low-dose fentanyl reduces pain perception, muscle sympathetic nerve activity responses, and blood pressure responses during the cold pressor test

Abstract

Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10 females/13 males; 27 ± 7 yr; 26 ± 3 kg·m^-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ∼0.4°C ice bath for 2 min) before and 5 min after drug/placebo administration (75 μg fentanyl or saline). We compared pain perception (100-mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo timepoints) using paired, two-tailed t tests. Before drug/placebo administration, perceived pain (P = 0.8287), ΔMSNA burst frequency (P = 0.7587), and Δmean BP (P = 0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, P < 0.0001), ΔMSNA burst frequency (9 vs. 17 bursts/min, P = 0.0054), and Δmean BP (7 vs. 13 mmHg, P = 0.0174) during the CPT compared with placebo. Fentanyl-induced reductions in pain perception and Δmean BP were moderately related (r = 0.40, P = 0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.

Keywords: algometry; cerebral tissue oxygenation; opioids; respiration; sympathoexcitatory.

Figure 1.

Experimental protocol timeline. In a randomized crossover fashion, participants completed two experimental trials, on different days, that were identical except during one visit they received two administrations of low-dose fentanyl, and during the other visit, they received two administrations of placebo (saline). Before drug/placebo administration, we collected data during a rest period before participants completed a pressure pain threshold test using algometry and cold pressor test (CPT). Following the second drug/placebo administration, we repeated these assessments. Addressing an unrelated hypothesis, the data from the lower-body negative pressure (LBNP) test are presented in a companion manuscript (50). The primary data of interest for this manuscript are the comparisons between pain assessments made after placebo and fentanyl administration.

Figure 2.

Pain perception during the postdrug/placebo administration cold pressor test (CPT). Perceived pain during the CPT was lower after low-dose fentanyl compared with placebo administration. We present data as means ± SD with individual responses (n = 23). We compared data using a paired, two-tailed t test.

Figure 3.

Representative blood pressure and sympathetic tracings during the postdrug/placebo administration cold pressor test. We present representative mean blood pressure (BP) and muscle sympathetic nerve activity (MSNA) tracings during the cold pressor test from one participant after a placebo (left) and low-dose fentanyl (right) administration. The x-axis line break indicates the onset of the 2-min cold pressor test.

Figure 4.

Muscle sympathetic nerve activity (MSNA) responses during the postdrug/placebo administration cold pressor test (CPT). MSNA burst frequency and burst incidence values increased from rest to the CPT in both trials (A and C). The increases in MSNA burst frequency (Cohen’s d = 1.50) and burst incidence during the CPT were attenuated for fentanyl compared with placebo trials (B and D). We present data as means ± SD with individual responses (n = 11). For A and C, we compared data using repeated-measures two-way ANOVAs (main effects of rest/CPT and trial). We employed Tukey’s multiple comparison testing for post hoc analyses when appropriate. For B and D, we compared data using paired, two-tailed t tests.

Figure 5.

Blood pressure (BP) responses during the postdrug/placebo administration cold pressor test (CPT). Systolic, but not mean or diastolic, BP values were lower during rest after fentanyl compared with placebo administration and increased from rest to CPT in both trials (A, C, and E). Increases in systolic BP during the CPT were 6 mmHg lower on average for fentanyl compared with placebo trials (Cohen’s d = 0.60, B). Increases in mean (Cohen’s d = 0.68) and diastolic (Cohen’s d = 0.66) BP during the CPT were attenuated for fentanyl compared with placebo trials (D and F). We present data as means ± SD with individual responses (n = 23). For A, C, and E, we compared data using repeated-measures two-way ANOVAs (main effects of rest/CPT and trial). We employed Tukey’s multiple comparison testing for post hoc analyses when appropriate. For B, D, and F, we compared data using paired, two-tailed t tests.

Figure 6.

Hemodynamic responses during the postdrug/placebo administration cold pressor test (CPT). Heart rate and cardiac output, but not total vascular conductance, were higher during CPT compared with rest (A, C, and E). In addition, cardiac output was lower for fentanyl compared with placebo during the CPT (C). The increases in heart rate and cardiac output, but not total vascular conductance, during the CPT were attenuated for fentanyl compared with placebo (B, D, and F). For A, C, and E, we compared data using repeated-measures two-way ANOVAs (main effects of rest/CPT and trial). We employed Tukey’s multiple comparison testing for post hoc analyses when appropriate. We present these data as means ± SD with individual responses. For B and D, we compared data using Wilcoxon match-pairs signed-rank tests and present data as medians with 75% interquartile range bars and individual responses. For F, we compared data using a paired, two-tailed t test and are presented as means ± SD with individual responses. n = 23 for all comparisons.

Figure 7.

Relation between fentanyl-induced reductions in perceived pain and attenuated increases in mean blood pressure (BP) during the cold pressor test. We identified a moderate relation between reductions in pain perception and attenuations in the increases in mean BP after low-dose fentanyl administration (postfentanyl minus prefentanyl). We conducted Pearson’s correlations and present individual data for 22 paired datasets within fentanyl trials.