Low-dose morphine reduces pain perception and blood pressure, but not muscle sympathetic outflow, responses during the cold pressor test

Our knowledge about how low-dose (analgesic) morphine affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose morphine affects human autonomic cardiovascular responses during painful stimuli in conscious humans. Therefore, we tested the hypothesis that low-dose morphine reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-nine participants (14 females/15 males; 29 ± 6 yr; 26 ± 4 kg·m , 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 ∼35 min after drug/placebo administration (5 mg iv morphine or saline). We compared pain perception (100 mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography; 14 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo time points) using paired, two-tailed tests. Before drug/placebo infusion, perceived pain ( = 0.92), ΔMSNA burst frequency ( = 14, = 0.21), and Δmean BP ( = 0.39) during the CPT were not different between trials. After the drug/placebo infusion, morphine versus placebo attenuated perceived pain (morphine: 43 ± 20 vs. placebo: 57 ± 24 mm, < 0.001) and Δmean BP (morphine: 10 ± 7 vs. placebo: 13 ± 8 mmHg, = 0.003), but not ΔMSNA burst frequency (morphine: 10 ± 11 vs. placebo: 13 ± 11 bursts·min , = 0.12), during the CPT. Reductions in pain perception and Δmean BP were only weakly related ( = 0.34, = 0.07; postmorphine CPT minus postplacebo CPT). These data provide valuable information regarding how low-dose morphine affects autonomic cardiovascular responses during an experimental painful stimulus. In this randomized, crossover, placebo-controlled trial, we found that low-dose morphine administration reduced pain perception and blood pressure responses during the cold pressor test via attenuated increases in heart rate and cardiac output. We also determined that muscle sympathetic outflow responses during the cold pressor test seem to be unaffected by low-dose morphine administration. Finally, our exploratory analysis suggests that biological sex does not influence morphine-induced antinociception in healthy adults.