This randomized, crossover, placebo-controlled, lab-based trial (n=22) tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. The authors found that low dose ketamine administration attenuates perceived pain and pressor, but not MSNA burst frequency, responses during a CPT.
“Low dose ketamine is an effective analgesic medication. However, our knowledge of the effects of ketamine on autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low dose ketamine influences autonomic cardiovascular responses during painful stimuli in humans. We tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. Twenty-two adults (10F/12M; 27±6 y; 26±3 kg m-2 , mean±SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed cold pressor tests (CPT; hand in ∼0.4°C ice bath for two minutes) pre- and five minutes post-drug administration (20 mg ketamine or saline). We compared pain perception (100 mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 12 paired recordings) and beat-to-beat blood pressure (BP; photoplethysmography) during the pre- and post-drug CPT’s separately using paired, two-tailed t-tests. For the pre-drug CPT, perceived pain (p = 0.4378), MSNA burst frequency responses (p = 0.7375), and mean BP responses (p = 0.6457) were not different between trials. For the post-drug CPT, ketamine compared to placebo administration attenuated perceived pain (p<0.0001) and mean BP responses (p = 0.0047), but did not attenuate MSNA burst frequency responses (p = 0.3662). Finally, during the post-drug CPT, there was a moderate relation between cardiac output and BP responses after placebo administration (r = 0.53, p = 0.0121), but this relation was effectively absent after ketamine administration (r = -0.12, p = 0.5885). These data suggest that low dose ketamine administration attenuates perceived pain and pressor, but not MSNA burst frequency, responses during a CPT.”
Authors: Joseph C. Watso, Mu Huang, Gilbert Moralez, Matthew N. Cramer, Joseph M. Hendrix, Frank A. Cimino III, Luke N. Belval, Carmen Hinojosa‐Laborde & Craig G. Crandall
Ketamine reduces pain and pressor, but not sympathetic, responses.
Key Points Summary
Low dose ketamine reduces pain perception and blood pressure in healthy humans, but not muscle sympathetic nerve activity burst frequency, during a cold pressor test.
Low dose ketamine is an effective analgesic medication, but it is unknown if it influences autonomic cardiovascular responses during painful stimuli in humans. Twenty-two adults completed a randomized, crossover, placebo-controlled trial during two laboratory visits. Ketamine attenuated perceived pain and mean blood pressure responses, but not muscle sympathetic nerve activity burst frequency responses, during a cold pressor test.
Medical care includes pain management. When selecting a pain medication, clinicians must consider both the analgesic properties of a medication and any side effects that medication may have on vital physiological processes. Low dose ketamine, a N-methyl-D-aspartate receptor (NMDA) antagonist, has been shown to have little to no risk for eliciting hypotension. However, to date, there has been only one study in humans using a high dose of ketamine to determine how autonomic cardiovascular regulation is affected.
During experimental pain, autonomic cardiovascular responses are largely dependent on the intensity of perceived pain. However, the autonomic cardiovascular responses associated with experimental pain are likely dependent on the pain stimulus employed. The cold pressor test (CPT) is a commonly used stimulus that elicits pain-related cardiovascular responses. We tested the hypothesis that low dose ketamine attenuates perceived pain and the subsequent MSNA burst frequency and BP responses, and also determined the contribution of cardiac output on increases in BP.
Low dose ketamine has been used for cardiovascular support, peri- and post-operative analgesia, and off-label uses for treatment of depression. Our work will provide fundamental information regarding the effects of low dose ketamine on autonomic cardiovascular regulation.
22 participants were recruited from the Dallas -Fort Worth metroplex and provided verbal and written consent prior to enrollment in the study. The data in this manuscript are associated with a registered clinical trial.
This protocol consisted of two experimental visits separated by at least 48 hours. The data was collected to address two distinct research questions, i.e. pain perception and tolerance to progressive LBNP.
The study included participants aged 18-45, with a body mass index of 32 kg/m2, and no evidence of cardiovascular, neurological, renal, metabolic, or pulmonary disease.
Participants were instructed to refrain from drinking large quantities of water, eating for at least six hours, caffeine, strenuous exercise, alcohol, Naproxen, and NSAIDs for 24 hours, and over-the-counter cold or allergy medication and Aspirin for 36 hours before each trial.
Following baseline data collection, participants underwent a pressure pain tolerance test, a CPT, and a progressive LBNP test. A second drug/placebo dose was administered thirty minutes after the first drug/placebo dose to minimize carryover effects from the first drug/placebo administration.
In all 22 participants, the cold pressor test (CPT) was completed by having their hand placed in a 0.35 °C) ice bath for two minutes. Participants rated their pain on a 100 mm visual analog scale.
We applied pressure to the second and third digits of 12 participants and recorded the peak force when the participant first reported a feeling of discomfort. We repeated this test three to five times, approximately 10 seconds apart.
We recorded muscle sympathetic nerve activity using ultrasound-guided radial microneurography in 12 participants (6 males, 6 females) and amplified, bandpass filtered, rectified, and integrated the electrical signal using a nerve traffic analyzer.
We used single-lead ECG, photoplethysmography, Modelflow-derived cardiac output and total peripheral resistance, and auscultatory dimensional K-sound analysis to assess brachial BP at rest and during the CPT.
Data were collected using Biopac (MP150, Biopac, Santa Barbara, CA, USA) and analyzed using Ensemble (Elucimed, Wellington, New Zealand). MSNA bursts were quantified as burst frequency and burst incidence, but not as burst amplitude or area, due to variable position of microelectrode and LBNP-related shifts in the neurogram.
We obtained venous blood samples before drug administration and four minutes after drug administration. We stored the samples on ice until centrifugation and shipped the plasma samples to Arup Laboratory.
We compared pressure pain tolerance, pain perception, and cardiovascular and sympathetic measures between trial days prior to saline/drug administration, and between trial days within the “Post-Drug” time point.
We used paired, two-tailed t-tests, repeated measures two-way ANOVAs, and Tukey multiple comparison testing to analyze data from a secondary aim from a larger registered clinical trial. We also used Pearson correlations to determine if changes in cardiac output and total peripheral resistance were related to changes in mean blood pressure.
Participants did not report a history of posttramutic stress disorder, and spot urine specific gravity was not different between trials.
Pre-Drug Administration Pain Assessments, Sympathetic, and Cardiovascular Measures were not different between trials. There was also no difference in Perceived Pain during the Initial CPT (pre-placebo 66 14 mm vs. pre-ketamine 68 17 mm), or during CPT (pre-placebo 40 10 bursts – min-1). We did not observe a significant interaction effect for mean BP, heart rate, or MSNA burst frequency between trials, nor did we observe a significant interaction effect for any other cardiovascular or sympathetic values during the CPT.
Post-drug administration pain assessments showed that pressure pain tolerance was higher after low dose ketamine compared to placebo administration, and pain perception during the CPT was lower after low dose ketamine administration.
After placebo and low dose ketamine administration, the frequency and incidence of MSNA bursts increased from Rest to CPT, but the absolute increases in MSNA burst frequency and burst incidence were not different between placebo and low dose ketamine administration.
Post-drug administration cardiovascular measures were higher after low dose ketamine compared to placebo administration, but were attenuated after low dose ketamine compared to placebo administration.
After low dose ketamine administration, heart rate and cardiac output were higher and total peripheral resistance was lower during Rest and the CPT compared to placebo.
Cardiac output and total peripheral resistance were significantly related to mean BP responses after placebo, but not after low dose ketamine, administration.
Low dose ketamine administration reduced pain perception, did not alter increases in MSNA burst frequency, attenuated increases in systolic, mean, and diastolic BP, and increased pressure pain tolerance during the CPT.
Clinical pain conditions are associated with greater alterations in autonomic cardiovascular regulation, and in adults without chronic pain, perceived pain is associated with sympathetic nervous system mediated increases in BP.
We hypothesized that low dose ketamine, an NMDA-antagonist, would reduce pain perception and the subsequent increases in MSNA and BP during the CPT. However, the relation between reductions in pain perception and mean BP responses during the CPT was not even modestly strong.
A study reported increased blood pressure and reduced MSNA burst frequency after racemic ketamine administration, but the high dose used prevented analysis. While ketamine attenuated BP responses during the CPT, MSNA burst frequency responses were not attenuated, suggesting that these attenuated BP responses may not be sympathetically mediated. Additionally, ketamine may have reduced anxiety, but this is beyond the scope of this manuscript.
An investigation assessed MSNA responses to moderate pain induced by intramuscular infusion of hypertonic saline (7%) in a cohort of 12 participants. The authors found that MSNA burst frequency and amplitude were associated with BP responses, and that ketamine reduced MSNA burst amplitude responses while increasing MSNA burst frequency. The elevated plasma norepinephrine concentrations after low dose ketamine support the notion of greater MSNA burst amplitude at rest, but the increased functional relation between circulating norepinephrine concentrations and vascular responses to a given amount of synaptic norepinephrine release limits one’s ability to conclude that.
Previous animal studies have suggested that low dose ketamine increases resting heart rate and blood pressure, but we did not observe parallel increases in resting MSNA after low dose ketamine administration. Additional experiments are necessary to address the mechanism of low dose ketamine in humans.
We demonstrated that low dose ketamine administration blunted the increases in cardiac output during the CPT.
Low dose ketamine has been added to several prehospital pain management guidelines and is used in the United States military in combat settings. It also has additional clinical uses, such as improving blood pressure support and analgesia in peri- and post-operative settings.
Low dose ketamine may be considered to reduce opioid requirements to maintain analgesia, and may also be used to treat other disorders such as major depressive disorders, anxiety disorders, and migraine pain.
While this study contributes new knowledge to the understanding of how low dose ketamine alters pain perception, sympathetic , and cardiovascular responses to an acute experimental pain stimulus, there are several limitations to mention. We concluded that the pre-drug sympathetic and cardiovascular responses during the CPT were not different between trials, and that this was unlikely to have confounded the results or conclusions. 3) Previous studies have reported that increases in BP and MSNA during repeated CPTs are reproducible within a visit, but increases in HR are attenuated during the second compared to the first CPT.
The present study does not allow us to draw conclusions on how low dose ketamine might affect autonomic cardiovascular function with pain associated with real-world severe trauma.
Low dose ketamine administration significantly reduces pain perception, but not MSNA burst frequency. Additionally, low dose ketamine blunts the contribution of cardiac output on increases in mean BP.
We would like to thank all study volunteers for their participation, and the research nurses, research associates, and summer interns for their contributions.