Analgesic and Hemodynamic Effects of Dexmedetomidine–Ketamine vs Fentanyl–Ketamine in Healthy Volunteers: A Randomized Trial

Maja Green,1,2 Amie C Hayley,3,4 Luke A Downey,3,4 Michael Keane,4,5 Michaela Elise Kenneally,6 Krishnan Chakravarthy,1,2 Yahya Shehabi5,7 1NXTSTIM, Department of Pain Medicine, San Diego, CA, USA; 2Soalris Research Institute, Temecula, CA, USA; 3Institute for Breathing and Sleep, Austin Hospital, Melbourne, Victoria, Australia; 4Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, Australia; 5Critical Care and Anaesthesia, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia; 6Forensic Science, Adelaide, South Australia, Australia; 7Clinical School of Medicine, University of New South Wales, Sydney, New South Wales, AustraliaCorrespondence: Maja Green, NXTSTIM Inc., Department of Pain Medicine, San Diego, CA, 92130, USA, Email [email protected]: Dexmedetomidine is an α 2-agonist sedative with opioid-sparing properties, is limited by dose-dependent hypotension and bradycardia. Ketamine, an NMDA receptor antagonist, has sympathomimetic effects and may attenuate these cardiovascular effects while contributing analgesia. Whether low-dose ketamine can stabilize dexmedetomidine-induced hemodynamic changes and provide comparable analgesia to an opioid-based regimen is uncertain.Methods: In this open-label trial, we enrolled 41 healthy volunteers aged 18 to 45 years. All participants received a ketamine infusion (0.3 mg/kg bolus, then 0.15 mg/kg/hour for 3 hours). At 90 minutes, participants were randomized to receive either dexmedetomidine (0.7 μg/kg/hour for 90 minutes, KET/DEX group) or fentanyl (three 25 μg boluses, KET/FENT group). The primary outcomes were change in blood pressure and pain tolerance (measured by pressure algometry). Secondary outcomes included heart rate, subjective mood and sedation, and adverse events. Data were analyzed using mixed-effects models and Fisher’s exact tests.Results: Of 41 randomized participants, 39 completed the protocol (KET/DEX, 19; KET/FENT, 20). KET/DEX resulted in greater reductions in systolic blood pressure (mean decrease 35– 40 mm Hg; ~25– 30%) compared to KET/FENT (mean change minimal; between-group P< 0.001). Heart rate declined modestly with KET/DEX but did not differ significantly between groups. Both regimens increased pain tolerance to a similar degree (mean threshold rise ~30– 50 kPa; between-group P=0.80). Participants in the KET/DEX group reported greater sedation and transient negative mood effects (eg, disinterest), while KET/FENT was associated with mild nausea in a minority. Clinically significant hypotension occurred in 4 participants (21%) in the KET/DEX group and in none of the KET/FENT group (P=0.047). All events were transient and responsive to fluid boluses. No respiratory depression occurred in either group.Conclusion: Ketamine plus dexmedetomidine produced analgesia equivalent to ketamine plus fentanyl but with more pronounced hypotension and deeper sedation. The hemodynamic effects of dexmedetomidine were not fully offset by low-dose ketamine. These findings suggest that while ketamine–dexmedetomidine may offer an opioid-sparing alternative, careful dose selection and monitoring are required to ensure tolerability. (Funded by Monash University and Monash Health; ACTRN12617000787381).Clinical Trial Number and Registry Url: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372916.Keywords: ketamine, dexmedetomidine, fentanyl, sedation, haemodynamic changes