Nasal spray ketamine/dexmedetomidine for pain relief

INTERVENTION: Over a single 6 hour session, participants will be provided a combined dexmedetomidine + ketamine nasal solution, delivered as a titratable dose. Ketadex® is a 125mg/mL Ketamine and 250mcg/mL dexmedetomidine nasal solution that is administered in a proprietary nasal delivery device to administer up to 8 sprays of 12.5mg ketamine and 25mcg dexmedetomidine per 0.1ml spray. Each mL contains 144.175mg of ketamine hydrochloride equivalent to 125mg of ketamine, 295 mcg of dexmedetomidine hydrochloride equivalent to 250 mcg (0.25mg) of dexmedetomidine, 1.05mg of sodium citrate dihydrate and 0.15 mg of edetate disodium dihydrate in water. The dosing conditions are as follows: 1. Low dose: 25µg dexmedetomidine + 12.5mg ketamine (1 intranasal spray) OR 2. Medium dose: 100µg dexmedetomidine + 50mg ketamine (4 intranasal sprays performed by 1 X 0.1ml in each nostril initially followed by 1 X 0.1ml in each nostril one minute later) OR 3. High dose: 200µg dexmedetomidine + 100mg ketamine [8 intranasal sprays, performed by 1 X 0.1ml in each nostril, followed by 1 X 0.1ml in each nostril one minute later (4 intranasal sprays). Repeated one minute later with 1 X 0.1ml in each nostril, followed by 1 X 0.1ml in each nostril one minute later (4 intranasal sprays)]. CONDITION: Anaesthesiology ‐ Other anaesthesiology Analgesia; ; Analgesia PRIMARY OUTCOME: Sedation [Richmond Agitation‐Sedation Scale (RASS) score (mean)][At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] SECONDARY OUTCOME: 02 saturation using pulse oximetry [At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Attention (Attention Switching) [At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Cardiovascular events (Systolic BP <85mmHg), as assessed using bench‐top sphygmomanometer ; [At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Cardiovascular side effects (Heart rate <55/minute), as assessed using pulse oximetry[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Cessation of study drugs due to intolerance or aforementioned side effects[Monitored continuously throughout] Difference in concentration of ketamine in the blood between groups[Immediately prior to administration of the treatment (baseline) and thereafter at 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 360mins post‐dose ] Difference in lapses (change in mean lateral position of the car greater than 100cm, lasting for at least 8 seconds) across time, measured using the driving simulator [At baseline and at 6‐hours post‐treatment] Difference in standard deviation of speed (SDS) as measured by the driving simulator across time[At baseline and 6‐hours post treatment] Driving performance, measured as difference in standard deviation of the lateral position (SDLP) over time, as assessed by a computerised driving simulator[Baseline and 6 hours post treatment] Gastrointestinal (GIT) side effect (Bowel movements/constipation), assessed using binary (y/n) questioning[on follow up at 24 hours post] Gastrointestinal (GIT) side effect (Nausea), assessed using binary (y/n) questioning[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours), at 12‐hours post discharge INCLUSION CRITERIA: ‐ Male/female, 21 to 45 years. ‐ Weight 50‐130kg ‐ Full drivers licence ‐ Free from neurological conditions, depression or psychiatric disorders. ‐ No history of drug abuse or dependence ‐ No known allergy to study drugs ; ] Gastrointestinal (GIT) side effect (Vomiting), assessed using binary (y/n) questioning[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours), at 24‐hours post discharge] Heart rate, assessed using pulse oximetry[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Individual subjective drug effects on alertness (0= alert, 100= drowsy)[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Local effects of intranasally administered solution (dry eye), assessed using binary (y/n) questioning[Every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24‐hours post discharge.] local effects of intranasally administered solution (eye watering), assessed using binary (y/n) questioning[Every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24‐hours post discharge ‐ Not currently taking medications that could affect the outcome of the study. ; ] Local effects of intranasally administered solution (taste), assessed using binary (y/n) questioning[Every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24‐hours post discharge] Local side effects of intranasally administered solution (burning), assessed using binary (y/n) questioning[Every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24‐hours post discharge] Local side effects of intranasally administered solution (stinging), assessed using binary (y/n) questioning[Every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24‐hours post discharge] Non‐invasive Blood pressure, as assessed using bench‐top sphygmomanometer[Baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours)] Paired Associates Learning (PAL) score[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Rapid Visual Information Processing (Sustained Attention) [At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Reaction Time (Processing and Psychomotor Speed) [At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Respiratory rate <8/minute, assessed using pulse oximetry[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Respiratory rate, assessed using bench‐top sphygmomanometer[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Respiratory side effects (O2 saturation <90%), as assessed using pulse oximetry[At baseline, every 30 minutes for the first three hours post‐dosing, and every hour thereafter (total 10 assessments over 6 hours).] Self reported coordination (0=well‐coordinated, 100=clumsy)[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Self‐reported attention (0=attentive, 100=dreamy) [At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Self‐reported clear‐headedness (0 = clear headed, 100=muzzy)[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Self‐reported mental ability (0=quick witted, 100=mentally slow)[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Self‐reported proficiency (0=proficient, 100=incompetent).[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Spatial Working Memory (Working Memory & strategy) [At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB] Subjective drug effects [Cambridge Neuropsychological Test Automated Battery (CANTAB)(CANTAB)][Baseline, 3 hours and 6‐hours post treatment] Verbal Recognition Memory (VRM)[At baseline, 3 hours and 6 hours post‐treatment. As assessed using the CABTAB]