1. Pain in the ED: Is Low Dose Ketamine Effective? Alyssa Morris, R2 Grand Rounds May 14, 2009

2. CASE 45M MVC, brought in by EMS 45M MVC, brought in by EMS GCS 15, P= 96, BP= 100/62, O2 94% 2L NP GCS 15, P= 96, BP= 100/62, O2 94% 2L NP Multiple orthopedic injuries Multiple orthopedic injuries CC of pain CC of pain

3. Objectives Briefly look at pain presentations in the ED Briefly look at pain presentations in the ED How well do we manage patient pain How well do we manage patient pain Ketamine as an analgesic Ketamine as an analgesic Pharmacology of its analgesic properties Pharmacology of its analgesic properties Evidence for its analgesic effectiveness Evidence for its analgesic effectiveness Mostly anesthesia literature Mostly anesthesia literature Evidence in ED population Evidence in ED population Discuss if this is an option in our ED Discuss if this is an option in our ED

4. Pain In ED Pain is most common reason for ED use Pain is most common reason for ED use Accounts for up to 78% of visits to EDs Accounts for up to 78% of visits to EDs Underuse of analgesia is well documented Underuse of analgesia is well documented “oligoanalgesia” “oligoanalgesia” Many of our patients leave still in pain Many of our patients leave still in pain Studies show that we have not improved in satisfactorily treating pain in the ED Studies show that we have not improved in satisfactorily treating pain in the ED

5. Pain In ED- How well do we do? Journal of Pain. 2007;8(6):460-466 Prospective, observational, multicenter, cohort study of 842 pts in US and Canada Prospective, observational, multicenter, cohort study of 842 pts in US and Canada 60% were given analgesics 60% were given analgesics Median wait time for administration was 90 min Median wait time for administration was 90 min 41% of pts pain rating did not change during ED visit 41% of pts pain rating did not change during ED visit 74% d/c in moderate to severe pain 74% d/c in moderate to severe pain

6. Pain Control IV Meds IV Meds Fentanyl Fentanyl Morphine Morphine PO Meds PO Meds Tylenol Tylenol Ibuprofen Ibuprofen Toradol Toradol Percocet Percocet Morphine Morphine Local anesthetics Local anesthetics

7. Ducharme’s Approach Ketamine 0.3 mg/kg IV bolus over 10 min 0.3 mg/kg IV bolus over 10 min 0.2-0.3 mg/kg/hr infusion 0.2-0.3 mg/kg/hr infusion

8. Ketamine- Background Derived from street drug PCP in 1962 Derived from street drug PCP in 1962 Been used in clinical practice since 1970s Been used in clinical practice since 1970s First used as an anesthetic agent, especially in pediatric population First used as an anesthetic agent, especially in pediatric population Became recognized as an analgesic when NMDA R was found to be important in pain response Became recognized as an analgesic when NMDA R was found to be important in pain response

9. Ketamine- Effects Sedation and amnesia Sedation and amnesia Analgesia (local and systemic) Analgesia (local and systemic) Cardiac hemodynamically stable agent Cardiac hemodynamically stable agent +inotropy and chronotropy +inotropy and chronotropy Respiratory reflexes usually well preserved Respiratory reflexes usually well preserved Bronchodilation and increased pulmonary compliance Bronchodilation and increased pulmonary compliance

10. Ketamine- Adverse Effects Emesis Emesis Salivary and tracheobronchial secretions Salivary and tracheobronchial secretions Increase in muscular tone Increase in muscular tone Emergence rxn Emergence rxn Transient laryngospasm Transient laryngospasm Respiratory depression Respiratory depression

11. Ketamine- Contraindications ABSOLUTE <3m old <3m old Known or suspected psychosis Known or suspected psychosis RELATIVE <12m old <12m old Procedures involving stimulation of the posterior pharynx Procedures involving stimulation of the posterior pharynx Known or suspected CAD Known or suspected CAD Glaucoma or acute globe injury Glaucoma or acute globe injury Uncontrolled HTN Uncontrolled HTN Lesions assoc w high ICP Lesions assoc w high ICP

12. Ketamine- Pharmacology Highly lipid soluble Highly lipid soluble Crosses BBB quickly Crosses BBB quickly Rapid onset of action and recovery Rapid onset of action and recovery Peak concentration: 1min w IV, 5min w IM Peak concentration: 1min w IV, 5min w IM Recover to baseline fxn: 15-30m w IV, 30-90 w IM Recover to baseline fxn: 15-30m w IV, 30-90 w IM Hepatic metabolism Hepatic metabolism At >1mg/kg = dissociative agent, 0.1-0.5mg/kg = analgesic At >1mg/kg = dissociative agent, 0.1-0.5mg/kg = analgesic

13. Ketamine- MOA 1 Noncompetitive antagonist of CNS NMDA Receptor Usually excited by neurotransmitter glutamate Usually excited by neurotransmitter glutamate Involved in sensory input at the spinal, thalamic, limbic and cortical levels Involved in sensory input at the spinal, thalamic, limbic and cortical levels 2 Agonist at α and β-adrenergic receptor 3 Antagonist at muscarinic receptor of the CNS 4 Blocks reuptake of catecholamines 5 Agonist at opioid μ and Σ Receptor

14. Ketamine Anesthesia Not fully understood and is very complex Not fully understood and is very complex Creates a dissociation b/t the cortical and limbic systems Creates a dissociation b/t the cortical and limbic systems Sensory associative areas of cortex, limbic system and thalamus are directly depressed by ketamine Sensory associative areas of cortex, limbic system and thalamus are directly depressed by ketamine Higher CNS centers unable to receive or process sensory info Higher CNS centers unable to receive or process sensory info Emotional significance cannot be assessed Emotional significance cannot be assessed Results are anesthesia, analgesia, suppression of fear and anxiety, amnesia Results are anesthesia, analgesia, suppression of fear and anxiety, amnesia

15. NMDA R and Pain Pain is detected by 2 types of peripheral nociceptive neurons Pain is detected by 2 types of peripheral nociceptive neurons A-delta nociceptors A-delta nociceptors C-fiber nociceptors C-fiber nociceptors Prolonged firing of C-fiber nociceptors causes release of glutamate which activates NMDA R in spinal cord Prolonged firing of C-fiber nociceptors causes release of glutamate which activates NMDA R in spinal cord 1 spinal cord neurons become more responsive to all of its inputs Hyperexcitable dorsal root ganglion Hyperexcitable dorsal root ganglion Wind-up phenomenon Wind-up phenomenon Pain memory Pain memory 2 Decreases neuronal sensitivity to opioid receptor agonists Tolerance can develop Tolerance can develop

16. Ann Emerg Med 2005;46:362-5 Prospective, convenience cohort Prospective, convenience cohort Quantify analgesic effect of a dose of o.1mg/kg IV morphine bolus is ED pts with acute, severe pain Quantify analgesic effect of a dose of o.1mg/kg IV morphine bolus is ED pts with acute, severe pain Outcome: %pts whose pain decreased by >50% in 30 min Outcome: %pts whose pain decreased by >50% in 30 min Results: Results: N-119 N-119 67% did not have a 50% reduction in pain 67% did not have a 50% reduction in pain

17. Anesthesiology 2004;100:292-301 Objective: measure the analgesic effect of ketamine with use of MRI 8 volunteers received noxious thermal and auditory stimuli and then given approx 0.5mg/kg of ketamine and brain areas mapped with MRI 8 volunteers received noxious thermal and auditory stimuli and then given approx 0.5mg/kg of ketamine and brain areas mapped with MRI Results: sig reduced pain scores with matched decrease in activity in brain Results: sig reduced pain scores with matched decrease in activity in brain Concluded that ketamine analgesia occurs thru lower cortical processing in pain-related regions of brain Concluded that ketamine analgesia occurs thru lower cortical processing in pain-related regions of brain

18. Anesth Analg 2005;100:169-74. ASA I/II, age 18-65, major elective open abdo, uro or ortho Sx ASA I/II, age 18-65, major elective open abdo, uro or ortho Sx Randomized, double-blinded, to receive morphine 3mg Q5m until pain VRS <2 and either placebo (N/S) or Ketamine 10mg IV Randomized, double-blinded, to receive morphine 3mg Q5m until pain VRS <2 and either placebo (N/S) or Ketamine 10mg IV End-pt: morphine consumption and time to effective analgesia (VRS 2) End-pt: morphine consumption and time to effective analgesia (VRS 2)

22. Conclusions Low-Dose bolus of Ketamine improves effects of morphine Low-Dose bolus of Ketamine improves effects of morphine 40% Less opiate needed 40% Less opiate needed Less time to analgesic effect Less time to analgesic effect Less analgesic failures Less analgesic failures No difference in adverse events No difference in adverse events

23. Anest Analg 2003;96:789-95. RDBCT RDBCT ASA I, II, III for abdo, ortho or thoracic Sx ASA I, II, III for abdo, ortho or thoracic Sx End points: morphine consumption and time to effective analgesia using VAS End points: morphine consumption and time to effective analgesia using VAS Received a bolus of 0.1mg/kg morphine IV Received a bolus of 0.1mg/kg morphine IV Then allowed 0.03mg/kg boluses of morphine (max of three) Then allowed 0.03mg/kg boluses of morphine (max of three) Randomized to saline or ketamine 0.25mg/kg bolus Randomized to saline or ketamine 0.25mg/kg bolus

26. Conclusions Low-dose Ketamine bolus decreased the morphine consumption Low-dose Ketamine bolus decreased the morphine consumption Low-dose Ketamine decreased the time to effective analgesia Low-dose Ketamine decreased the time to effective analgesia Low-dose ketamine group had better respiratory status and returned to baseline more quickly Low-dose ketamine group had better respiratory status and returned to baseline more quickly Morphine alone group had more adverse events and took much longer to return to baseline hemodynamics Morphine alone group had more adverse events and took much longer to return to baseline hemodynamics

27. Anesth Analg 2003;97:843-7. RDBCT of pts needing abdo surgery RDBCT of pts needing abdo surgery Outcome: consumption of morphine and VAS scores Outcome: consumption of morphine and VAS scores Intervention: morphine boluses until VAS<30 then randomized to either morphine PCA (1mg w 7min lock out) and placebo or ketamine bolus of 0.5mg/kg then 0.12mg/kg/hr infusion Intervention: morphine boluses until VAS<30 then randomized to either morphine PCA (1mg w 7min lock out) and placebo or ketamine bolus of 0.5mg/kg then 0.12mg/kg/hr infusion

31. Conclusion Low dose bolus and then infusion of Ketamine reduces morphine consumption Low dose bolus and then infusion of Ketamine reduces morphine consumption No difference in VAS pain scores No difference in VAS pain scores No difference in side effects No difference in side effects

32. AJEM. 2007;25:385-390. Prospective, multicenter, RDBCT Prospective, multicenter, RDBCT Objective: compare ketamine plus morphine to morphine alone Objective: compare ketamine plus morphine to morphine alone 0.1mg/kg of morphine IV, followed by 3mg Q5min until pain relief obtained (VAS<30/100) 0.1mg/kg of morphine IV, followed by 3mg Q5min until pain relief obtained (VAS<30/100) +/- 0.2mg/kg Ketamine IV over 10 mins +/- 0.2mg/kg Ketamine IV over 10 mins Outcomes: morphine consumption and VAS at 30 mins Outcomes: morphine consumption and VAS at 30 mins

33. Inclusion: Inclusion: Trauma pts with VAS>60/100 Trauma pts with VAS>60/100 18-70y.o 18-70y.o SBP>90, GCS 15, no resp distress SBP>90, GCS 15, no resp distress Exclusion: Exclusion: Pts with psych hx Pts with psych hx Renal/hepatic/resp failure Renal/hepatic/resp failure Chronic pain pts treated with opioids Chronic pain pts treated with opioids N= 73; K=38, P= 35 N= 73; K=38, P= 35

36. Conclusion Ketamine reduced morphine consumption Ketamine reduced morphine consumption No difference in hemodynamics No difference in hemodynamics Generalizable to only some of our trauma patients as some are HD unstable Generalizable to only some of our trauma patients as some are HD unstable Not enough to change practice, but gives us another option to think about Not enough to change practice, but gives us another option to think about

37. Summary Pain is one of the most common ED presentations Pain is one of the most common ED presentations Pain is inadequately managed in the ED Pain is inadequately managed in the ED Low-dose Ketamine has been shown to be an effective and safe adjunct for pain control Low-dose Ketamine has been shown to be an effective and safe adjunct for pain control Need more evidence Need more evidence