Pain in the ED:Pain in the ED:Is Low Dose Is Low Dose

Ketamine Ketamine Effective?Effective?Alyssa Morris, R2Alyssa Morris, R2

Grand RoundsGrand Rounds

May 14, 2009 May 14, 2009

CASECASE

45M MVC, brought in by EMS45M MVC, brought in by EMS

GCS 15, P= 96, BP= 100/62, O2 94% GCS 15, P= 96, BP= 100/62, O2 94% 2L NP2L NP

Multiple orthopedic injuriesMultiple orthopedic injuries

CC of painCC of pain

ObjectivesObjectives

Briefly look at pain presentations in Briefly look at pain presentations in the EDthe ED

How well do we manage patient painHow well do we manage patient pain

Ketamine as an analgesic Ketamine as an analgesic • Pharmacology of its analgesic Pharmacology of its analgesic

propertiesproperties• Evidence for its analgesic Evidence for its analgesic

effectivenesseffectiveness• Mostly anesthesia literatureMostly anesthesia literature• Evidence in ED populationEvidence in ED population

• Discuss if this is an option in our EDDiscuss if this is an option in our ED

Pain In EDPain In ED

Pain is most common reason for ED usePain is most common reason for ED use

Accounts for up to 78% of visits to EDsAccounts for up to 78% of visits to EDs

Underuse of analgesia is well Underuse of analgesia is well documented 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 Studies show that we have not improved in satisfactorily treating pain improved in satisfactorily treating pain in the EDin the ED

Pain In ED- How well do Pain In ED- How well do we do?we do?

Journal of PainJournal of Pain. 2007;8(6):460-466. 2007;8(6):460-466

Prospective, observational, Prospective, observational, multicenter, cohort study of 842 pts in multicenter, cohort study of 842 pts in US and CanadaUS and Canada

60% were given analgesics60% were given analgesics• Median wait time for administration Median wait time for administration

was 90 minwas 90 min

41% of pts pain rating did not change 41% of pts pain rating did not change during ED visitduring ED visit

74% d/c in moderate to severe pain74% d/c in moderate to severe pain

Pain ControlPain Control

IV MedsIV Meds• FentanylFentanyl• MorphineMorphine

PO MedsPO Meds• TylenolTylenol• Ibuprofen Ibuprofen • ToradolToradol• PercocetPercocet• Morphine Morphine

Local anestheticsLocal anesthetics

Ducharme’s ApproachDucharme’s Approach

KetamineKetamine

• 0.3 mg/kg IV bolus 0.3 mg/kg IV bolus over over 10 min10 min

• 0.2-0.3 mg/kg/hr 0.2-0.3 mg/kg/hr infusioninfusion

Ketamine- BackgroundKetamine- Background

Derived from street drug PCP in Derived from street drug PCP in 19621962

Been used in clinical practice since Been used in clinical practice since 1970s1970s

First used as an anesthetic agent, First used as an anesthetic agent, especially in pediatric population especially in pediatric population

Became recognized as an analgesic Became recognized as an analgesic when NMDA R was found to be when NMDA R was found to be important in pain response important in pain response

Ketamine- EffectsKetamine- Effects

Sedation and amnesiaSedation and amnesia

Analgesia (local and systemic)Analgesia (local and systemic)

Cardiac hemodynamically stable Cardiac hemodynamically stable agentagent• +inotropy and chronotropy+inotropy and chronotropy

Respiratory reflexes usually well Respiratory reflexes usually well preservedpreserved

Bronchodilation and increased Bronchodilation and increased pulmonary compliancepulmonary compliance

Ketamine- Adverse Ketamine- Adverse EffectsEffects

EmesisEmesis

Salivary and tracheobronchial Salivary and tracheobronchial secretionssecretions

Increase in muscular toneIncrease in muscular tone

Emergence rxnEmergence rxn

Transient laryngospasmTransient laryngospasm

Respiratory depression Respiratory depression

Ketamine- Ketamine- ContraindicationsContraindications

ABSOLUTEABSOLUTE

<3m old<3m old Known or suspected Known or suspected

psychosispsychosis

RELATIVERELATIVE

<12m old<12m old Procedures involving Procedures involving

stimulation of the stimulation of the posterior pharynxposterior pharynx

Known or suspected CADKnown or suspected CAD Glaucoma or acute globe Glaucoma or acute globe

injuryinjury Uncontrolled HTNUncontrolled HTN Lesions assoc w high ICPLesions assoc w high ICP

Ketamine- Ketamine- PharmacologyPharmacology

Highly lipid solubleHighly lipid soluble• Crosses BBB quicklyCrosses BBB quickly

Rapid onset of action and recoveryRapid onset of action and recovery• Peak concentration: 1min w IV, 5min w Peak concentration: 1min w IV, 5min w

IMIM• Recover to baseline fxn: 15-30m w IV, Recover to baseline fxn: 15-30m w IV,

30-90 w IM30-90 w IM

Hepatic metabolismHepatic metabolism

At >1mg/kg = dissociative agent, 0.1-At >1mg/kg = dissociative agent, 0.1-0.5mg/kg = analgesic0.5mg/kg = analgesic

Ketamine- MOAKetamine- MOA

11 Noncompetitive antagonist of CNS NMDA Noncompetitive antagonist of CNS NMDA ReceptorReceptor• Usually excited by neurotransmitter Usually excited by neurotransmitter

glutamateglutamate• Involved in sensory input at the spinal, Involved in sensory input at the spinal,

thalamic, limbic and cortical levelsthalamic, limbic and cortical levels

22 Agonist at α and β-adrenergic receptorAgonist at α and β-adrenergic receptor

33 Antagonist at muscarinic receptor of the Antagonist at muscarinic receptor of the CNSCNS

44 Blocks reuptake of catecholaminesBlocks reuptake of catecholamines

55 Agonist at opioid μ and Σ ReceptorAgonist at opioid μ and Σ Receptor

Ketamine AnesthesiaKetamine Anesthesia

Not fully understood and is very complexNot fully understood and is very complex

Creates a dissociation b/t the cortical and Creates a dissociation b/t the cortical and limbic systemslimbic systems

Sensory associative areas of cortex, limbic Sensory associative areas of cortex, limbic system and thalamus are directly depressed system and thalamus are directly depressed by ketamineby ketamine• Higher CNS centers unable to receive or process Higher CNS centers unable to receive or process

sensory infosensory info• Emotional significance cannot be assessedEmotional significance cannot be assessed• Results are anesthesia, analgesia, suppression Results are anesthesia, analgesia, suppression

of fear and anxiety, amnesiaof fear and anxiety, amnesia

NMDA R and PainNMDA R and Pain Pain is detected by 2 types of peripheral nociceptive Pain is detected by 2 types of peripheral nociceptive

neuronsneurons• A-delta nociceptorsA-delta nociceptors• C-fiber nociceptors C-fiber nociceptors

Prolonged firing of C-fiber nociceptors causes release Prolonged firing of C-fiber nociceptors causes release of glutamate which activates NMDA R in spinal cordof glutamate which activates NMDA R in spinal cord11 spinal cord neurons become more responsive to all of spinal cord neurons become more responsive to all of

its inputsits inputs• Hyperexcitable dorsal root ganglion Hyperexcitable dorsal root ganglion • Wind-up phenomenonWind-up phenomenon• Pain memoryPain memory

22 Decreases neuronal sensitivity to opioid receptor Decreases neuronal sensitivity to opioid receptor agonists agonists • Tolerance can developTolerance can develop

Ann Emerg MedAnn Emerg Med 2005;46:362-5 2005;46:362-5

Prospective, convenience cohortProspective, convenience cohort

Quantify analgesic effect of a dose of Quantify analgesic effect of a dose of o.1mg/kg IV morphine bolus is ED pts with o.1mg/kg IV morphine bolus is ED pts with acute, severe painacute, severe pain

Outcome: %pts whose pain decreased by Outcome: %pts whose pain decreased by >50% in 30 min>50% in 30 min

Results:Results:• N-119N-119• 67% did not have a 50% reduction in pain 67% did not have a 50% reduction in pain

AnesthesiologyAnesthesiology 2004;100:292-301 2004;100:292-301

Objective: measure the analgesic effect of Objective: measure the analgesic effect of ketamine with use of MRIketamine with use of MRI

8 volunteers received noxious thermal and 8 volunteers received noxious thermal and auditory stimuli and then given approx 0.5mg/kg auditory stimuli and then given approx 0.5mg/kg of ketamine and brain areas mapped with MRIof ketamine and brain areas mapped with MRI

Results: sig reduced pain scores with matched Results: sig reduced pain scores with matched decrease in activity in braindecrease in activity in brain

Concluded that ketamine analgesia occurs thru Concluded that ketamine analgesia occurs thru lower cortical processing in pain-related regions lower cortical processing in pain-related regions of brainof brain

Anesth Analg Anesth Analg 2005;100:169-74.2005;100:169-74.

ASA I/II, age 18-65, major elective ASA I/II, age 18-65, major elective open abdo, uro or ortho Sxopen abdo, uro or ortho Sx

Randomized, double-blinded, to Randomized, double-blinded, to receive morphine 3mg Q5m until pain receive morphine 3mg Q5m until pain VRS <2 and either placebo (N/S) or VRS <2 and either placebo (N/S) or Ketamine 10mg IV Ketamine 10mg IV

End-pt: morphine consumption and End-pt: morphine consumption and time to effective analgesia (VRS<2) time to effective analgesia (VRS<2) and time to return of pain (VRS>2)and time to return of pain (VRS>2)

ConclusionsConclusions

Low-Dose bolus of Ketamine Low-Dose bolus of Ketamine improves effects of morphineimproves effects of morphine• 40% Less opiate needed40% Less opiate needed• Less time to analgesic effectLess time to analgesic effect• Less analgesic failuresLess analgesic failures

No difference in adverse eventsNo difference in adverse events

Anest Analg Anest Analg 2003;96:789-95. 2003;96:789-95.

RDBCTRDBCT

ASA I, II, III for abdo, ortho or thoracic SxASA I, II, III for abdo, ortho or thoracic Sx

End points: morphine consumption and End points: morphine consumption and time to effective analgesia using VAS time to effective analgesia using VAS

Received a bolus of 0.1mg/kg morphine Received a bolus of 0.1mg/kg morphine IVIV• Then allowed 0.03mg/kg boluses of Then allowed 0.03mg/kg boluses of

morphine (max of three) morphine (max of three) • Randomized to saline or ketamine 0.25mg/kg Randomized to saline or ketamine 0.25mg/kg

bolus bolus

ConclusionsConclusions

Low-dose Ketamine bolus decreased Low-dose Ketamine bolus decreased the morphine consumptionthe morphine consumption

Low-dose Ketamine decreased the Low-dose Ketamine decreased the time to effective analgesiatime to effective analgesia

Low-dose ketamine group had better Low-dose ketamine group had better respiratory status and returned to respiratory status and returned to baseline more quicklybaseline more quickly

Morphine alone group had more Morphine alone group had more adverse events and took much longer adverse events and took much longer to return to baseline hemodynamics to return to baseline hemodynamics

Anesth AnalAnesth Analg 2003;97:843-7.g 2003;97:843-7.

RDBCT of pts needing abdo surgeryRDBCT of pts needing abdo surgery

Outcome: consumption of morphine Outcome: consumption of morphine and VAS scoresand VAS scores

Intervention: morphine boluses until Intervention: morphine boluses until VAS<30 then randomized to either VAS<30 then randomized to either morphine PCA (1mg w 7min lock out) morphine PCA (1mg w 7min lock out) and placebo or ketamine bolus of and placebo or ketamine bolus of 0.5mg/kg then 0.12mg/kg/hr infusion 0.5mg/kg then 0.12mg/kg/hr infusion

ConclusionConclusion

Low dose bolus and then infusion of Low dose bolus and then infusion of Ketamine reduces morphine Ketamine reduces morphine consumptionconsumption

No difference in VAS pain scores No difference in VAS pain scores

No difference in side effects No difference in side effects

AJEMAJEM. 2007;25:385-390.. 2007;25:385-390.

Prospective, multicenter, RDBCTProspective, multicenter, RDBCT

Objective: compare ketamine plus morphine Objective: compare ketamine plus morphine to morphine alone to morphine alone • 0.1mg/kg of morphine IV, followed by 3mg 0.1mg/kg of morphine IV, followed by 3mg

Q5min until pain relief obtained Q5min until pain relief obtained (VAS<30/100)(VAS<30/100)

• +/- 0.2mg/kg Ketamine IV over 10 mins +/- 0.2mg/kg Ketamine IV over 10 mins

Outcomes: morphine consumption and VAS Outcomes: morphine consumption and VAS at 30 minsat 30 mins

Inclusion:Inclusion:• Trauma pts with VAS>60/100Trauma pts with VAS>60/100• 18-70y.o18-70y.o• SBP>90, GCS 15, no resp distressSBP>90, GCS 15, no resp distress

Exclusion:Exclusion:• Pts with psych hxPts with psych hx• Renal/hepatic/resp failureRenal/hepatic/resp failure• Chronic pain pts treated with opioidsChronic pain pts treated with opioids

N= 73; K=38, P= 35 N= 73; K=38, P= 35

Conclusion Conclusion

Ketamine reduced morphine Ketamine reduced morphine consumptionconsumption

No difference in hemodynamicsNo difference in hemodynamics

Generalizable to only some of our Generalizable to only some of our trauma patients as some are HD trauma patients as some are HD unstableunstable

Not enough to change practice, but Not enough to change practice, but gives us another option to think gives us another option to think about about

SummarySummary

Pain is one of the most common ED Pain is one of the most common ED presentationspresentations

Pain is inadequately managed in the Pain is inadequately managed in the EDED

Low-dose Ketamine has been shown to Low-dose Ketamine has been shown to be an effective and safe adjunct for be an effective and safe adjunct for pain controlpain control

Need more evidence Need more evidence