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 RoundsMay 14, 2009 May 14, 2009

CASECASE

45M MVC, brought in by EMS45M MVC, brought in by EMSGCS 15, P= 96, BP= 100/62, O2 94% GCS 15, P= 96, BP= 100/62, O2 94%

2L NP2L NPMultiple orthopedic injuriesMultiple orthopedic injuriesCC of painCC of pain

ObjectivesObjectivesBriefly look at pain presentations in the Briefly look at pain presentations in the

EDEDHow well do we manage patient painHow well do we manage patient painKetamine as an analgesic Ketamine as an analgesic

• Pharmacology of its analgesic Pharmacology of its analgesic propertiesproperties

• Evidence for its analgesic effectivenessEvidence for its analgesic effectiveness• 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 EDPain is most common reason for ED usePain is most common reason for ED useAccounts for up to 78% of visits to EDsAccounts for up to 78% of visits to EDsUnderuse 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 improved Studies show that we have not improved

in satisfactorily treating pain in the EDin satisfactorily treating pain in 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):460-466Prospective, observational, multicenter, Prospective, observational, multicenter,

cohort study of 842 pts in US and cohort study of 842 pts in US and CanadaCanada

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

was 90 minwas 90 min41% of pts pain rating did not change 41% of pts pain rating did not change

during ED visitduring ED visit74% 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 over 0.3 mg/kg IV bolus over 10 min10 min

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

Ketamine- BackgroundKetamine- BackgroundDerived from street drug PCP in Derived from street drug PCP in

19621962Been used in clinical practice since Been used in clinical practice since

1970s1970sFirst 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- EffectsSedation and amnesiaSedation and amnesiaAnalgesia (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

EmesisEmesisSalivary and tracheobronchial Salivary and tracheobronchial

secretionssecretionsIncrease in muscular toneIncrease in muscular toneEmergence rxnEmergence rxnTransient laryngospasmTransient laryngospasmRespiratory 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 IMPeak concentration: 1min w IV, 5min w IM• Recover to baseline fxn: 15-30m w IV, 30-Recover to baseline fxn: 15-30m w IV, 30-

90 w IM90 w IMHepatic metabolismHepatic metabolismAt >1mg/kg = dissociative agent, 0.1-At >1mg/kg = dissociative agent, 0.1-

0.5mg/kg = analgesic0.5mg/kg = analgesic

Ketamine- MOAKetamine- MOA11 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 levels22 Agonist at α and β-adrenergic receptorAgonist at α and β-adrenergic receptor33 Antagonist at muscarinic receptor of the Antagonist at muscarinic receptor of the

CNSCNS44 Blocks reuptake of catecholaminesBlocks reuptake of catecholamines55 Agonist at opioid μ and Σ ReceptorAgonist at opioid μ and Σ Receptor

Ketamine AnesthesiaKetamine AnesthesiaNot fully understood and is very complexNot fully understood and is very complexCreates a dissociation b/t the cortical and Creates a dissociation b/t the cortical and

limbic systemslimbic systemsSensory 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 of Results are anesthesia, analgesia, suppression of

fear and anxiety, amnesiafear 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 its spinal cord neurons become more responsive to all of its

inputsinputs• Hyperexcitable dorsal root ganglion Hyperexcitable dorsal root ganglion • Wind-up phenomenonWind-up phenomenon• Pain memoryPain memory

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

Ann Emerg MedAnn Emerg Med 2005;46:362-5 2005;46:362-5Prospective, convenience cohortProspective, convenience cohortQuantify 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 open ASA I/II, age 18-65, major elective open

abdo, uro or ortho Sxabdo, uro or ortho SxRandomized, double-blinded, to receive Randomized, double-blinded, to receive

morphine 3mg Q5m until pain VRS <2 morphine 3mg Q5m until pain VRS <2 and either placebo (N/S) or Ketamine and either placebo (N/S) or Ketamine 10mg IV 10mg IV

End-pt: morphine consumption and End-pt: morphine consumption and time to effective analgesia (VRS<2) and time to effective analgesia (VRS<2) and time to return of pain (VRS>2)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 SxEnd 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 IVReceived a bolus of 0.1mg/kg morphine IV• Then allowed 0.03mg/kg boluses of morphine Then allowed 0.03mg/kg boluses of morphine

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

bolus bolus

ConclusionsConclusionsLow-dose Ketamine bolus decreased Low-dose Ketamine bolus decreased

the morphine consumptionthe morphine consumptionLow-dose Ketamine decreased the Low-dose Ketamine decreased the

time to effective analgesiatime to effective analgesiaLow-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 surgeryOutcome: consumption of morphine Outcome: consumption of morphine

and VAS scoresand VAS scoresIntervention: 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, RDBCTObjective: 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 at Outcomes: morphine consumption and VAS at

30 mins30 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

consumptionconsumptionNo difference in hemodynamicsNo difference in hemodynamicsGeneralizable 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 EDPain is inadequately managed in the EDLow-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