Why Ketamine? - Hospice & Palliative CareCenter Be familiar with the pharmacology, dosing, and...

Why Ketamine?Why Ketamine?

Jennifer Davis, M.D.Jennifer Davis, M.D.

Hospice and Palliative Care CenterHospice and Palliative Care Center

May 13, 2011May 13, 2011

ObjectivesObjectives

�� Be familiar with the pharmacology, dosing, and Be familiar with the pharmacology, dosing, and

administration of Ketamineadministration of Ketamine

�� Understand the indications, contraindications, Understand the indications, contraindications,

benefits, and side effects of Ketaminebenefits, and side effects of Ketamine

�� Know the various uses of Ketamine and its abuse Know the various uses of Ketamine and its abuse

potentialpotential

HistoryHistory

�� Developed in early 1960s and FDA approved in 1970Developed in early 1960s and FDA approved in 1970

�� First used in soldiers in Vietnam War for warfare First used in soldiers in Vietnam War for warfare

surgical proceduressurgical procedures

�� Classified as schedule III drug August 1999Classified as schedule III drug August 1999

�� Outlawed in United Kingdom January 2006Outlawed in United Kingdom January 2006

HistoryHistory

�� According to DEA, 80% seized is from MexicoAccording to DEA, 80% seized is from Mexico

�� Most commonly used in clubs at ravesMost commonly used in clubs at raves

�� 2002 statistic, almost 3% of 122002 statistic, almost 3% of 12thth grade students grade students

admitted to using ketamine in the last yearadmitted to using ketamine in the last year

Rave?Rave?

HistoryHistory

�� The Scientist by John LillyThe Scientist by John Lilly

�� Journeys into the Bright World by Marcia Moore Journeys into the Bright World by Marcia Moore

and Howard Alltounianand Howard Alltounian

�� The Essential Psychedelic Guide by D.M. The Essential Psychedelic Guide by D.M.

TurnerTurner

PharmacologyPharmacology

�� Dissociative anesthetic and analgesic that binds Dissociative anesthetic and analgesic that binds

the phencyclidine (PCP) sitethe phencyclidine (PCP) site

�� Noncompetitively blocks the excitatory NMDANoncompetitively blocks the excitatory NMDA--

glutamate receptor, a calcium channel in the glutamate receptor, a calcium channel in the

transmission of pain signals via dorsal horntransmission of pain signals via dorsal horn

�� NMDA receptor plays a role in opioid toleranceNMDA receptor plays a role in opioid tolerance


�� Also interacts with other calcium and sodium Also interacts with other calcium and sodium

channels, dopamine receptors, cholinergic channels, dopamine receptors, cholinergic

transmission, noradrenergic and serotoninergic transmission, noradrenergic and serotoninergic

reuptake, mu/delta/kappa opioid receptors, reuptake, mu/delta/kappa opioid receptors,

monoaminergic and muscarinic receptors, and monoaminergic and muscarinic receptors, and

possibly GABA receptorspossibly GABA receptors

�� = DIRTY DRUG= DIRTY DRUG


�� Central sensitization:Central sensitization: persistent noxious stimuli lead persistent noxious stimuli lead

to progressively higher pain intensity via NMDA to progressively higher pain intensity via NMDA

receptor hyperexcitationreceptor hyperexcitation

�� Wind up phenomenon:Wind up phenomenon: repeated transmission of repeated transmission of

nociceptive stimuli resulting in summation of the nociceptive stimuli resulting in summation of the

stimuli with costimuli with co--release of excitatory amino acid and release of excitatory amino acid and

slow lasting potentials leading to hyperslow lasting potentials leading to hyper--responsive responsive

spinal neurons and decreased opioid responsivenessspinal neurons and decreased opioid responsiveness


�� Hyperalgesia:Hyperalgesia: an exaggerate pain response to an exaggerate pain response to

mildly noxious stimulimildly noxious stimuli

�� Secondary hyperalgesia:Secondary hyperalgesia: perception of pain perception of pain

outside the area initially injuredoutside the area initially injured

�� Allodynia:Allodynia: pain elicited by nonpain elicited by non--noxious stimulinoxious stimuli


�� Mostly a racemic mixture of two stereoisomers: Mostly a racemic mixture of two stereoisomers: R(R(--) and S(+)) and S(+)

�� S enantiomer is 4 times more potent than R S enantiomer is 4 times more potent than R enantiomer and twice as potent as mixtureenantiomer and twice as potent as mixture

�� S(+) produces longer hypnosis, greater BP and S(+) produces longer hypnosis, greater BP and HR, less locomotor activity, shorter recovery HR, less locomotor activity, shorter recovery time time


�� Metabolism:Metabolism: 80% first pass hepatic metabolism80% first pass hepatic metabolism

�� Metabolite:Metabolite: norketamine is 1/3 as potent as parenteral norketamine is 1/3 as potent as parenteral

form as anesthetic but equipotent as an analgesicform as anesthetic but equipotent as an analgesic

�� Bioavailability:Bioavailability: ranges from 93% IM to 16% POranges from 93% IM to 16% PO

�� Excretion:Excretion: in the urine primarilyin the urine primarily


�� Onset of action: Onset of action:

IV=30sec, IM=3IV=30sec, IM=3--5min, SC=155min, SC=15--30min, PO=30min30min, PO=30min

�� Duration of action:Duration of action:

IV=5IV=5--10min, IM=12min10min, IM=12min--2hr, PO=42hr, PO=4--6hr6hr

�� Half life:Half life: 3 hours3 hours

�� Steady state:Steady state: 1212--15 min15 min


�� No adjustment needed for renal impairment, No adjustment needed for renal impairment,

and insufficient data for liver impairmentand insufficient data for liver impairment

�� Binding is less in elderly, so dose reduction Binding is less in elderly, so dose reduction

would be reasonablewould be reasonable

�� Avoid in pregnancy and breastfeeding, no dataAvoid in pregnancy and breastfeeding, no data


�� Adverse drug reactions:Adverse drug reactions: clonidine, clonidine, anticholinergics, benzodiazepines, barbiturates, anticholinergics, benzodiazepines, barbiturates, risperidone, opioids, anesthetics, alcoholrisperidone, opioids, anesthetics, alcohol

�� Generic ketamine 50mg/ml in 10ml vial ($17.70) Generic ketamine 50mg/ml in 10ml vial ($17.70) vs. Ketalar ($33)vs. Ketalar ($33)

�� 100ml of 50mg/5ml solution for IV: 2x10ml 100ml of 50mg/5ml solution for IV: 2x10ml ketamine vials (50mg/ml) + 80ml purified water ketamine vials (50mg/ml) + 80ml purified water

IndicationsIndications

�� Induction and maintenance anesthesiaInduction and maintenance anesthesia

�� Pain unresponsive to standard treatmentPain unresponsive to standard treatment

�� Failure of opioid rotationFailure of opioid rotation

�� Severe neuropathic pain Severe neuropathic pain

�� Opioid tolerance based on rapid escalationOpioid tolerance based on rapid escalation

�� Bronchospasm in asthma and COPDBronchospasm in asthma and COPD

�� Depression in bipolar disorderDepression in bipolar disorder

�� Minor proceduresMinor procedures

�� Migraine headachesMigraine headaches

ContraindicationsContraindications

�� Increased blood pressureIncreased blood pressure

�� Increased intracranial pressureIncreased intracranial pressure

�� Acute intermittent porphyria (induces ALA syn)Acute intermittent porphyria (induces ALA syn)

�� Current or history of psychiatric disorder, Current or history of psychiatric disorder,

seizures, glaucoma, heart failure, ischemic heart seizures, glaucoma, heart failure, ischemic heart

disease, CVA, severe hepatic impairment, severe disease, CVA, severe hepatic impairment, severe

neurologic impairmentneurologic impairment

WHO LadderWHO Ladder

�� Is there a place Is there a place for Ketamine?for Ketamine?

ProsPros

�� Can be given PO, IV, IM, SL, SC, PR, Can be given PO, IV, IM, SL, SC, PR,

intranasal, transdermal, topical, and epidural, intranasal, transdermal, topical, and epidural,

intrathecalintrathecal

�� Can be applied directly to the skin as an aerosol Can be applied directly to the skin as an aerosol

spray to woundsspray to wounds

�� Can be used as an oral rinse for mucositisCan be used as an oral rinse for mucositis

ProsPros

�� Opioid sparing effect leads to reduced opioid Opioid sparing effect leads to reduced opioid

requirement and opioid associated side effectsrequirement and opioid associated side effects

�� May prevent opioid tolerance and reduce central May prevent opioid tolerance and reduce central

sensitization and hyperalgesiasensitization and hyperalgesia

�� May have antiMay have anti--inflammatory effectsinflammatory effects

ProsPros

�� Excellent analgesia with limited respiratory Excellent analgesia with limited respiratory

depressiondepression

�� Patient can remain awake and breathe unassisted Patient can remain awake and breathe unassisted

but not awarebut not aware

�� Used in ICU for prolonged status epilepticusUsed in ICU for prolonged status epilepticus

ProsPros

�� Recent use in treatment of alcoholism, heroin Recent use in treatment of alcoholism, heroin addiction, and depressionaddiction, and depression

�� Rapid onset and minimal side effects at Rapid onset and minimal side effects at subanesthetic dosessubanesthetic doses

�� Small dose ketamine has been shown useful and Small dose ketamine has been shown useful and safe as additive to standard opioid therapy in safe as additive to standard opioid therapy in 54% of studies (A&A 2004)54% of studies (A&A 2004)

ConsCons

�� There are not sufficient DBRCT studies showing There are not sufficient DBRCT studies showing efficacy as an analgesic, but numerous case reports and efficacy as an analgesic, but numerous case reports and small trialssmall trials

�� Concern for withdraw and associated hyperalgesia and Concern for withdraw and associated hyperalgesia and allodynia upon sudden cessationallodynia upon sudden cessation

�� Significant number of clinical trials 45% demonstrated Significant number of clinical trials 45% demonstrated no benefit to adding ketamine to opioids explained by no benefit to adding ketamine to opioids explained by the nature of the procedure, degree of postthe nature of the procedure, degree of post--op pain, op pain, and method of administrationand method of administration

ConsCons

�� Should require informed consentShould require informed consent

�� Requires close monitoringRequires close monitoring

�� Irritation to SC siteIrritation to SC site

�� Crosses the blood brain barrierCrosses the blood brain barrier

�� Bitter tasteBitter taste

�� Concern for side effectsConcern for side effects

ConsCons

�� Studies have shown no benefit when added to opioid Studies have shown no benefit when added to opioid PCA after major abdominal surgeryPCA after major abdominal surgery

�� Ineffective in intrathecal route, peripheral regional use, Ineffective in intrathecal route, peripheral regional use, local anesthesia, intralocal anesthesia, intra--articular, nerve block, and would articular, nerve block, and would infiltrationinfiltration

�� Preemptive and postoperative benefits have been Preemptive and postoperative benefits have been difficult to determine with conflicting results and many difficult to determine with conflicting results and many different kinds of surgeriesdifferent kinds of surgeries

HOLIDAYSHOLIDAYS

PainPain

�� Post spinal cord injury chronic painPost spinal cord injury chronic pain

�� Sickle cell Sickle cell vasovaso--occlusive painocclusive pain

�� Chronic post surgical painChronic post surgical pain

�� Major surgery with high opioid requirement Major surgery with high opioid requirement

PainPain

�� Pre and post Pre and post incisionalincisional

�� Chronic regional pain syndrome IChronic regional pain syndrome I

�� Fracture reductionsFracture reductions

�� CalciphylaxisCalciphylaxis

PainPain

�� Incident pain from movementIncident pain from movement

�� Opioid refractory painOpioid refractory pain

�� Neuropathic pain: postNeuropathic pain: post--herpetic neuralgia, trigeminal herpetic neuralgia, trigeminal

neuralgia, spinal cord injury, phantom limb pain, limb neuralgia, spinal cord injury, phantom limb pain, limb

ischemia, fibromyalgia, multiple sclerosis, ischemia, fibromyalgia, multiple sclerosis, GuillainGuillain--

BarreBarre syndromesyndrome

�� Chronic abdominal pain such as pancreatitis and anginaChronic abdominal pain such as pancreatitis and angina

PainPain

�� Chronic neck, back, and leg painChronic neck, back, and leg pain

�� Migraine headachesMigraine headaches

�� Cancer related pain in children and adultsCancer related pain in children and adults

�� Painful dressing changes such as burnsPainful dressing changes such as burns

How much do we give?How much do we give?

LetLet’’s look at the evidence . . .s look at the evidence . . .

Trials and Case SeriesTrials and Case Series

Fine JPSM 1999Fine JPSM 1999 (2 case reports):(2 case reports):

�� Ketamine bolus 0.1Ketamine bolus 0.1--0.2mg/kg IV or 0.5mg/kg 0.2mg/kg IV or 0.5mg/kg SC or IMSC or IM

�� After 15 minutes if no relief double doseAfter 15 minutes if no relief double dose

�� Continue to reassess and increase dose until pain Continue to reassess and increase dose until pain relief or undesirable side effects occurrelief or undesirable side effects occur

�� Convert to constant IV infusionConvert to constant IV infusion

�� Decrease opioid by 50% every 6Decrease opioid by 50% every 6--12 hours as 12 hours as toleratedtolerated

�� Rebolus and increase infusion as neededRebolus and increase infusion as needed


Mercadante JPSM 2000Mercadante JPSM 2000 (DBRCT):(DBRCT):

�� On 3 separate days, 2 days apart, 10 patients given slow On 3 separate days, 2 days apart, 10 patients given slow bolus of either 0.25mg/kg vs. 0.50mg/kg vs. normal bolus of either 0.25mg/kg vs. 0.50mg/kg vs. normal salinesaline

�� Ketamine, but not saline, significantly reduced pain in Ketamine, but not saline, significantly reduced pain in almost all patients at both dosesalmost all patients at both doses

Berger AJHPC 2000Berger AJHPC 2000 (small trial):(small trial):

�� IV KIV K--FF--M 2mg/ml M 2mg/ml -- 5ug/ml 5ug/ml -- 0.1mg/ml at rate range 0.1mg/ml at rate range of 2of 2--12ml/hr12ml/hr

�� All 9 patients showed improvementAll 9 patients showed improvement


Reeves A&A 2001Reeves A&A 2001 (DBRCT):(DBRCT):

�� 71 patients either received morphine 1mg/ml or 71 patients either received morphine 1mg/ml or morphine 1mg/ml + ketamine 1mg/ml via PCAmorphine 1mg/ml + ketamine 1mg/ml via PCA

�� PostPost--op, there was no difference except worse cognitive op, there was no difference except worse cognitive testing in the MK grouptesting in the MK group

Jackson JPSM 2001Jackson JPSM 2001 (unblinded trial):(unblinded trial):

�� 39 patients received 339 patients received 3--5 day ketamine infusion at 5 day ketamine infusion at 100mg/24h for 3 days or increased to 300mg/24h for 3 100mg/24h for 3 days or increased to 300mg/24h for 3 days or increased to 500mg/24h for 3 daysdays or increased to 500mg/24h for 3 days

�� Overall response rate of 67%Overall response rate of 67%


Kannan JPSM 2002Kannan JPSM 2002 (small trial) : (small trial) :

�� 0.5mg/kg three times daily PO as adjuvant0.5mg/kg three times daily PO as adjuvant

�� 7/9 patients showed improvement7/9 patients showed improvement

Mitchell Pain 2002Mitchell Pain 2002 (DBRCT):(DBRCT):

�� 35 patients received either Opioids + ketamine infusion 35 patients received either Opioids + ketamine infusion

(0.6mg/kg) vs. opioids + placebo over 4 hours(0.6mg/kg) vs. opioids + placebo over 4 hours

�� OK group (16/28) showed statistically significant OK group (16/28) showed statistically significant

difference in pain improvementdifference in pain improvement


Fitzgibbon JPM 2005Fitzgibbon JPM 2005 (retrospective audit):(retrospective audit):

�� Ketamine was effective in 11/16 patients with range of use from Ketamine was effective in 11/16 patients with range of use from 11--120 days120 days

�� Starting dose of 40Starting dose of 40--90mg/24h increased by 5090mg/24h increased by 50--100mg/24h every 100mg/24h every 24 hours with stable dose of 5024 hours with stable dose of 50--768mg/24h768mg/24h

Lossignol SCC 2005Lossignol SCC 2005 (small trial):(small trial):

�� 12 patients received a test dose of 5mg and if tolerated were 12 patients received a test dose of 5mg and if tolerated were given starting dose of 1.5mg/kg/24hgiven starting dose of 1.5mg/kg/24h

�� Final doses ranged from 195Final doses ranged from 195--1000mg/24h with duration of 1000mg/24h with duration of treatment ranging from 7treatment ranging from 7--350 days350 days

�� Pain control remained acceptable in 11/12 patientsPain control remained acceptable in 11/12 patients


Polizzotto JPSM 2006Polizzotto JPSM 2006 (case series):(case series):

�� Calciphylaxis patients received doses ranging from Calciphylaxis patients received doses ranging from boluses of SC ketamine 50mg for dressing changes and boluses of SC ketamine 50mg for dressing changes and continuous infusions of 300continuous infusions of 300--500mg/24hr500mg/24hr

Finkel JP 2007Finkel JP 2007 (small trial):(small trial):

�� 8/11 children on adjuvant ketamine infusion had 8/11 children on adjuvant ketamine infusion had opioid sparing effects, improvement of pain, and more opioid sparing effects, improvement of pain, and more family interactionfamily interaction

�� Doses ranged from 0.1Doses ranged from 0.1--1mg/kg/hr and duration 1mg/kg/hr and duration ranged from 1ranged from 1--75 days75 days


Mercadante CJP 2009Mercadante CJP 2009 (2 case reports):(2 case reports):

�� Opioid switching from morphine to methadone and Opioid switching from morphine to methadone and burst ketamine in incident painburst ketamine in incident pain

�� 2 day infusion of ketamine 100mg/d then stopped, 2 day infusion of ketamine 100mg/d then stopped, continued on methadone, and D/Ccontinued on methadone, and D/C

Schwartzman Pain 2009Schwartzman Pain 2009 (DBRCT):(DBRCT):

�� 19 CRPS patients infused with saline with or without 19 CRPS patients infused with saline with or without ketamine (50mg/h) 4 hours/day for 5 days on, 2 days ketamine (50mg/h) 4 hours/day for 5 days on, 2 days off, 5 days on off, 5 days on

�� Ketamine group had statistically significant reduction in Ketamine group had statistically significant reduction in many pain parametersmany pain parameters


Zempsky CJP 2010Zempsky CJP 2010 (retrospective case review):(retrospective case review):

�� 5 children received ketamine infusion for Sickle Cell pain (4 wi5 children received ketamine infusion for Sickle Cell pain (4 with th opioids and 1 in place of)opioids and 1 in place of)

�� 2 patients has significant pain control and 1 patient had 2 patients has significant pain control and 1 patient had significant opioid reductionsignificant opioid reduction

�� Dose ranged from 0.06Dose ranged from 0.06--0.2 mg/kg/h and duration ranged from 0.2 mg/kg/h and duration ranged from 1919--90 hours90 hours

Amr Pain Physician 2010Amr Pain Physician 2010 (DBRCT):(DBRCT):

�� 40 patients randomized to ketamine + gabapentin and placebo + 40 patients randomized to ketamine + gabapentin and placebo + gabapentingabapentin

�� Ketamine dose 80mg IV over 5hours daily for 7 daysKetamine dose 80mg IV over 5hours daily for 7 days

�� KG group showed significant improvement over PG group KG group showed significant improvement over PG group during infusion and 2 weeks afterduring infusion and 2 weeks after


Irwin JPM 2010Irwin JPM 2010 (case series):(case series):

�� 2 cases of anxiety and depression treated with 2 cases of anxiety and depression treated with

ketamineketamine

�� 0.5mg/kg PO single dose0.5mg/kg PO single dose

PORTRAITSPORTRAITS

DosingDosing

�� Initial test dose given to assess tolerability and Initial test dose given to assess tolerability and efficacyefficacy

�� Some give prophylactic concurrent Some give prophylactic concurrent benzodiazepine or antipsychoticbenzodiazepine or antipsychotic

�� Often mixed with other drugs such as opioidsOften mixed with other drugs such as opioids

�� Opioid dose should be reduced by 25Opioid dose should be reduced by 25--50% with 50% with parenteral ketamineparenteral ketamine

�� Conversion: after few days CSCI=PO, after Conversion: after few days CSCI=PO, after weeks to months 25weeks to months 25--50%CSCI=PO50%CSCI=PO

DosingDosing

PO:PO:

�� 1010--25mg TID25mg TID--QID and QID and prnprn, increase by 10, increase by 10--

25mg increments up to 200mg QID25mg increments up to 200mg QID

�� Or weight based 0.25Or weight based 0.25--0.5mg/kg TID0.5mg/kg TID

�� Give smaller more frequent doses if side effects Give smaller more frequent doses if side effects

occuroccur

�� Direct from vial or diluted mixed in tasty liquidDirect from vial or diluted mixed in tasty liquid

DosingDosing

SL:SL:

�� 1010--25mg, do not swallow for 2 minutes25mg, do not swallow for 2 minutes

�� Use higher concentrations to minimize volumeUse higher concentrations to minimize volume

SC:SC:

�� 1010--25mg 25mg prnprn

�� Increase in increments of 25Increase in increments of 25--33%33%

IV:IV:

�� 0.50.5--1mg/kg1mg/kg

�� Give over 1Give over 1--2 minutes preceded by benzodiazepine2 minutes preceded by benzodiazepine

DosingDosing

CSCI:CSCI:

�� Dilute in large volume to avoid site irritationDilute in large volume to avoid site irritation

�� 11--2.5mg/kg/24h2.5mg/kg/24h

�� Increase by 50Increase by 50--100mg/24h, max dose 3.6g/24h100mg/24h, max dose 3.6g/24h

�� Some use loading dose 0.5mg/kg over 30 min, Some use loading dose 0.5mg/kg over 30 min,

followed by continuous 2mg/hfollowed by continuous 2mg/h

�� Some just start with 100mg/24h, Some just start with 100mg/24h, ““burstburst””

�� Increase to 300mg/24h, then 500mg/24h and Increase to 300mg/24h, then 500mg/24h and

stop 3 days after last incrementstop 3 days after last increment

DosingDosing

CIVI:CIVI:

�� 5050--200microgram/kg/h and titrate200microgram/kg/h and titrate

�� Single burst 600micrograms/kg up to 6mg/4hSingle burst 600micrograms/kg up to 6mg/4h

�� Increase next dose by 30% if no responseIncrease next dose by 30% if no response

�� Repeat daily for up to 5 days Repeat daily for up to 5 days

�� Various titration techniques reportedVarious titration techniques reported

�� Some start with 0.1mg/kg and double Q15minSome start with 0.1mg/kg and double Q15min

�� Others start at 10mg/h and titrate up from thereOthers start at 10mg/h and titrate up from there

Side EffectsSide Effects

euphoria, dysphasia, blunted affect, euphoria, dysphasia, blunted affect,

psychomotor retardation, vivid dreams, psychomotor retardation, vivid dreams,

nightmares, impaired attention, memory nightmares, impaired attention, memory

problems, impaired judgment, illusions, problems, impaired judgment, illusions,

hallucinations, altered body image, delirium, hallucinations, altered body image, delirium,

dizziness, diplopia, blurred vision, nystagmus, dizziness, diplopia, blurred vision, nystagmus,

altered hearing, hypertension, tachycardia, altered hearing, hypertension, tachycardia,

hypersalivation, nausea, vomiting, erythema, hypersalivation, nausea, vomiting, erythema,

pain at injection site, fatigue, increased muscle pain at injection site, fatigue, increased muscle

tone, increased pulmonary artery pressuretone, increased pulmonary artery pressure


slurred speech, confusion, disorientation, slurred speech, confusion, disorientation, hypotension, bradycardia, respiratory hypotension, bradycardia, respiratory depression, apnea, malignant hyperthermia, depression, apnea, malignant hyperthermia, agitation, coma, seizure, laryngospasm, agitation, coma, seizure, laryngospasm, bronchorrhea, arrhythmia, increased intracranial bronchorrhea, arrhythmia, increased intracranial pressure, morbilliform rash, anorexia, pressure, morbilliform rash, anorexia, anaphylaxis, outanaphylaxis, out--ofof--body experience, sedation, body experience, sedation, euphoria, sense of calm and serenity, increased euphoria, sense of calm and serenity, increased energy, open and closed eye visuals, meaningful energy, open and closed eye visuals, meaningful spiritual experiences, ataxiaspiritual experiences, ataxia


�� For analgesic doses, impaired attention, For analgesic doses, impaired attention,

memory, and judgmentmemory, and judgment

�� Occur less with subanesthetic dose given PO or Occur less with subanesthetic dose given PO or

CSCI and seem to be dose relatedCSCI and seem to be dose related

�� Can be controlled with concurrent Can be controlled with concurrent

benzodiazepine or haloperidolbenzodiazepine or haloperidol


�� Can be reduced by slowing dose titration and Can be reduced by slowing dose titration and

providing medications for side effectsproviding medications for side effects

�� Occur more often in the elderly, in women, and Occur more often in the elderly, in women, and

patients with anxiety disorderspatients with anxiety disorders

�� Chronic use leads to cognitive impairmentChronic use leads to cognitive impairment

Urinary Side EffectsUrinary Side Effects

Urinary ToxicityUrinary Toxicity

�� Frequency, urgency, dysuria, hematuriaFrequency, urgency, dysuria, hematuria

�� Suprapubic pain, Suprapubic pain, ““KK--painspains”” and and ““Ketamine CrampsKetamine Cramps””usually with greater than 1gm/dayusually with greater than 1gm/day

�� Interstitial cystitis, detrusor overactivity, decreased Interstitial cystitis, detrusor overactivity, decreased bladder capacitybladder capacity

�� VesicoVesico--ureteric reflux, hydronephrosis, papillary ureteric reflux, hydronephrosis, papillary necrosis, renal impairment, renal failurenecrosis, renal impairment, renal failure


�� Urinalysis negative for bacteria or sterile pyuriaUrinalysis negative for bacteria or sterile pyuria

�� 2020--30% of frequent users of high quantities 30% of frequent users of high quantities

report bladder symptomsreport bladder symptoms

�� Appears to be a temporal link where severity of Appears to be a temporal link where severity of

damage is determined by chronicity of abusedamage is determined by chronicity of abuse


�� Cystoscopy:Cystoscopy: epithelial inflammation, ulceration, epithelial inflammation, ulceration, petechial hemorrhage, neovascularization, contact petechial hemorrhage, neovascularization, contact bleedingbleeding

�� Histology:Histology: denuded bladder epithelium, eosinophilic denuded bladder epithelium, eosinophilic infiltrationinfiltration

�� Urography:Urography: shrunken bladder, decreased bladder shrunken bladder, decreased bladder compliance, detrusor overactivity, papillary necrosis, compliance, detrusor overactivity, papillary necrosis, hydronephrosishydronephrosis


�� Withdrawal of ketamine results in some degree Withdrawal of ketamine results in some degree

of resolution of symptoms depending on of resolution of symptoms depending on

severityseverity

�� Other treatments:Other treatments: NSAIDs, steroids, NSAIDs, steroids,

anticholinergics, cystodistension, intravesical anticholinergics, cystodistension, intravesical

instillation of hyaluranic acid, oral pentosan instillation of hyaluranic acid, oral pentosan

polysulfphate, and tyrosinepolysulfphate, and tyrosine

NicknamesNicknamesKK

Super KSuper K

Vitamin KVitamin K

Special KSpecial K

Mean greenMean green

RockmescRockmesc

KetKet

KittiesKitties

K2K2

JetJet

Super acidSuper acid

GreenGreen

Cat valiumCat valium

KitKatKitKat

CombinationsCombinations

Strawberry: ketamine + ephedrine + selegilineStrawberry: ketamine + ephedrine + selegiline

Sitting Duck: ketamine + ecstasySitting Duck: ketamine + ecstasy

CK1: ketamine + cocaineCK1: ketamine + cocaine

Ketamine AbuseKetamine Abuse

AbuseAbuse

�� Similar to PCP but with less violent, confused Similar to PCP but with less violent, confused

behavior when coming offbehavior when coming off

�� Severe impairment of working, episodic, and Severe impairment of working, episodic, and

semantic memorysemantic memory

�� Increased Increased schizotypalschizotypal and dissociative symptomsand dissociative symptoms

�� ““K holeK hole””: at the brink of being fully sedated, : at the brink of being fully sedated,

outout--ofof--body or nearbody or near--death experiencedeath experience

�� Desired depersonalization and Desired depersonalization and derealizationderealization

AbuseAbuse

�� Mortality is lowMortality is low

�� Consequences are related to dangerous Consequences are related to dangerous

behaviors and accidentsbehaviors and accidents

�� Used as a date rape drugUsed as a date rape drug

�� Long term adverse effects: flashbacks, Long term adverse effects: flashbacks,

attentionalattentional dysfunction, memory impairment, dysfunction, memory impairment,

tolerance, high dependency potentialtolerance, high dependency potential

AbuseAbuse

�� Rapid onset and duration means quick recoveryRapid onset and duration means quick recovery

�� Only 4% of dose recovered in urineOnly 4% of dose recovered in urine

�� Not included in standard urine toxicology Not included in standard urine toxicology

screens screens

�� Blood levels: therapeutic use: 0.5Blood levels: therapeutic use: 0.5--5mg/L, arrest 5mg/L, arrest

for impairment: 1for impairment: 1--2mg/L, fatal overdose: 32mg/L, fatal overdose: 3--

20mg/L20mg/L

AbuseAbuse

�� Powder can be insufflated, injected or oralPowder can be insufflated, injected or oral

�� Injection bypasses liver metabolism providing Injection bypasses liver metabolism providing

more efficient, smoother high up to 2 hoursmore efficient, smoother high up to 2 hours

�� Oral route requires more drug but longer trip Oral route requires more drug but longer trip

without dissociative statewithout dissociative state

�� Onset for injection: 1Onset for injection: 1--5min, snorted: 55min, snorted: 5--15min, 15min,

oral: 5oral: 5--30min30min

What have we learned?What have we learned?

�� A little History and A LOT of PharmacologyA little History and A LOT of Pharmacology

�� About Use and Abuse of this mystic drugAbout Use and Abuse of this mystic drug

�� Recent Supportive Evidence in PalliationRecent Supportive Evidence in Palliation

�� Dosing and Administration and Side EffectsDosing and Administration and Side Effects

�� Who is ready to give some Ketamine ???Who is ready to give some Ketamine ???

TALENTSTALENTS

ReferencesReferences

QuibellQuibell R et al. Therapeutic Reviews: R et al. Therapeutic Reviews: KetamineKetamine. Journal of Pain and Symptom Management 2011; 41 (3): 640. Journal of Pain and Symptom Management 2011; 41 (3): 640--649.649.

Irwin SA et al. Oral Irwin SA et al. Oral KetamineKetamine for the Rapid Treatment of Depression and Anxiety in Patients Rfor the Rapid Treatment of Depression and Anxiety in Patients Receiving Hospice eceiving Hospice Care. Journal of Palliative Medicine 2010; 13 (7): 903Care. Journal of Palliative Medicine 2010; 13 (7): 903--908.908.

AmrAmr YM. MultiYM. Multi--Day Low Dose Day Low Dose KetamineKetamine Infusion as Adjuvant to Oral Infusion as Adjuvant to Oral GabapentinGabapentin in Spinal Cord Injury Related in Spinal Cord Injury Related Chronic Pain: A Prospective, Randomized, Double Blind Trial. PaiChronic Pain: A Prospective, Randomized, Double Blind Trial. Pain Physician 2010; 13: 245n Physician 2010; 13: 245--249.249.

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