KetamineKetamine

Carina SaxbyCarina Saxby

OverviewOverview

Why?Why?

Case presentationCase presentation

Mechanism of action in neuropathic painMechanism of action in neuropathic pain

Evidence for its use in cancer patientsEvidence for its use in cancer patients

PharmacologyPharmacology

Protocols for useProtocols for use

Implications for use in communityImplications for use in community

Ketamine –Why?Ketamine –Why?

Experience of use in 3 different hospicesExperience of use in 3 different hospices

Developed a protocol for use in St Developed a protocol for use in St Gemma’s HospiceGemma’s Hospice

Recent review of available literature for Recent review of available literature for book chapter on neuropathic painbook chapter on neuropathic pain

A+E experienceA+E experience

Case Presentation (1)Case Presentation (1)

D.C. 63yr D.C. 63yr

Jan 06 Metastatic prostate cancerJan 06 Metastatic prostate cancer

Disease progression (↑ PSA) despite Disease progression (↑ PSA) despite orchidectomy, hormone therapy and orchidectomy, hormone therapy and chemotherapychemotherapy

Now having regular transfusions and Now having regular transfusions and bisphosphonatesbisphosphonates

Case Presentation (2)Case Presentation (2)

16/1 Admitted to hospice for S/C16/1 Admitted to hospice for S/COn Cocodamol 30/500 QDS, Pregabalin 225mg On Cocodamol 30/500 QDS, Pregabalin 225mg BD, Diclofenac PO/PR Oramorph PRN, BD, Diclofenac PO/PR Oramorph PRN, Prednisalone 10mg ODPrednisalone 10mg OD17/1 Had Zometa17/1 Had Zometa23.30 c/o ↑ pain23.30 c/o ↑ pain

Fell in toiletFell in toilet Standing unaided but power 4/5, Standing unaided but power 4/5, ? Numbness on soles of feet? Numbness on soles of feetPred → Dex 8mgPred → Dex 8mg

Case (3)Case (3)

18/118/1 Difficulty PUingDifficulty PUingMRI confirmed SCC @ T11MRI confirmed SCC @ T11

1# Rt at CKR1# Rt at CKR

19/119/1 Returned to hospice late pmReturned to hospice late pm

20/120/1 Flaccid paralysis, sensory level at Flaccid paralysis, sensory level at umbilicus, c/o ↑ pain and allodyniaumbilicus, c/o ↑ pain and allodynia

Numerous prn doses of Diamorphine/MidazolamNumerous prn doses of Diamorphine/Midazolam

Pin point pupilsPin point pupils

Agitated cf painAgitated cf pain

S/D Diamorphine and Midazolam commencedS/D Diamorphine and Midazolam commenced

Case (4)Case (4)

Consultant on call suggested commencing Consultant on call suggested commencing Ketamine S/D 100mg and PRN KetamineKetamine S/D 100mg and PRN Ketamine

Complete control of pain following this Complete control of pain following this

Continued on both S/D for 4 daysContinued on both S/D for 4 days

Diamorphine →MSTDiamorphine →MST

Midazolam→Diazepam 2mgMidazolam→Diazepam 2mg

Ketamine stoppedKetamine stopped

Now pain free and other analgesics etc being Now pain free and other analgesics etc being reducedreduced

Mechanism of actionMechanism of action

Ketamine is a dissociative anaesthetic which has Ketamine is a dissociative anaesthetic which has analgesic properties at sub-anaesthetic dosesanalgesic properties at sub-anaesthetic dosesKetamine is a potent NMDA receptor antagonist Ketamine is a potent NMDA receptor antagonist (N methyl D aspartame). NMDA receptors are (N methyl D aspartame). NMDA receptors are glutamate receptors and glutamate is the main glutamate receptors and glutamate is the main excitatory transmitter in the CNS.excitatory transmitter in the CNS.NMDA receptor activation is critical for the NMDA receptor activation is critical for the induction and subsequent maintenance of induction and subsequent maintenance of enhanced pain states enhanced pain states ““Wind up phenomenon” – Hyperalgesia, Wind up phenomenon” – Hyperalgesia, allodynia and prolonged pain response allodynia and prolonged pain response

Indications for useIndications for use

AnaesthesiaAnaesthesiaSedation (dressing changes)Sedation (dressing changes)In pain that has failed to respond fully to opioids In pain that has failed to respond fully to opioids despite escalating doses and combination with despite escalating doses and combination with appropriate adjuvantsappropriate adjuvants– Neuropathic pain esp. when the clinical triad of Neuropathic pain esp. when the clinical triad of

allodynia, hyperalgesia and prolongation of pain allodynia, hyperalgesia and prolongation of pain response is present.response is present.

– Ischaemic and phantom limb painIschaemic and phantom limb pain– Inflammatory pain?Inflammatory pain?– Chronic pancreatitis?Chronic pancreatitis?

Evidence for use in cancer pts 1Evidence for use in cancer pts 1

Cochrane review (Bell 2003)Cochrane review (Bell 2003)The use of Ketamine as an adjuvant to opioids in The use of Ketamine as an adjuvant to opioids in the treatment of cancer painthe treatment of cancer pain

4 RCTs identified 4 RCTs identified

2 were excluded because of poor quality2 were excluded because of poor quality

Remaining 2 – 30 patients in totalRemaining 2 – 30 patients in total

Positive results with few side effects BUTPositive results with few side effects BUT

Insufficient evidence that ketamine improves the Insufficient evidence that ketamine improves the effectiveness of opioids in cancer pain effectiveness of opioids in cancer pain

Evidence 2Evidence 2

32 case reports, open label audits or open label 32 case reports, open label audits or open label uncontrolled trials were identified during the Cochrane uncontrolled trials were identified during the Cochrane searchsearchThe majority supported improved opioid analgesia with The majority supported improved opioid analgesia with Ketamine but routes and doses varied greatlyKetamine but routes and doses varied greatly– IV “burst” ketamineIV “burst” ketamine– Open label audit (Jackson 2001)Open label audit (Jackson 2001)– 39 patients39 patients– Refractory cancer painRefractory cancer pain– 3-5 day infusion of ketamine 3-5 day infusion of ketamine – 67% response rate, 30% incidence of psychomimetic s/e’s67% response rate, 30% incidence of psychomimetic s/e’s

Pharmacology 1Pharmacology 1

NMDA receptor antagonist binding to the NMDA receptor antagonist binding to the phencyclidine site when the channels are in an phencyclidine site when the channels are in an open activated stateopen activated stateAlso interacts with Na and Ca channels, Also interacts with Na and Ca channels, cholinergic transmission, noradrenergic and cholinergic transmission, noradrenergic and serotoninergic re-uptake inhibition and serotoninergic re-uptake inhibition and μμ, , δδ, , κκ opioid like effects.opioid like effects.Synergism with morphine has been observed Synergism with morphine has been observed with a possible reversal of the rightward shift of with a possible reversal of the rightward shift of the dose-analgesic response curve ie re the dose-analgesic response curve ie re appearance of opioid sensitivity appearance of opioid sensitivity

Pharmacology (2)Pharmacology (2)

Bioavailability IM/IV 93%, PO 16%Bioavailability IM/IV 93%, PO 16%Metabolised in the liver. Principal Metabolised in the liver. Principal metabolite is Norketamine. This appears metabolite is Norketamine. This appears to be more potent than ketamine as an to be more potent than ketamine as an analgesic and the maximum blood analgesic and the maximum blood concentration of norketamine is greater concentration of norketamine is greater after oral administration than after injectionafter oral administration than after injection– The equianalgesic oral dose of ketamine is The equianalgesic oral dose of ketamine is

approx 30-40% of the previous parenteral approx 30-40% of the previous parenteral dose dose

Pharmacology(3)Pharmacology(3)

Consider a dose reduction in significant hepatic Consider a dose reduction in significant hepatic impairmentimpairment

Less than 10% of ketamine is excreted Less than 10% of ketamine is excreted unchanged unchanged

No need to reduce dose in renal impairmentNo need to reduce dose in renal impairment

Long term use leads to hepatic enzyme Long term use leads to hepatic enzyme induction and enhanced ketamine metabolisminduction and enhanced ketamine metabolism

Plasma concentration is increased by DiazepamPlasma concentration is increased by Diazepam

CautionsCautions

Uncontrolled hypertensionUncontrolled hypertension

Raised intracranial pressure (probable C.I)Raised intracranial pressure (probable C.I)

Cardiac failureCardiac failure

Ischaemic heart diseaseIschaemic heart disease

History of psychosisHistory of psychosis

Previous cerebrovascular accidentsPrevious cerebrovascular accidents

Raised intraocular pressureRaised intraocular pressure

Undesirable EffectsUndesirable Effects

Occur in approx 40% patients when given by Occur in approx 40% patients when given by subcutaneously; probably less when given by mouth subcutaneously; probably less when given by mouth (Kannan 2002)(Kannan 2002)Side effects appear to be dose related (Jackson 2001)Side effects appear to be dose related (Jackson 2001)HypertensionHypertensionTachycardiaTachycardiaPsychomimetic phenomena (Special K)Psychomimetic phenomena (Special K)DeliriumDeliriumExcess salivationExcess salivationDizzinessDizzinessErythema and pain at the injection siteErythema and pain at the injection site

Preparations availablePreparations available

1.1. Ketamine injection – KetalarKetamine injection – Ketalar• 10mg/ml, 50mg/ml, 100mg/ml multidose 10mg/ml, 50mg/ml, 100mg/ml multidose

vialsvials• £8-17£8-17

2.2. Oral ketamine solutionOral ketamine solution• 10mg/ml available in peppermint, lemon, 10mg/ml available in peppermint, lemon,

ginger and aniseed flavoursginger and aniseed flavours• 100ml and 500ml bottles100ml and 500ml bottles• £85.46 and £118.84 (incl del. + VAT)£85.46 and £118.84 (incl del. + VAT)

Commencing a patient on Commencing a patient on KetamineKetamine

Ketamine should only be initiated in the Ketamine should only be initiated in the hospice after discussion with a Consultanthospice after discussion with a Consultant

The patient should have an explanation The patient should have an explanation about the use of medicines outside a about the use of medicines outside a licenselicense

Starting oral KetamineStarting oral Ketamine

Consider a reduction in the patients opiate Consider a reduction in the patients opiate medication (30-50%) +/- a change from medication (30-50%) +/- a change from sustained release to immediate release sustained release to immediate release morphinemorphineStarting dose 10-25mg 6-8hrlyStarting dose 10-25mg 6-8hrlyTitrate the dose every 1-2 days in steps of 10-Titrate the dose every 1-2 days in steps of 10-25mgs up to a maximum of 100mg QDS (max 25mgs up to a maximum of 100mg QDS (max reported dose 200mg QDS)reported dose 200mg QDS)Give a smaller dose more frequently if Give a smaller dose more frequently if psychomimetic phenomena or drowsiness psychomimetic phenomena or drowsiness occurs which does not respond to a decrease in occurs which does not respond to a decrease in opioid medicationopioid medication

Oral Ketamine - contOral Ketamine - cont

If pain is returning before the next dose is If pain is returning before the next dose is due the dosing interval can be reduced to due the dosing interval can be reduced to 4-6hrly4-6hrly

Ensure that Haloperidol 1.5-5mg and a Ensure that Haloperidol 1.5-5mg and a benzodiazepine eg Lorazepam 1mg is benzodiazepine eg Lorazepam 1mg is prescribed on the “as required” section of prescribed on the “as required” section of the chart if psychomimetic phenomena the chart if psychomimetic phenomena developdevelop

Starting a subcutaneous infusion of Starting a subcutaneous infusion of KetamineKetamine

Consider a reduction in the patients opiate dose Consider a reduction in the patients opiate dose (by 30-50%) +/- a change from sustained (by 30-50%) +/- a change from sustained release preparation to an immediate release release preparation to an immediate release form.form.Starting dose 50-100mg/24hrsStarting dose 50-100mg/24hrsTitrate the dose every 1-2 days increasing by Titrate the dose every 1-2 days increasing by 50-100mg50-100mgEnsure that Haloperidol 1.5-5mg and a Ensure that Haloperidol 1.5-5mg and a benzodiazepine eg Lorazepam 1mg or benzodiazepine eg Lorazepam 1mg or Midazolam 2.5-10mg is prescribed on the “as Midazolam 2.5-10mg is prescribed on the “as required” section of the medicine chart if required” section of the medicine chart if psychomimetic phenomena developpsychomimetic phenomena develop

Subcutaneous ketamineSubcutaneous ketamine

Can be irritant and if used alone is best diluted Can be irritant and if used alone is best diluted with sodium chloride 0.9%.with sodium chloride 0.9%.

If using with other drugs use water for injectionIf using with other drugs use water for injection

Use a dilute solution- 18ml in 20ml luer lock Use a dilute solution- 18ml in 20ml luer lock syringesyringe

Ketamine is compatible with Dexamethasone Ketamine is compatible with Dexamethasone (low dose), diamorphine, haloperidol, (low dose), diamorphine, haloperidol, levomepromazine, metoclopramide, midazolam levomepromazine, metoclopramide, midazolam and morphineand morphine

Monitoring patients on KetamineMonitoring patients on Ketamine

A baseline BP and HR should be taken A baseline BP and HR should be taken prior to and 24 hrs after commencing prior to and 24 hrs after commencing treatmenttreatment

Patients should be observed for signs of Patients should be observed for signs of opiate toxicity and psychomimetic opiate toxicity and psychomimetic phenomenaphenomena

Changing from subcutaneous to Changing from subcutaneous to oral ketamineoral ketamine

Because of the first pass mechanism from Because of the first pass mechanism from ketamine to its more potent active metabolite ketamine to its more potent active metabolite norketamine, oral ketamine is more potent than norketamine, oral ketamine is more potent than parenteral ketamine.parenteral ketamine.When switching to oral ketamine the dose When switching to oral ketamine the dose should be reduced to 30-40% of the previous should be reduced to 30-40% of the previous parenteral dose parenteral dose eg 200mg/24hrs SC → 60-80mg/24hrs PO eg 200mg/24hrs SC → 60-80mg/24hrs PO Prescribe the appropriate dose as a TDS regime Prescribe the appropriate dose as a TDS regime eg 20mg TDS and discontinue the subcutaneous eg 20mg TDS and discontinue the subcutaneous infusion 6 hours after the first oral dose.infusion 6 hours after the first oral dose.

Discharging a patient on Ketamine Discharging a patient on Ketamine (1)(1)

Since January 2006 Ketamine became a control Since January 2006 Ketamine became a control drug in Schedule 4 under the Misuse of drugs drug in Schedule 4 under the Misuse of drugs act.act.

The hospice will provide 10 days supply as a The hospice will provide 10 days supply as a TTOTTO

The hospice pharmacist should liaise with the The hospice pharmacist should liaise with the patients community pharmacist and information patients community pharmacist and information (including a leaflet) should be given to them re (including a leaflet) should be given to them re ordering of the oral solution from Martindaleordering of the oral solution from Martindale

Discharging a patient on Ketamine Discharging a patient on Ketamine (2)(2)

The medical team must speak to the patients GP The medical team must speak to the patients GP to ensure that they are happy to continue to to ensure that they are happy to continue to prescribe Ketamine.prescribe Ketamine.Both patient and GP must be made aware that Both patient and GP must be made aware that as there is a delay in the supply of the oral as there is a delay in the supply of the oral preparation and that their pharmacist must be preparation and that their pharmacist must be given advance notice of at least a week so that given advance notice of at least a week so that the drug may be ordered.the drug may be ordered.The patient should be given an information The patient should be given an information leaflet about Ketamine that should include on it leaflet about Ketamine that should include on it who they should contact in the event of any who they should contact in the event of any problemsproblems

SummarySummary

Although the evidence to support the use of ketamine Although the evidence to support the use of ketamine above other adjuvants is weak it does appear to have a above other adjuvants is weak it does appear to have a role in the treatment of refractory neuropathic painrole in the treatment of refractory neuropathic painMain side effects are psychomimetic and may be Main side effects are psychomimetic and may be reduced by the concomitant Rx of BDZ or Haloperidol as reduced by the concomitant Rx of BDZ or Haloperidol as well as by administration by mouthwell as by administration by mouthPatients should be selected carefully – look for the Patients should be selected carefully – look for the clinical triad of “wind up”clinical triad of “wind up”PO dose is approx 1/3 that of the IV/SC routePO dose is approx 1/3 that of the IV/SC routeThere are prescribing issues There are prescribing issues – Unlicensed product/useUnlicensed product/use– Supply on discharge Supply on discharge – Familiarity in Rx lacking Familiarity in Rx lacking