Ketamine

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Ketamine

• Carina Saxby

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Overview

• Why?
• Case presentation
• Mechanism of action in neuropathic pain
• Evidence for its use in cancer patients
• Pharmacology
• Protocols for use
• Implications for use in community

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Ketamine Why?

• Experience of use in 3 different hospices
• Developed a protocol for use in St Gemmas
  Hospice
• Recent review of available literature for book
  chapter on neuropathic pain
• AE experience

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Case Presentation (1)

• D.C. 63yr
• Jan 06 Metastatic prostate cancer
• Disease progression (? PSA) despite orchidectomy,
  hormone therapy and chemotherapy
• Now having regular transfusions and
  bisphosphonates

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Case Presentation (2)

• 16/1 Admitted to hospice for S/C
• On Cocodamol 30/500 QDS, Pregabalin 225mg BD,
  Diclofenac PO/PR Oramorph PRN, Prednisalone 10mg
  OD
• 17/1 Had Zometa
• 23.30 c/o ? pain
• Fell in toilet
• Standing unaided but power 4/5, ?
  Numbness on soles of feet
• Pred ? Dex 8mg

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Case (3)

• 18/1 Difficulty PUing
• MRI confirmed SCC _at_ T11
• 1 Rt at CKR
• 19/1 Returned to hospice late pm
• 20/1 Flaccid paralysis, sensory level at
  umbilicus, c/o ? pain and allodynia
• Numerous prn doses of Diamorphine/Midazolam
• Pin point pupils
• Agitated cf pain
• S/D Diamorphine and Midazolam commenced

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Case (4)

• Consultant on call suggested commencing Ketamine
  S/D 100mg and PRN Ketamine
• Complete control of pain following this
• Continued on both S/D for 4 days
• Diamorphine ?MST
• Midazolam?Diazepam 2mg
• Ketamine stopped
• Now pain free and other analgesics etc being
  reduced

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Mechanism of action

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

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Indications for use

• Anaesthesia
• Sedation (dressing changes)
• In pain that has failed to respond fully to
  opioids despite escalating doses and combination
  with appropriate adjuvants
• Neuropathic pain esp. when the clinical triad of
  allodynia, hyperalgesia and prolongation of pain
  response is present.
• Ischaemic and phantom limb pain
• Inflammatory pain?
• Chronic pancreatitis?

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Evidence for use in cancer pts 1

• Cochrane review (Bell 2003)
• The use of Ketamine as an adjuvant to opioids in
  the treatment of cancer pain
• 4 RCTs identified
• 2 were excluded because of poor quality
• Remaining 2 30 patients in total
• Positive results with few side effects BUT
• Insufficient evidence that ketamine improves the
  effectiveness of opioids in cancer pain

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Evidence 2

• 32 case reports, open label audits or open label
  uncontrolled trials were identified during the
  Cochrane search
• The majority supported improved opioid analgesia
  with Ketamine but routes and doses varied greatly
• IV burst ketamine
• Open label audit (Jackson 2001)
• 39 patients
• Refractory cancer pain
• 3-5 day infusion of ketamine
• 67 response rate, 30 incidence of psychomimetic
  s/es

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Pharmacology 1

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

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Pharmacology (2)

• Bioavailability IM/IV 93, PO 16
• Metabolised in the liver. Principal metabolite is
  Norketamine. This appears to be more potent than
  ketamine as an analgesic and the maximum blood
  concentration of norketamine is greater after
  oral administration than after injection
• The equianalgesic oral dose of ketamine is approx
  30-40 of the previous parenteral dose

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Pharmacology(3)

• Consider a dose reduction in significant hepatic
  impairment
• Less than 10 of ketamine is excreted unchanged
• No need to reduce dose in renal impairment
• Long term use leads to hepatic enzyme induction
  and enhanced ketamine metabolism
• Plasma concentration is increased by Diazepam

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Cautions

• Uncontrolled hypertension
• Raised intracranial pressure (probable C.I)
• Cardiac failure
• Ischaemic heart disease
• History of psychosis
• Previous cerebrovascular accidents
• Raised intraocular pressure

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Undesirable Effects

• Occur in approx 40 patients when given by
  subcutaneously probably less when given by mouth
  (Kannan 2002)
• Side effects appear to be dose related (Jackson
  2001)
• Hypertension
• Tachycardia
• Psychomimetic phenomena (Special K)
• Delirium
• Excess salivation
• Dizziness
• Erythema and pain at the injection site

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Preparations available

• Ketamine injection Ketalar
• 10mg/ml, 50mg/ml, 100mg/ml multidose vials
• 8-17
• Oral ketamine solution
• 10mg/ml available in peppermint, lemon, ginger
  and aniseed flavours
• 100ml and 500ml bottles
• 85.46 and 118.84 (incl del. VAT)

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Commencing a patient on Ketamine

• Ketamine should only be initiated in the hospice
  after discussion with a Consultant
• The patient should have an explanation about the
  use of medicines outside a license

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Starting oral Ketamine

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

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Oral Ketamine - cont

• If pain is returning before the next dose is due
  the dosing interval can be reduced to 4-6hrly
• Ensure that Haloperidol 1.5-5mg and a
  benzodiazepine eg Lorazepam 1mg is prescribed on
  the as required section of the chart if
  psychomimetic phenomena develop

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Starting a subcutaneous infusion of Ketamine

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

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Subcutaneous ketamine

• Can be irritant and if used alone is best diluted
  with sodium chloride 0.9.
• If using with other drugs use water for injection
• Use a dilute solution- 18ml in 20ml luer lock
  syringe
• Ketamine is compatible with Dexamethasone (low
  dose), diamorphine, haloperidol, levomepromazine,
  metoclopramide, midazolam and morphine

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Monitoring patients on Ketamine

• A baseline BP and HR should be taken prior to and
  24 hrs after commencing treatment
• Patients should be observed for signs of opiate
  toxicity and psychomimetic phenomena

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Changing from subcutaneous to oral ketamine

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

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Discharging a patient on Ketamine (1)

• Since January 2006 Ketamine became a control drug
  in Schedule 4 under the Misuse of drugs act.
• The hospice will provide 10 days supply as a TTO
• The hospice pharmacist should liaise with the
  patients community pharmacist and information
  (including a leaflet) should be given to them re
  ordering of the oral solution from Martindale

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Discharging a patient on Ketamine (2)

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

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Summary

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