Ketamine
Carina Saxby
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
Ketamine –Why?
Experience of use in 3 different hospices
Developed a protocol for use in St
Gemma’s Hospice
Recent review of available literature for
book chapter on neuropathic pain
A+E experience
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
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
Case (3)
18/1
Difficulty PUing
MRI confirmed SCC @ T11
1# Rt at CKR
19/1
20/1
Returned to hospice late pm
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
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
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
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?
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
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/e’s
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, δ, κ
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
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
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
Cautions
Uncontrolled hypertension
Raised intracranial pressure (probable C.I)
Cardiac failure
Ischaemic heart disease
History of psychosis
Previous cerebrovascular accidents
Raised intraocular pressure
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
Preparations available
1. Ketamine injection – Ketalar
• 10mg/ml, 50mg/ml, 100mg/ml multidose
vials
• £8-17
2. 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)
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
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 1025mgs 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
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
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
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
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
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.
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
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
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