1. Ketamine
Carina Saxby

2. 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

3. 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

4. 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

5. 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

6. Case (3) 18/1 Difficulty PUing 19/1 Returned to hospice late pm
MRI confirmed 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

7. 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

8. 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

9. 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?

10. 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

11. 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

12. 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

13. 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

14. 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

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

16. 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

17. 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 £ (incl del. + VAT)

18. 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

19. 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

20. 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

21. 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 mg/24hrs
Titrate the dose every 1-2 days increasing by mg
Ensure that Haloperidol 1.5-5mg and a benzodiazepine eg Lorazepam 1mg or Midazolam mg is prescribed on the “as required” section of the medicine chart if psychomimetic phenomena develop

22. 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

23. 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

24. 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.

25. 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

26. 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

27. 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