1. Nicola Holtom Palliative Medicine Consultant NNUH 2007
KETAMINE
Painting by Richard Tennant Cooper ‘man being attacked by demons’ was part of an exhibtion in 2004 on physical, psychological and social aspects of pain
Nicola Holtom
Palliative Medicine Consultant
NNUH 2007

2. ADJUVANT ANALGESICS IN CANCER PAIN
WHO ladder controls 80% of pains
Adjuvant analgesia is required for 20% pains
Nerve injury: 59% require adjuvants
Nerve compression: 32% require adjuvants
Stute et al 2003 Journal of Pain+ Symptom management 26(6)

3. NERVE INJURY PAIN Spinal NMDA receptor analgesia blocker / class 1
Step 4
antiarrhythmic
TCA +
Richard Tennant Cooper . Man being attacked by demons
Step 3
TCA or
anticonvulsant
anticonvulsant
Step 2
+steroid
Step 1

4. NEUROPHYSIOLOGY OF PAIN PATHWAYS
C fibres (slow myelinated 0.5 m/s)
Polymodal : heat, mechanical, chemical
Silent population - woken by inflammation
A fibres (moderate myelination)
Responsible for static allodynia
A fibres
Responsible for dynamic allodynia (pain on brushing movements)
Nociceptors
Complex: up to 20 different receptors on C fibres responsible for transmitting pain
Na+ channels are particularly found on C fibres

5. NEUROPHYSIOLOGY OF PAIN PATHWAYS
Inflammation  prostanoids, bradykinin, 5HT
These chemical mediators  peripheral sensitisation of C fibre  wakes up silent receptors
Vasodilatation + plasma extravasation  increased transmission along C fibre  central sensitisation and allodynia
Ectopic action potentials accumulate at point of damage in C fibres  allodynia and hyperalgesia
NB NSAID’s + Aspirin inhibit prostanoids via COX
There are no drugs that target bradykinin or triptans

6. FOLLOWING NERVE INJURY
Major changes in sodium channel
Entirely new sodium channels appear
Sodium 1.7 and 1.8 are only found on C-fibres
Currently no drugs which specifically target these sodium channels
In chronic pain there is also an increase in calcium channels in spinal cord
CB2 mexiletine and lamotrigine work on sodium channels
Gabapentin and pregabalin are useful in non-neuropathic pain states because all pains release transmitters acting on calcium channels

7. Mechanisms of neuropathic pain
Increased activity in primary sensory neurones
Central hypersensitivity (NMDA)
Activation of calcium channels

8. MECHANISMS OF NEUROPATHIC PAIN
1.Increased activity in primary sensory neurones
Sensory neurone specific voltage-gated sodium channels (SNS)
SNS1 + SNS2 are expressed in sensory neurones, particularly nociceptors
Ectopic action potentials accumulate at point of nerve injury ( SNS1 + SNS2 )
Patients with chronic local hyperalgesia + allodynia have  SNS1 but little or no SNS2
This suggests SNS1 is responsible for persistent hypersensitive state

9. MECHANISMS OF NEUROPATHIC PAIN
2. Central hypersensitivity
The AMPA receptor sets the baseline response of the spinal neurones
Kainate receptors may also be important
Release of peptides and glutamate allow the NMDA receptor to be activated
NMDA activation underlies wind-up

10. MECHANISMS OF NEUROPATHIC PAIN
3. Ca 2+ channel activity
Following nerve damage there are more activated Ca2+ channels (N type)
No changes in P or T type
Influx of Ca2+ into cells  release of neurotransmitters

11. K+ K+ Ca2+ Ca2+ GLU SP Cl- K+ a2d a2 Primary afferent
OP1
OP2
OP3
CB1 a2
Primary afferent
Ca2+
5HT3 a2
Ca2+
Mg2+
NMDA
GABAB
CB1
OP1
OP2
OP3
GLU
GLU
Na+
AMPA
Na+
Postsynaptic neurone SP SP
5HT2
NK1
Ca2+
Mg2+ Gs
NMDA
NK1
Inhibitory receptor
GABAA
Excitatory receptor
GABAB
5HT1B
ADN
Cl- K+

12. NMDA receptors Receptors require glutamate or system does not operate
Normally Mg2+ prevents influx of ions
Accumulated activation of neurones depletes Mg2+ so system can operate
Once Mg2+ is depleted there is influx of Ca2+
Ketamine sits in the NMDA channel and blocks it

13. NMDA RECEPTOR
Blocking the NMDA receptor with ketamine blocks the hyperalgesic response preventing wind-up
NR2 ABCD subgroups of NMDA receptor exist
Drugs targeted towards subgroups might be better tolerated

14. INTERPERSONAL VARIATIONS
Three factors which dictate interpersonal variations in pain :
Ca2+ channel receptor
Opiate receptor
5HT genes

15. Mechanism of action of anti-neuropathic drugs
Block peripheral sensitisation (sodium channels : Valproate)
Block central sensitisation (Ketamine)
Restore inhibitory control (TCA,SNRI)
Modulate release of neurotransmitters (Gabapentin / Pregabalin)

16. OPIOIDS Opioids work on C fibres and fibres with NMDA receptors
If wind-up has occurred higher doses of opiates are required to ‘chase’ neuropathic pain
Consensus is that opioids are useful in neuropathic pain
MORPHEUS : GOD OF DREAMS
SON OF HYPNOS : GOD OF SLEEP

17. GABAPENTIN + PREGABALIN
Gabapentin and Pregabalin work on α-2 delta subunit of calcium channels
Reduce calcium influx and reduces neurotransmitter release
Pregabalin binds to receptor better than gabapentin
Pregabalin has linear pharmacokinetics
Response to pregabalin more predictable.90% oral bioavailability
Pregabalin S/E : dizziness+somnolence 30%, peripheral oedema, dry mouth, amblyopia
Pregabalin has more predictable response because it has linear pharmacokinetics.there is no pharmacological differenceConversion pgabapentin to pregabalin –divide by 4

18. TCA’s Desipramine Fewest SE’s Nortrptyline Imipramine Doxepin
Analgesic effect is independent of antidepressant effect
Desipramine Fewest SE’s
Nortrptyline
Imipramine
Doxepin
Amitriptyline Most adverse effects

19. KETAMINE Pharmacology Indications Contra-indications
NMDA receptor blocker
Reduces post-synaptic excitation
Interactions with Ca and Na channels
NA + 5HT reuptake inhibition
μ + К opioid like actions
Indications
Neuropathic
Inflammatory
Ischaemic
Contra-indications
Epilepsy, raised intracranial pressure

20. FORMULATIONS BNF 4.7.3 / 15.1.1 Oral ketamine solution 50mg / 5mls
Injection 10mg/ml : 20ml vial
Injection 50mg/ml : 10ml vial
Injection 100mg/ml : 10ml vial

21. PHARMACOKINETICS
Extensive first- pass hepatic metabolism to nor-ketamine
<10% excreted unchanged by kidneys and in faeces
Hepatic enzyme induction with long term use of ketamine
Plasma concentration increased by diazepam
Adverse effects
Dysphoria, vivid dreams, hallucinations, altered body image
Hypertension
Tachycardia
Delirium
Diplopia,nystagmus

22. KETAMINE AUDIT NNUH 2005-2006 29 patients
9 outpatients ( 9% new referrals with pain)
20 inpatients (14% new inpatient pain) referrals)
27/29 excellent response
1/29 dysphoria
1/29 disliked taste
4patients were also on methadone

23. PAIN
AUTONOMY
HETERONOMY
X is where the patient wants to be X
NO PAIN