Post on 28-Dec-2015
transcript
KETAMINE
Nicola HoltomPalliative Medicine Consultant
NNUH 2007
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) 1123-1131
NERVE INJURY PAIN
Spinal
NMDA receptor analgesia
blocker / class 1
Step 4
antiarrhythmic
TCA +
TCA or anticonvulsant
anticonvulsant
+steroid
Step 1
Step 2
Step 3
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
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
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
Mechanisms of neuropathic pain
1. Increased activity in primary sensory neurones
2. Central hypersensitivity (NMDA)
3. Activation of calcium channels
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
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
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
SP
GLU
Na+
Ca2+
Na+AMPA
NMDA
Mg2+
Gs
NMDAMg
2+
OP1 OP2 OP3
GABA B
NK1
5HT2
Ca2+
OP2 OP3
K+
GABAB 5HT1B
K+
ADN
OP1
GABA A
Cl-5HT
3
NK1
Primary afferent
Postsynaptic neurone
Inhibitory receptor
Excitatory receptor
GLU
SP
CB1
K+
Ca2+
CB1
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
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
INTERPERSONAL VARIATIONS
Three factors which dictate interpersonal variations in pain :
• Ca2+ channel receptor• Opiate receptor• 5HT genes
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)
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
KETAMINE
• Pharmacology– 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
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
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
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
PAIN
NO PAIN
AUTONOMY HETERONOMY
X