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

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 + Richard Tennant Cooper . Man being attacked by demons Step 3 TCA or anticonvulsant anticonvulsant Step 2 +steroid Step 1

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 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

Mechanisms of neuropathic pain Increased activity in primary sensory neurones Central hypersensitivity (NMDA) 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

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+

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

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

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

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

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 4patients were also on methadone

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