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