T2L11 physiology of pain 2

Question 1

acute vs chronic pain

Answer 1

less than 3 months is acute

more than 3 months is chronic

Question 2

acute pain

Answer 2

1. nociceptive
2. inflammatory
3. neuropathic

eg post op, msk injury, burn

stops when site recovers

Question 3

peripheral sensitization

Answer 3

• major mechanism of acute pain
• leads to pain hypersensitivity (hyperalgesia)

it is reduction in threshold of ends of peripheral nociceptors:

1. reduction of threshold of TRPV1 channels (by bradykinin, nerve growth factor)
2. reduction in threshold of sodium channels (by prostaglandins)

Question 4

local anaesthetic

Answer 4

eg lidocaine (topically applied to skin)
- sodium channel blockers

eg topical capsaicin treatment

• TRPV1 channel agonist
• repeat use reduces nociceptor firing by depleting substance P, causing peripheral terminals to die back (calcium overload causes mitochondrial dysfunction)

Question 5

non steroidal anti-inflammatory drugs

Answer 5

eg aspirin, ibuprofen

• inhibit prostaglandin synthesis
• prevent peripheral sensitization
• overall reduces Na+ channel threshold

Question 6

paracetamol

Answer 6

• not and NSAID
• inhibits cyclooxygenase COX enzymes
• does not reduce inflammation
• acts on descending serotonergic pathways

Question 7

opioids

Answer 7

eg morphine, codeine, tramadol
- most effective pain relief but many side effects

• agonist of endogenous opioid system

sites of action at brainstem, spinal chord, periphery

Question 8

gate control theory

Answer 8

• modulation of pain at spinal chord level
• pain evoked by nociceptors can be reduced by simultaneous activation of low threshold mechanorecepors (Aβ fibres) ie rubbing a hurting area will reduce pain
• stimulation of Aβ fibres in vicinity of injury activates interneurons in dorsal horn, which inhibit spinothalamic neurons

C fibres inhibit inhibitory interneurons (open gate)
Aβ fibres activate inhibitory interneurons (close gate)

s14

Question 9

chronic pain

Answer 9

1. inflammatory eg rheumatoid arthritis

2. neuropathic eg cns injury

Question 10

neuropathic pain

Answer 10

• complex and both peripheral and cns

peripheral:
1. peripheral sensitization

2. spontaneous firing of nociceptors
   - increase axonal firing at injury site, due to accumulation of ions at regenerating tip eg spontaneous pain at knife wounds

central:

1. central sensitization in spinal chord
   - increase in the responsiveness of nociceptive neurons within the cns
   - normal input produces abnormal responses
   - due to reduced threshold in 2nd order neurons:

constant firing from periphery following injury&raquo_space; sustained release of glutamate&raquo_space;
prolonged depolarisation of postsynaptic membrane&raquo_space;
influx of ca2+ through NMDA receptors&raquo_space;
activation of kinases&raquo_space;
phosphorylation of NMDA/AMPA&raquo_space;
channel protein synthesis&raquo_space;
more channels inserted

this is central hyperalgesia

SIMILAR TO LTP

2. changes in activation patterns/cortical remapping in brain

the problem with central changes is they are not easily reversible

Question 11

central allodynia

Answer 11

• non noxious Aβ fibres also synapse onto 2nd order spinothoracic neurons (normally nonfunctional)

following central sensitization:
- non noxious Aβ afferents activate sensitized 2nd order neurons

s25

Question 12

other mechanisms of chronic pain

Answer 12

1. altered synaptic connections:
   - Aβ fibres form new sprouts that synapse into spinothalamic tract neurons
2. loss of inhibitory interneurons eg GABA/glycine

Question 13

treatment for chronic pain

Answer 13

• difficult to treat
• good individual management is critical

can lead to

• depression
• sleep problems
• fatigue

Drugs:
		- Tricyclic antidepressants
		- Anticonvulsants
		- NMDA antagonists
			(All have analgesic properties)

Physiotherapy – e.g. manipulation of tissues, pacing

Psychological therapies – e.g. cognitive behavioral therapy

Surgery – e.g. spinal cord stimulator

Question 14

tricyclic antidepressants

Answer 14

eg amitriptyline

mechanism of action is unclear

• acts on descending inhibitory pathways
• inhibits serotonin and noradrenaline reuptake

Question 15

anticonvulsants

Answer 15

eg carbamazepine, pregabalin

• reduce spinal chord excitability
• blocks calcium channels (carbamazepine)
• blocks sodium channels (carbamazepine)

Pregabalin/gabapentin do not act on GABAergic interneurons

- Blocks presynaptic voltage-gated Ca2+ channels
- Prevent release of glutamate from nociceptors

Question 16

NMDA antagonists

Answer 16

eg KETAMINEEEEEEE

• nmda antagonist (Reduces glutamate influx)
• prevents 2nd order neuron depolarising
• hallucinations and bad dreams

Question 17

nice guidelines on neuropathic pain

Answer 17

First-line of treatment:
- Amitriptyline or pregabalin

Second-line of treatment:
- Switch drugs or combine

Third-line of treatment:
- Refer patient to a specialist pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine

Question 18

placebo and complimentary alternative therapies

Answer 18

• placebo activates descending inhibitory pathways

works

Question 19

5 things that cause chronic pain

Answer 19

1. peripheral terminal axon sensitization
2. axon of nociceptors spontaneously firing
3. dorsal root ganglion synthesizing new ion channels
4. central sensitization of dorsal horn/ spinal chord
5. changes in brain activation patterns