Physiology of pain 2

Question 1

Acute pain

Answer 1

<3 months

Inflammatory (and nocioceptive)
- due to tissue injury or inflammation

e.g. following surgery, musculoskeletal injury, burn

Question 2

Chronic pain

Answer 2

> 3 months

Affects 20-50% population

e.g. chronic back pain, cancer, carpal tunnel syndrome, arthritis, fibromyalgia, diabetes, migraine, post surgery, multiple sclerosis

Due to injury to nervous system

Question 3

Peripheral sensitisation

Answer 3

Major mechanism of acute pain

Leads to pain hypersensitivity

Question 4

Acute pain treatments sites of action

Answer 4

PNS (site of injury)

CNS

Both

Question 5

Local anaesthetics

Answer 5

e. g. lidocaine, lignocaine
- topically applied to skin

Mechanism of action
- sodium channel blockers

Question 6

Topical capsaicin treatment

Answer 6

TRPV1 channel agonist

Mechanism of action

• depletes substance P
• causes peripheral terminal to die back

Question 7

Non-steroidal anti-inflammatory drugs

Answer 7

e.g. aspirin, ibuprofen

Mechanism of action

• reduces the inflammatory response by inhibiting prostaglandin synthesis
• prevents peripheral sensitisation

Cyclooxygenase inhibited ->
Prostaglandin synthesis reduced ->
Prevents decrease in Na+ channel threshold

Question 8

Paracetamol/ acetominophen

Answer 8

Not NSAID

Mechanism of action

• inhibits cyclooxygenase enzymes
• acts on descending serotonergic pathways

Question 9

Opioids

Answer 9

e.g. morphine, codeine, tramadol

Most effective pain relief but numerous side effects

Mechanisms of action

• agonists of the endogenous opioid system
• multiple sites of action (brainstem, spinal cord, peripheral)

Question 10

Gate control theory

Answer 10

Modulation of pain at the spinal cord level

Pain evoked by nocioceptors can be reduced by simultaneous activation of low threshold mechanoreceptors

Rubbing/ blowing on the painful area can reduce the pain sensation

Stimulation of Aβ fibres in vicinity of injury activates interneurones in dorsal horn which inhibits spinothalamic neurones

Question 11

Neuropathic pain mechanisms

Answer 11

Mechanisms are complex and involve both peripheral and central nervous systems

Question 12

Spontaneous firing of nocioceptors

Answer 12

Following a peripheral nerve injury increase in axonal firing at the site of injury

Due to accumulation of ion channels at regenerating tip of axon

Responsible for spontaneous pain

Underlies central neuropathic pain mechanisms

Question 13

Main peripheral mechanisms

Answer 13

Peripheral sensitisation

Spontaneous firing of nocioceptors

Question 14

Central mechanisms

Answer 14

Central sensitisation
- with spinal cord

Changes in activation patterns/ cortical remapping
- within brain

Question 15

Central sensitisation

Answer 15

Increase in the responsiveness of nocioceptive neurones within the CNS

Normal inputs begin to produce abnormal responses

Due to reduced threshold for activation of 2nd order neurones

Question 16

Reduced threshold for activation

Answer 16

Constant firing of axons from the periphery (following injury)

Sustained release of glutamate

Prolonged depolarisation of the postsynaptic membrane

Massive influx of Ca2+ through NMDA receptors

Activation of kianses

Phosphorylation of NDMA/ AMPA receptors

Channel protein synthesis

Alters kinetics of channels and causes insertion of more channels

Question 17

Central hyperalgesia mechanism

Answer 17

Following central sensitisation

Activation of nocioceptors results in amplified spinal cord activation

Question 18

Central allodynia mechanism

Answer 18

Non-noxious Aβ fibres also synapse onto 2nd order spinothalamic neurones (normally non-functional)

Following central sensitisation

Non- noxious afferents activate sensitised 2nd order neurones

Question 19

Altered synaptic connections

Answer 19

Aβ fibres form new sprouts that synapse onto spinothalamic tract neurones

Question 20

Loss of inhibitory interneurones

Answer 20

e.g. GABA and glycine

Question 21

Chronic pain treatments

Answer 21

Difficult to treat

Acute pain treatments do not work

Good individual patient management is critical

Important to manage primary condition and other associated symptoms

• depression
• sleep disturbances
• fatigue

Question 22

Current treatments for chronic pain

Answer 22

Drugs

• tricyclic antidepressants
• anticonvulsants
• NMDA antagonists

Physiotherapy

Psychological therapies

Surgery

Question 23

Tricyclic antidepressants

Answer 23

e.g. amitriptyline

Mechanism of actions

• unclear
• act on descending inhibitory pathways
• inhibits reuptake of serotonin

Question 24

Anticonvulsants

Answer 24

Pregabalin/ gabapentin, carbamazepine

Mechanism of action

• unclear
• act in spinal cord to reduce excitability
• blocks calcium and sodium channels

Question 25

Pregabalin/ gabapentin

Answer 25

Do not act on GABAergic interneurones Blocks presynaptic voltage gated Ca2+ channels Prevents release of glutamate from nocioceptors

Question 26

NMDA antagonists

Answer 26

Ketamine Mechanism of action - NMDA receptor antagonist - prevents depolarisation of second order neurone - adverse side effects

Question 27

NICE guideline neuropathic pain

Answer 27

First line - amitriptyline or pregabalin Second line - switch drugs or combine Third line - refer to specialist pain serve and consider oral tramadol or in combination with second line consider topical lidocaine

Question 28

Placebo effect

Answer 28

Placebo analgesia has been demonstrated for the treatment of neuropathic pain Due to activation of descending inhibitory pathways

Question 29

What's gone wrong in chronic pain?

Answer 29

Peripheral terminals - peripheral sensitisation Axon - spontaneous firing of nocioceptors Dorsal root ganglia - synthesis of new ion channels Dorsal horn/ spinal cord - central sensitisation Brain - changes in brain activation patterns