5.1: Neural Basis of Pain and Analgesia

Question 1

Define Nociception and Pain

What is the relationship between these?

Answer 1

Nociception: non-conscious neural traffic in response to (potential) trauma.

Pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Nociception leads to pain BUT pain isn’t only nociception

Question 2

How can pain be good and bad?

Answer 2

Pain can be good: stops us from hurting ourself (eg. putting hand on something hot)

Pain is bad because it is unpleasant to live with (eg. chronic pain can be extremely debilitating)

Question 3

List 4 other factors, in additon to nociception, that can lead to pain

Answer 3

1) Cognitive set: attention, distraction, catastrophising
2) Mood: depression, anxiety
3) Context: pain beliefs, placebo, expectation
4) Chemical and structure: neurodegeration, metabolic

Question 4

Which gender and age group is most commonly affected by chronic pain?

Answer 4

Women and elderly

Question 5

List 3 things chronic pain is associated with

Answer 5

1) increased mortality
2) worsening mental health
3) social deprivation

Question 6

What parts of the brain are responsible for the following?

a) perception of pain
b) fear
c) memories
d) planning and reaction

Answer 6

a) somatosensory cortex
b) amygdala
c) hippocampus
d) prefrontal cortex

Question 7

What type of nerves are pain nociceptors?

Give 3 stimuli they are sensitive to

Answer 7

They are free nerve endings

Sensitive to mechanical, thermal and/or chemical stimulation

Question 8

What kind of channels do pain nociceptors contain?

Name five factors that may potentially trigger these channels

Answer 8

TRP channels- cation channels (resemble voltage gated K+ channels but more unspecific)

Triggered by:

1. Inflammation
2. Injury
3. Injury to CNS
4. Nerve invasion (i.e cancer)
5. Abnormal activity (i.e chronic regional pain syndrome)

Question 9

What is complex regional pain syndrome (CRPS)

Answer 9

A condition that causes severe pain which won’t go away

Eg. a minor injury such as a sprained ankle, where pain persists even after the injury has healed. This is because of abnormal healing processes

Question 10

What are the spinothalamic tracts responsible for?

Answer 10

Pain, temperature and crude touch

Question 11

Define the sensation of crude touch

Answer 11

Being able to sense the feeling of touch without being able to localize where you were touched

Question 12

What 2 fibre types transmit pain?

Compare these fibres

Answer 12

Pain is transmitted via Aδ and C fibres

Aδ fibres are myelinated and transmit fast, sharp and well localized pain

C fibres are unmyelinated and transmit slow, diffuse and dull pain

Question 13

Describe the sensation of visceral organ pain and state 2 reasons why

Answer 13

Visceral/organ pain is diffuse and poorly localised

1) Organs have relatively few pain sensors
2) Enter the spinal cord at many levels, leading to potential crossing over of signals. This which is what results in ‘referred pain’

Question 14

Give 3 examples of reffered pain

Answer 14

1) Appendix pain: reffered from peri-umbilical area to RLQ
2) Flank pain from the kidney and/or radiating down the lower abdomen from the ureter
3) MI: pain presents in the upper chest, left arm, neck and lower jaw

Question 15

What theroy describes how the spinal cord modulates pain?

Answer 15

The gate theory of pain: suggests that stimulation of non-nociceptive receptors can inhibit transmission of nociceptive information in the dorsal horn.

Question 16

Explain the Gate theory of pain (use the example of stubbing toe)

Answer 16

1) Painful stimuli (eg. stubbing toe) will stimulate first order nociceptor C fibres and Aδ fibres
2) These will synaps with the second order fibres in the substantia gelatinosa of the dorsal horn and carry the signal to the brain via the spinothalamic tract (perception of pain)
3) If we rub the area, we stimulate touch/pressure fibres
4) The touch pathway neurons activate an inhibitory interneuron which reduces ascending pain signals from the C fibres and Aδ fibres
5) This therefore reduces the sensation of pain

Question 17

Name two ways the CNS can modulate pain

Answer 17

1) Endogenous opioids in brain and spinal cord
2) Central modulation/ descending signals from the brain

Question 18

Explain the mechanism of central modulation of pain

Answer 18

Central modulation of pain involves descending analgesia producing pathways from the brain stem to the spinal cord

1) This starts at the Periaqueductal grey matter (PAG) of the midbrain in the brain stem
2) Passes down through the rostroventromedial medulla (RVM) into the spinal cord
3) As it does this it receives inputs from other areas of the brain (eg hippocampus, PFC, amygdala etc…) as part of regulatory processes
4) These travel down to the dorsal horn where they release Serotonin and NA
5) These NT’s stimulate interneurons to release Enkephalins, beta-endorphins and/or dynorphin which bind to opioid receptors
6) This has an inhibitory affect on the synapses between the first and second order neurones of the nociceptive pathways, thus modulating pain

Question 19

Explain why we encourage patients with chronic pain (ie. Trigeminal neuralgia) to exercise?

Answer 19

Targeting the central modulation of pain! Excersise releases endorphins which can bind to the opioid receptors and help relieve pain

Question 20

Give 3 substances which bind opioid receptors

Give 2 substances which bind non-opioid receptors

Answer 20

Opioid: Enkephalins, beta-endorphins, dynorphin

Non-opioid: Serotonin and noradrenaline

Question 21

Define chronic pain and list 3 influential factors?

Answer 21

Any pain that lasts for more that 3 months past the normal healing time for an injury or disease

Has extensive psychological, social and economical factors

Question 22

List 3 broad catagories that may cause chronic pain and give 2 examples of each

Answer 22

1) Nociceptive/inflammatory

• Osteoarthritis and Rheumatoid arthritis
• Post-op pain

2) Neuropathic

• Trigeminal neuralgia
• Nerve injuries/ neuropathies

3) Idiopathic

• Fibromyalgia
• Irritable bowel disorders

Question 23

List 2 reasons we may have increased sensitisation to pain

Answer 23

1) increased activity of nociceptors
2) lower threshold of nociceptors

Question 24

Hyperalgesia and Allodynia are both examples of sensitisation, define and expalin each of these

Answer 24

Hyperalgesia: Increased pain from a stimulus that normally provokes pain due to an increased response at a normal threshold

• Eg. a stimulus that would normally be perceived as slightly painful is perceived as significantly more so

Allodynia: Pain due to a stimulus that does not normally provoke pain due to increased excitability of neurons in the dorsal horn of the spinal cord (CNS)

• Eg. perception of pain from something that is normally an innocuous stimulus (such as a feather)

Question 25

What is central sensitisation and what does this lead to?

Answer 25

Increased excitability of neurons in the dorsal horn of the spinal cord (CNS) Leads to allodynia: perception of pain from something that is normally an innocuous stimulus

Question 26

Compare nociceptive vs neuropathic pain

Answer 26

Nociceptive pain is pain elicited by an INTACT nervous system * Pain pathways is acting normally, it is an actual stimulus affecting the nerve endings Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. * Can occur anywhere along the pain pathway

Question 27

Why can neuropathic pain be difficult to treat? What 2 things commonly occur alongside neuropathic pain

Answer 27

Cannot be explained by a single disease process or specific location of damage Neuropathic pain commonly occurs alongside hyperalgesia and allodynia

Question 28

Name 4 examples of neuropathic pain

Answer 28

1. cancer 2. phantom limb 3. diabetes (diabetic neuropathy) 4. MS 5. spinal injury 6. postherpetic neuralgia

Question 29

What causes postherpetic neuralgia and what is it?

Answer 29

Most common complication of shingles, it's a condition affecting the nerve fibres on the skin which causes burning and pain lasting long after the shingles have disappeared

Question 30

Name 2 potential causes of neuropathic pain for each of the following locations: a) thalamic/cortical level b) brainstem c) spinal level d) peripheral level

Answer 30

a) Infarctions, tumors, MS b) Infarctions (Wallenberg’s syndrome), tumors, MS c) spinal cord injuries, MS d) diabetic neuropathies, peripheral trauma, plexus avulsion, herpes zoster

Question 31

What is Wallenberg's syndrome?

Answer 31

When an infarction or stroke occurs in the lateral medulla (part of the brainstem)

Question 32

Pathophysiology of neuropathic pain: After a peripheral nerve injury sensitization occurs, give 6 things this can lead to:

Answer 32

1) decreased threshold of the nociceptor to activation 2) Increased receptive field of nociceptors 3) Allodynia and/or Hyperalgesia 4) Prolonged post stimulus sensations – hyperpathia 5) Emergence of spontaneous activity/increased excitability 6) Damaged peripheral nerves can develop abnormal Na+ channels which fire dysfunctionally and demonstrate different depolarisation properties

Question 33

Give 3 symptoms of neuropathic pain

Answer 33

1) Shooting and burning 2) Tingling and numbness 3) Unpredictable

Question 34

Give 2 treatments of neuropathic pain and explain the MoA of these

Answer 34

Amitriptyline: Tricycline which is an antidepressant Duloxetine: NA/ Serotonin re-uptake inhibitor Both of these increase the amount of Serotonin and NA that is available in the dorsal horn. This activates the inhibitory interneurons thus reducing the pain signals sent up the spinothalamic tract (Non-pharmacological treatments must also be considered: eg psychological therapies)

Question 35

Explain the pathophysiology of chronic pain

Answer 35

1) Tissue injury (nociceptive pain) or nerve damage (neuropathic pain) may cause persistent activation of the pain pathway 2) This leads to excess Glutamate release and thus excess excitation of the NMDA receptor 3) This leads to excess activation of 2nd order neurone firing, continued stimulation is known as ‘wind up’ 4) This results in long term changes in the second order nociceptive neurones which become hyper-excitable (respond at lower stimulus intensity)... 'hyperalgesia' 5) Wind up can also lead to receptive field expansion at the peripheral site or allodynia

Question 36

Explain how wind up leads to receptive field expansion at the peripheral site

Answer 36

There is a certain amount of cross-over at the dorsal horn, so there is link between the second order neurones. Normally a first order neurone will predominantly link to one second order neurone. However, with wind up stronger links form between first order neurones synapsing with two or three second order neurones This causes expansion of the receptive field, making the location of pain perceived more diffuse

Question 37

Pain relief is multifactoral, not simply pain reduction Give 4 other considerations we must make when treating pain

Answer 37

Context, cognition, mood, personality

Question 38

Give 5 types of analgesia

Answer 38

1. Paracetamol 2. NSAIDS 3. Opioids 4. Adjuvants 5. Placebo

Question 39

Compare paracetamol vs NSAIDS

Answer 39

Both are COX enzyme inhibitors which block the formation of prostaglandins (trigger pain pathways at nerve endings) and thromboxane from arachidonic acids. Paracetamol: * Main action is in the **CNS** * Has an analgesic and anti-pyretic effect (reduce temperature) NSAIDS: * Main action is in the **PNS** * Has an analgesic, anti-pyretic **AND** anti-inflammatory effect

Question 40

Give 3 examples of an NSAID

Answer 40

Ibuprofen, naproxen and aspirin

Question 41

What is an Adjuvant? Give an example

Answer 41

Adjuvants are drugs that have few or no pharmacological effects by themselves, but may increase the efficacy or potency of other drugs when given at the same time. Eg. patients with arthritis may be given pain relief meds alongside corticosteriods (to reduce inflammation)

Question 42

Give 2 examples of the following analgesia: * Non-opioids * Weak opioids * Strong opioids

Answer 42

Non-opioid: Paracetamol, NSAIDs Weak opioids: Codeine, Tramadol Strong opioids: Morphine, diamorphine, fentanyl, alfentanyl

Question 43

Give 4 examples of an adjuvant Give 4 examples of non-pharmacological analgesia

Answer 43

Adjuvants: Antidepressants, anticonvulsants, steroids, muscle relaxants, bisphosphonates, radiotherapy, nitrous oxide Non-pharmacological: TENS, CBT, meditation, acupuncture, massage, hypnosis

Question 44

Explain how exogenous opioids work as an analgesia

Answer 44

1) Exogenous opioids interact with specific receptors: * μ (mu) * δ (delta) * ƙ (kappa) 2) This has an inhibitory effect on pain pathways 3) It also has an central effect of creating a feeling of euphoria, which helps the patients short-term dealing with pain (this is a side effect)

Question 45

Give 4 side effects of exogenous opioids

Answer 45

Euphoria, sedation, respiratory depression, tolerance, miosis, nausea and vomiting, cough suppression, constipation, dependence, addiction

Question 46

Compare codeine vs morphine Briefly explain how morphine works

Answer 46

Codeine: partial/weak mu-opioid receptor agonist Morphine: full agonist at mu-opioid receptors in the CNS * Binds receptors in CNS involved in transmission and modulation of pain and dampens nerve signals transmitting pain

Question 47

What 'effect' demonstrates the higher brain functions and the complexity of pain in an individual Give 2 examples of studies demostrating this effect

Answer 47

The placebo effect Numerous studies: * Students and stimulants vs sedatives * Alcohol vs non-alcohol * Post-operative pain