7.2 () Pathophysiology of pain in cancer and other terminal illnesses

Question 1

What is the source of nociceptive pain versus neuropathic pain?

Answer 1

Nociceptive pain - activation of sensory afferents

Neuropathic pain - damage to nerves

Question 2

Which afferent sensory fibers carry nociceptive information?

Where do these fibers terminate?

Answer 2

A-delta (thin myelinated) and C fibers (thin unmyelinated)

Lamina I in the dorsal horn of spinal cord

Question 3

Second order neurons (project to the brain) express the receptor for which neurotransmitter

Answer 3

Substance P (aka neurokinin 1)

Question 4

What is the process in which peripheral stimuli is converted to signals carried by nerves to the CNS?

Answer 4

Transduction

Question 5

How does gabapentin and pregabalin work

Answer 5

Bind to alpha-2-delta accessory subunit of calcium channel (thus reducing excessive hyperexcitability)

FS: Calcium channel blocker

Question 6

NMDA receptor is blocked by what ion under normal neuronal activity?

Answer 6

Mg

Question 7

What are 2 main types of bone - where is bone pathology largely evident

Answer 7

Cortical bone - dense outer layer of all bones (80% of all skeletal mass) compact hard bone

Trabecular bone - found in the epiphyseal regions of long bones, greater amount of remodelling, bone pathology is largely evident in bone of this type spongy bone

Question 8

What 2 areas of bone receives the most sensory afferent fibers?

Answer 8

Bone marrow followed by mineralized bone

Question 9

What factor released by cancer increases osteoclast activity

Answer 9

Parathyroid hormone related peptide (PTHrP)

Question 10

What are two mechanisms cancer induce bone pain?

Answer 10

Peripheral mechanisms:
- Factors released in periphery (e.g. cytokines, interleukins, growth factors) which excited or sensitize nociceptive fibers
- Abnormal osteoclast activity which destroys bone and cause pain
- Structural damage to bone

Central mechanism

SS: Central - enhanced 2nd order neuron excitability.
Also higher order cognitive/emotional process can increase pain

Question 11

Name 3 medications and 1 intervention to treat cancer bone pain

Answer 11

Opioids
Gaba
NSAIDs
Bisphosphonates

Radiation

Question 12

How does bisphosphonate work?

Answer 12

Osteoclast inhibition (reduce activity and cause apoptosis) -> prevent bone resorption

Question 13

Chemo and antiretroviral treatment damages what structure in the cell leading to increased development of pain

Answer 13

Mitochondria

Question 14

What happens after nerve injury?

Answer 14

Ion channel dysregulation ->
Peripheral nerves display ectopic discharge ->
increased nociceptive signaling onto dorsal horn transmission neurons without a peripheral stimulus

Other things:
Increased substance P
Decreased inhibitory GABA interneuron
Decreased inhibitory opioid receptor

Question 15

What are 2 ions involved with neuropathy and ion channel dysregulation - name medications that target these ions

Answer 15

Sodium - Lidocaine, Carbamazepine

Calcium - Gabapentin, pregabalin

Question 16

List 4 chemical mediators of pain (also known as algogenic ligands) involved in the transduction of nociceptive stimuli

• signal stimulate first order neurons -

Answer 16

ATP
Adenosine

Bradykinin

Cold

Prostaglandin (key)

5-HT
Heat / capsaicin
H+
Histamine

IL-1

Nerve Growth Factor
Noradrenaline

Question 17

Good YouTube video to watch

Answer 17

https://m.youtube.com/watch?v=uOaiaYDoUnA

Question 18

Good video

Answer 18

https://m.youtube.com/watch?v=5c8maFAhqIc

Question 19

What is the difference in pathophysiology of acute vs chronic pain

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Answer 19

1. Acute pain = pain has overt relationship to identifiable peripheral damage or lesion.
2. Chronic pains = altered neurophysiological and pharmacological substrates from the periphery to CNS, and the relationship between noxious phenomena and the level of pain experienced can become altered.

Question 20

Define plasticity

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Answer 20

1. Plasticity, the ability of the nervous system to alter in response to injury-evoked dysfunction, leads to changes in the perception of pain

(can arise with any type of pain but particularly with chronic neuropathic pains)

Question 21

Explain 1 example of altered neurophysiology in chronic pain

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Answer 21

In some neuropathic conditions with occult sources of injury, pain may be present, or unexpectedly severe, in the absence of a peripheral process (allodynia/hyperalgesia/spont pain)

Question 22

List 1 major difference in the peripheral mechanism of nociceptive vs neuropathic pain

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Answer 22

Neuropathic pain = prominently feature disturbances in ion channels.

(Thus, treatments aimed at the peripheral mechanisms are different for neuropathic pain vs nociceptive)

Question 23

Plasticity in the CNS may lead to symptoms reflecting expanded receptive fields.

1. Give 3 examples of such symptoms
2. The influence of what non-somatic system must be considered as pain becomes chronic?

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Answer 23

1. increased amplitude of response to a given stimulus (HYPERALGESIA)
2. pain elicited by normally innocuous stimuli (ALLODYNIA)
3. SPONTANEOUS pain in the absence of external stimuli.
4. as pain persists, AFFECTIVE and EMOTIONAL responses must be considered along with the sensory aspects of the stimulus. Although the sensory and psychological aspects of pain are separable, their neural pathways are interlinked
   (somatic + limbic systems converge)

Question 24

List 2 mechanisms of peripheral sensitization

Answer 24

1. Neurogenic inflammation - nerve endings release pro-inflammatory compounds themselves –> amplifies peripheral response of nociceptors
2. Changes in ion channels - lowering of the nociceptive threshold in peripheral fibres and how hyperalgesia can result

Question 25

1. Explain central sensitization
2. Describe 1 example of central sensitization - with a specific receptor

Answer 25

1. CNS can amplify the inputs it receives and cause increased pain perception

2.
-At spinal levels, upregulation and enhancement of transmitter release via wind up phenomenon via NMDA receptor. Usually, NMDA receptors are plugged/blocked by Mg.

Prolonged afferent drive —> increased substance P —> release of magnesium –> calcium influx –> potentiation of post-synaptic response (Fig. 7.2.2.)