L31 & 32 - Pain Control

Question 1

What is pain?

Answer 1

Unpleasant sensory and emotional experience associated with actual or potential tissue damage

Question 2

Chronic pain is defined as pain lasting for x amount of time

Answer 2

More than 3 months

Question 3

Broad groups of pain

Answer 3

1) Defined nociceptive basis e.g. chronic arthritis
2) Well-defined neuropathological basis - e.g. postherpetic neuralgia, phantom limb pain
3) Idiopathic - pathogenesis not well accepted e.g. chronic musculoskeletal pain

Question 4

Nociceptive circuit

Answer 4

1) Noxious stimuli
2) Activation of peripheral termal
3) AP
4) Dorsal horn
5) CNS neurons
6) Brainstem areas, thalamus, cortex -> action
7) Descending modulatory control pathways

Question 5

List 2 thermal receptors

Answer 5

TRPV1/2

Question 6

List a few chemical receptors

Answer 6

ASIC, P2X, P2Y, B1, B2 (bradykinin)

Question 7

Which cortical area is involved in descending modulatory control?

Answer 7

Brainstem

Question 8

Major inhibitory NT in dorsal horn

Answer 8

Gly, GABA, opioids, NA, 5-HT

Question 9

T/F - Inhibitory NT only act presynaptically

Answer 9

F - they act pre and post e.g. miu opioid receptors on both

Question 10

How is presynaptic inhibition mediated?

Answer 10

Inhibition of Ca2+ voltage sensitive channels

e.g. opioid miu receptor, alpha-2 adrenoceptors, cannabanoid CB1 receptor(All are negatively coupled to Ca2+ channels),

Question 11

How is postsynaptic inhibition mediated?

Answer 11

Enhanced Cl- influx and K+ efflux

Question 12

What pharmacological treatments (for acute pain) would you give in mild, moderate, severe pain?

Answer 12

Mild - Paracetamol
Moderate - Paracetamol, oral opioid, NSAID
Severe - Same as mod but increased oral opioid dosage with i.v./s.c. opioid or transdermal fentanyl patch

Question 13

Pharmacological treatment for chronic pain?

Answer 13

Opioid therapy

Question 14

List two naturally occurring opioids and 2 synthetic

Answer 14

Natural - Morphine, Codeine

Synthetic - Fentanyl, Methadone

Question 15

Where are miu opioid Gi found?

Answer 15

Brain, spinal cord, peripheral tissues - acting on primary sensory, local-circuit interneurons and descending inhibitory fibres to inhibit central relaying of nociceptive stimuli

Question 16

In what areas of the brain do opioids induce analgesia in?

Answer 16

Cortex, PAG region, medulla, dorsal horn - enhancing descending inhibition to dorsal horn

Question 17

Morphine actions and side effects? How about its actions in the periphery?

Answer 17

Actions:
Euphoria, Analgesia, Sedative, respiratory depression (due to decreased sensitivity of medullary resp centre to CO2)

SE:
Nausea, miosis, antitussive

Periphery:
GIT (constipation) due to miu receptors on myenteric neurons decreasing ACh release, decreased motility, urinary retention, CV decreases sympathetic tone due to orthostatic hypotension and bradycardia, Histamine from mast cells = vasodilation, bronchoconstriction, itching

Question 18

What does morphine tolerance affect and doesn’t affect (in terms of its actions and side effects)?

Answer 18

Affects euphoria, analgesia, sedative, resp dep, nausea

NOT constipation, miosis

Question 19

Nalaxone - what is it? Treats? metabolism?

Answer 19

Opioid Antag that has affinity for ALL opioid R
Treats overdose and induces withdrawal
Metabolised rapidly with half life of 1 hour so given i.v

Question 20

For chronic pain, opioid therapy only works in _ of patients and decreases pain by up to __

Answer 20

1/3, 50%

Question 21

Does neuropathic pain have poor or good response to opioids?

Answer 21

Poor

Question 22

Mechanisms of neuropathic pain

Answer 22

• Inflammatory cytokines from macrophages and schwann cells and loss of support from neurotrophic factors
• Nav1.3 channels (not normally detectable) are up-regulated - more AP = more cytokines

Question 23

What happens during withdrawal of peripheral trophic support?

Answer 23

C-fibres lost and Abeta-fibres invade space normally occupied by C-fibre terminals - this results in responding to non-noxious stimuli (A-beta fibres) as noxious (C-fibres)

Excitotoxic loss of inhibitory neurons in dorsal horn -> loss of inhibition -> heightened pain sensitivity

Question 24

Subunits of Voltage-gated Ca2+ channel pore

Answer 24

4 subunits
alpha 1 = 4 homologous domains, with 6 TM segments = the pore forming subunit

alpha 2 delta = ANCILLARY subunit - extracellular modulator function

Question 25

How many genes encode a1 subunits?

Answer 25

10

Question 26

Alpha 2 delta protein is present on all Ca2+ channels?

Answer 26

No - not in periphery

Question 27

What does alpha2 delta protein do?

Answer 27

Increasing inactivation time for Ca2+ hence increasing Ca2+ opening time

Question 28

Gabapentinoids

Answer 28

Gabapentin and Pregablin

• Mimics GABA action but not at GABA R
• Binds to a2d subunit

Question 29

Gabapentin and pregabalin - which is more potent, faster onset of action and more predictable oral bioavailability

Answer 29

Pregablin

Question 30

Bioavailability of Pregabalin

Answer 30

90% - no-liver metab, metab in kidney, non-saturable absorption

Question 31

Synergistic effects - using low doses of gabapetin and morphine TOGETHER is more effective than using each by itself

Answer 31

Synergistic effects - using low doses of gabapetin and morphine TOGETHER is more effective than using each by itself