W4: Control Of Pain

Question 1

What is pain?

Answer 1

Subjective element produced by the stimulation of nociceptic neurones in the periphery.

Question 2

What is neuropathic pain?

Answer 2

Damage to neurones in nociceptive pathways.

Question 3

What are analgesics?

Answer 3

Drugs that relieve pain, e.g., opioids, NSAIDS

Question 4

Where do opioids act?

Answer 4

On opioid receptors

Question 5

Examples of endogenous opioids

Answer 5

Enkephalins

Question 6

What are opioids used for?

Answer 6

Treating moderate to severe pain, e.g., post-operation

Question 7

How are different opioids given?

Answer 7

Strong agonists are usually given parenterally (by injection):

• morphine can be given orally for chronic pain but usually by injection
• pethidine by injection for acute pain like after childbirth
• fentanyl given in patches for chronic pain states

Question 8

Agonists of morphine (therapeutic opioids)

Answer 8

Heroin (strong), codeine (weak)

Question 9

Antagonists of morphine (therapeutic opioids)

Answer 9

Naloxone

Question 10

Synthetic opioid agonists

Answer 10

Pethidine, fentanyl, methadone

Question 11

Synthetic opioid partial agonists

Answer 11

Buprenorphine

Question 12

What can be given to treat headaches?

Answer 12

Mild pain so weak agonists like codeine given orally

Question 13

What can be given to treat inflammatory pain?

Answer 13

Combine codeine with NSAIDS

Question 14

Where can opioids act?

Answer 14

At receptors at different sites: spinal cord, brainstem, periphery

Question 15

Describe the site of action of opioids at the spinal cord

Answer 15

Dorsal horn: opioids inhibit (decrease) synaptic transmission at the synapse between the spinach sensory afferent (nociceptive neurone) and the second order neurone that will travel up the spinothalamic tract to the thalamus, by binding to receptors presynaptically and postsynaptically

Question 16

Describe the site of action of opioids in the brainstem

Answer 16

• acts in the Periacqueductal Grey (PAG) and then Rostro-ventral medulla (RVM) (in brainstem)
• opioids increase activity of inhibitory pathways (down the spinal cord) onto the dorsal horn, enhancing the inhibition of nociceptic transmission
• they act via the PAG, increasing activity of RVM, which sends inhibitory signals to the dorsal horn, reducing the nociceptive signals of pain.

Question 17

Describe the site of action of opioids in the periphery

Answer 17

• opioids reduce excitability of nociceptive neurones in the periphery
• stimulation of opioid receptors in the terminals of nociceptive neurones means they are less likely to generate APs, due to inhibition brought about by opioid drugs.

Question 18

How do opioids affect mood?

Answer 18

Psychogenic element of pain is due to the activity of the limbic system, impacting nociceptive pathways. Opioids affect limbic system. Can cause addiction.

Question 19

What opioid receptors are there?

Answer 19

mew, delta, k

Question 20

What type of receptors are opioid receptors?

Answer 20

G protein coupled receptors

Question 21

Describe the mechanism of action at opioid receptors upon agonist binding

Answer 21

G protein activation leads to modulation of ion channels (direct)
- increased opening of K+ channels leading to hyperpolarisation of neurones, making them less excitable and thus inhibited
- decreased opening of Ca2+ channels leading to decreased release of transmitter at the synapse
Inhibition of adenylyl cyclase leading to a decrease in cAMP

Question 22

Functional effects of opioids at mew receptors

Answer 22

Analgesia (all sites), euphoria (in the eye to cause pupil constriction), miosis, respiratory depression, physical dependence

Question 23

Functional effects of opioids at delta receptors

Answer 23

Analgesia (spinal)

Question 24

Functional effects of opioids at k receptors

Answer 24

Analgesia (peripheral), miosis, sedation, dysphasia (altered mood and anxiety)

Question 25

What are functional effects of opioids at all receptors?

Answer 25

Constrict smooth muscle (GIT, bronchi), nausea/vomiting, constipation

Question 26

What are the problems with opioid use?

Answer 26

Hyperalgesia with prolonged use Tolerance Dependence

Question 27

Describe the issue of hyperalgesia with opioid use

Answer 27

Pain sensitisation due to the pain pathways expressing more receptors to allow transmission

Question 28

Describe tolerance due to opioid use

Answer 28

Increased dose needed to maintain the effect due to desensitisation of receptors. Little tolerance to GIT and pupil effects, so patients will get more and more constipated with constricted pupils.

Question 29

Describe dependence due to opioid use

Answer 29

Due to increased expression of adenylyl cyclase - causing over-activity of signalling when drug is removed. Physically causes nausea, diarrhoea, restlessness, fever, piloerection - withdrawal symptoms Psychologically causes craving

Question 30

What is the action of NSAIDs?

Answer 30

Action via inhibition of production of prostaglandins (which are released in high amounts during inflammation)

Question 31

How do NSAIDs have analgesic effects?

Answer 31

- PGs sensitive nociceptive nerve terminals to inflammatory mediators (e.g., bradykinin which binds to nerve terminals and sets up APs) - inflammatory pain: toothache, dysmenorrhoea, bone metastases - PGs cause cerebral vasodilation = headache

Question 32

How do NSAIDs have anti-inflammatory effects?

Answer 32

Since PGs cause vasodilation. | NB NSAIDs don’t prevent tissue damage (caused in chronic inflammation)

Question 33

How do NSAIDS have antipyretic effects?

Answer 33

Antipyretic = to reduce fever | - inflammation leads to increased PGs, affecting the hypothalamus, leading to increased temperature set-point = fever

Question 34

What are the main classes of NSAIDS

Answer 34

``` Salicylates (aspirin) Proprionic acids (ibuprofen) ```

Question 35

What is the mechanism of action of NSAIDs?

Answer 35

Suppresses PG production | Inhibits cyclo-oxygenase (COX)

Question 36

What does COX do?

Answer 36

COX catalysed arachidonic acid (rate limiting step in the production of PGs)

Question 37

What is the difference between COX-1 and COX-2?

Answer 37

COX-1: constitutive (homeostasis) - able to regulate blood vessel diameter, controlling blood flow COX-2: induced by inflammation

Question 38

What are the differential actions on COX?

Answer 38

Aspirin has irreversible effects on COX-1 and 2 Ibuprofen has a competitive effect on COX-1 and 2 Celecoxib has selective effects on COX-2

Question 39

Describe paracetamol

Answer 39

May affect another subtype of COX but is not an NSAID. Little anti-inflammatory action but is good for pain relief (action in CNS)

Question 40

How do NSAIDS cause gastric mucosal damage?

Answer 40

- PGs (via COX-1) stimulate mucous release, protecting the mucosa and stomach lining - so NSAIDS are direct irritants - NSAIDS allow exposure of the mucosal lining and damage due to the drug and HCl in stomach - causes inflammation, bleeding, ulceration

Question 41

What conditions can cause neuropathic pain?

Answer 41

Trigeminal neuralgia, diabetic neuropathy, postherpetic neuralgia