Pharmacology of Pain: Opioids

Question 1

what are the 4 stages in treating chronic pain?

Answer 1

1. on diagnosis, OTC pain meds
2. NSAIDs, psychological therapy, nerve blocks
3. then opioids, neurolysis, thermal procedures
4. neurostimulation, implantable surgical intervention, neuroablation

Question 2

how do opioids work?

Answer 2

• they decrease the signal conduction from the spinal cord to the brain
• prevent the signal from reaching the spinal cord i.e. CNS

Question 3

what class of opioids are morphine and codeine?

Answer 3

naturally occurring compounds

Question 4

what is the opioid system made up of?

Answer 4

opioid receptors and endogenous ligands

Question 5

where does morphine act in the nervous system?

Answer 5

1. on nociceptors
2. on the spinal cord
3. on the supraspinal sites i.e. area above the spinal cord
4. on the limbic system - the part of the brain dealing with emotions and memories.

Question 6

what makes up the limbic system?

Answer 6

1. HYPOTHALAMUS - for producing hormones to control water levels (ADH), sleeping cycles, body temp
2. THALAMUS - for thinking and movement and our senses
3. CINGULATE GYRUS - for transmitting signals between inner and outer parts of the limbic system
4. AMYGDALA - for storing memories
5. HIPPOCAMPUS - for creating new memories about past experiences
6. BASAL GANGLIA - works as a gating area to decide whether or not to carry out a movement.

Question 7

where are opioid receptors commonly found?

Answer 7

1. CNS - cortex, thalamus, spinal cord, periaqueductal gray
2. peripheral neurons
3. inflamed tissue
4. immune cells
5. respiratory and GI tract

Question 8

what are the pharmacological effects of opioids?

Answer 8

1. sedation and anxiolysis
2. depression of respiration
3. cough suppression
4. pupillary constriction
5. nausea and vomiting
6. GI symptoms i.e. constipations
7. can affect immune function
8. can cause allergic reactions i.e. bronchoconstrictions

Question 9

what is the mechanism of opioid action?

Answer 9

1. activated peripheral nociceptive fibres releases substance P and other pain neurotransmitters from nerve terminals in the dorsal horn.
2. this is regulated by endogenous endorphins or by exogenous opioid agonists which act presynaptically to inhibit substance P release - causing analgesia.
3. this reduces and inhibits neurotransmission of pain signal
4. this works by affecting ion transmembrane conductance mainly potassium and calcium channels.

Question 10

what intracellular changes occur following the binding of the opioid agonist to the G-protein coupled opioid receptor?

Answer 10

1. the opioid agonist binds to the receptor which causes the dissociation of the alpha unit from the beta-gamma unit
2. this inhibits cAMP formation from ATP + adenylate cyclase
3. also inhibits Ca2+ influx and K+ efflux.
4. resulting in cell hyper polarisation i.e. cell not in resting state.

Question 11

what type of pain are opioids good for?

Answer 11

acute and postoperative pain and cancer pain

Question 12

what type of pain are opioids less effective in?

Answer 12

chronic non-cancer pain and neuropathic pain

Question 13

when do opioids become addictive?

Answer 13

when repeatedly used due to their rewarding effects

Question 14

common side effects of opioids are…?

Answer 14

1. drowsiness
2. dizziness
3. nausea
4. constipation
5. itching
6. breathing slows down

Question 15

what happens when someone becomes tolerant to an opioid?

Answer 15

-they become tolerant to its analgesic effect leading to increased doses

Question 16

what is the ‘within’ process of opioid tolerance?

Answer 16

administered drug causes an opposing reaction within the same system - this desensitises opioid receptors.

Question 17

what is the ‘between’ process of opioid tolerance?

Answer 17

administered drug recruits neuronal circuits to oppose the primary effect of opioids by activating pronociceptors, after opioid administration, which then counteracts opioid analgesia i.e. by engaging NMDA receptors

Question 18

how does the NMDA receptor work?

Answer 18

• activated when glutamate and Glycine bind to it
• this allows Ca2+ ions into the postsynaptic neurone
• glutamate works as the neurotransmitter from the presynaptic neurone to activate the postsynaptic one.
• Ca2+ influx causes depolarisation in the cell hence pain signal transmission.
• works to increase morphine tolerance to reduce its analgesic effects

Question 19

what is the effect on Mg2+ and NMDA following the influx of Ca2+ after MOR activation from morphine?

Answer 19

Mg2+ is removed from blocking the NMDA receptor contributing to morphine tolerance

Question 20

how do NMDA receptor antagonists work?

Answer 20

prevent or reverse morphine tolerance by decreasing the activation of the pronociceptive processes triggered by opioids.

Question 21

what is opioid induced hyperalgesia?

Answer 21

An enhanced pain response to a noxious stimulus.

Question 22

what are the opposite effects experienced when one becomes too dependent of opioids?

Answer 22

1. restlessness
2. sleep disturbance
3. hypesthesia
4. neuralgia
5. irritability

Question 23

what causes opioid induced hyperalgesia (OIH)?

Answer 23

when opioid administration is abruptly terminated or reversed by giving an opioid antagonist e.g. naloxone

Question 24

what are the 5 proposed mechanisms of how opioid induced hyperalgesia (OIH) occurs?

Answer 24

1. The central glutamatergic system (NMDA, CRGP, sub P),
2. Spinal dynorphins (with CCK),
3. Descending facilitation (from RVM, on and off cells),
4. Genetic mechanisms (genetic polimorphism; 500 genes!),
5. Decreased re-uptake of neurotransmitters from the primary afferents.

Question 25

which of the 5 proposed mechanisms of how opioid induced hyperalgesia (OIH) occurs is the most common possibility?

Answer 25

the central glutamatergic system

Question 26

what can be given to prevent or reduce OIH?

Answer 26

ketamine