Pain

Question 1

on what basis are opioids classified?

Answer 1

their actions are reversed by the opioid receptor antagonist naloxone

Question 2

what type of pain are opioids used for? when are they not effective?

Answer 2

they’re used for mild - severe pain

but they cannot be used for neuropathic pain

Question 3

what is spinal analgesia?

which opiate receptors are used?

Answer 3

spinal analgesia involves the the MU and delta opioid receptors.

opioid receptors are inhibitory- most of them are pre-synaptic:

• prevent neurotransmitter release at the C fibre nerve terminals
• they do this by opening potassium channels

the remaining post-synaptic receptors:

• prevent the generation of an AP by
• hyperporalsing dendrites of projection neurones, and interneurones and disinhibiting inhibitory neurones

Question 4

why is complete C fibre inhibition not possible when nerve damage is associated?

Answer 4

in nerve damage:

• there is excessive NMDA firing, which is hard to inhibit
• CCK is immobilised in the spinal cord, which interferes with opiate action

pre-emptive analgesia, aid in the reduction of post operative pain by preventing the activations of these systems

Question 5

what is supraspinal analgesia?

Answer 5

those involve nuclei in the brainstem and mid-brain
e.g.
locus corelus - producing noradrenaline
raphe nuclei - producing 5HT
periaqueductal grey - producing encephalin

those nuclei have opiate receptors, and thus they alter activity of the descending pathways from these zones to the level of the spinal cord

mechanism of action not known:

• blur pain sensation?
• turn off spinal cord transmission of pain?

Question 6

list some of the drugs used in neuropathic pain

Answer 6

amitriptyline - used to inhibit Na and 5HT re-uptale
-actually an anti-depressant

gabapetine- calcium channel blocker (an anti -epileptic drug)

phenytoin and carbamazepine (used to stabilise membrane potential)
lidocaine (LA - used to stabilise membrane potential)

Question 7

what are the CNS affects of opiates?

Answer 7

reduced sensitivity to PCo2 causes respiratory depression (most common cause of death)
activation of chemoreceptor trigger zone: causing nausea and vomitting

inhibition of reflex pathways due to opiate inhibition of brainstem nuclei: causes cough suppression

Question 8

why does the use of opiate raise fear of addiction? why is that not the case?

Answer 8

opioids raise dopamine levels in the ventral tegmentum
they also raise noradrenaline levels and transmission in the locus coreulus

both sites are involved with the reward and dependance processes - but dependance does not occur in cases of pain

Question 9

what is the difference between the Mu opioid receptors and the kappa/delta receptors!

Answer 9

kappa and delta - they’re associated with less respiratory depression
kappa no danger of dependance, but accompanied by aversion and non-rewards side-effects

Question 10

what are the peripheral affects of opiates?

Answer 10

• constriction of GI smooth muscle causes constipation
• constriction of pupils, because they act on the oculmotor nucleus
• diminished propulsion coupled with their lack of secretion, causes an anti-dirroheal effect
• constricts all sphincters within the GI tract
• morphine can cause histamine release from mast cells (leading to bronchospasm and irritation, but only at very high concentrations)
• at therapeutic dosages, the opiate agonists do not have cardiovascular effect)

Question 11

which receptor do all clinically significant opioid agonists work on?
give the name of three agonists?

what is the exception?

Answer 11

all significant ones act on Mu receptors

• codeine (weak opiate, orally effective)
• methadone (long duration, orally effective)
• fentanyl (very potent, short duration)

exception: pentazocine which acts on a kappa receptor

Question 12

how do heroine and tramdol produce analgesia?

Answer 12

herione:

• very lipophilic, crosses the blood brain barrier
• in brain is metabolised to morphine
• acts on MU receptors

tramadol:

• only weak opiate actions
• prevents the reuptake of 5HT and NA
• thus producing analgesia

Question 13

what is nalaxone? when is it used?

Answer 13

naloxone is a competitive antagonist at all three opioid receptors, but with the highest affinity to the mu receptor

used in cases of overdose, in particular to reverse respiratory depression.
antagonists used to probe the function of the opioid receptors

Question 14

what role does inflammation play in peripheral sensitisation

Answer 14

inflammation causes the release of many mediators
prostaglandins - from membrane
bradykinin - from vasculature
5HT release

those act on C fibre nerve terminals at high concentration, activating the C fibres

they lower the threshold stimulus of nociceptors, so that they respond to lower stimulus

Question 15

how is pain associated with inflammation treated, mainly?

Answer 15

using NSAIDs - those block prostanglandin production, but this has major affect in the GI system

cyclooxygenase inhibitors can also be used, with less marked GI side effects?

Question 16

what are triptans?

Answer 16

they’re selective 5HT1 (B/D) agonists - and they’re used in the treatment of migraines. those probably cause vasoconstriction of cerebral vessels which are abnormally dilated during a migraine attack

ergotamine is an ergot alkaloid which can be used in the treatment of an acute migraine attack

Question 17

what is the difference between nociceptive and neuropathic pain?

Answer 17

nociceptive pain is due to inflammation triggered by tissue damage

neuropathic pain is due to nerve damage, it is a sensory disorder, it is characterised by negative and positive symptoms
e.g. abnormal/evoked sensation
negative symptoms: loss of sensation

Question 18

what are the changes in the peripheral nervous system associated with neuropathic pain?
(3 main changes)

Answer 18

1. ecotopic beats within DRG or neuroma (contributes to allodynia
2. re-organisation at the termination of Aa fibres in the spinal cord, meaning low threshold stimulu (that are not pain) gain entry into the nociceptive spinal pathways
3. some peptides are deleted, while other transmitter peptides are novally expressed

Question 19

what is the classical component seen in areas of nerve damage?

how are drugs targetted at this feature

Answer 19

clustering of sodium channels at nerve terminals, this contributes to:

• ecotopic beats
• this is further enhanced by sympathetic nerve stimulation

drugs:

• phenytoin and carbamazepine (anti-convulsants)
• LA
• drugs that act on the sympathetic nervous system

Question 20

what are the role of AMPA receptors in pain?

Answer 20

they’re activated in spinal neurones, by fast excitatory amino acids
they set the baseline threshold for response of the spinal neruones,
they’re activated by noxious and innocus stimulus

Question 21

what are the role NMDA receptors in pain?

Answer 21

they’re activated by peptides (because they cause slow depolarisation)

they’re involved in amplification and prolongation of baseline threshold of spinal neurones
they’re required for induction and maintenance of neuropathic nerve states