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Physiology of Analgesia Flashcards

1
Q

which analgesics work by acting at site of injury

A

NSAIDs - decrease sensation in inflammation by blocking prostaglandin synthesis

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2
Q

which analgesics work by suppressing nerve conduction by blocking / inactivating voltage gated sodium channels?

A

local anaesthetics eg lidocaine

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3
Q

which analgesics work by suppressing synaptic transmission of nociceptive signals in dorsal horn of spinal cord?

A

opioids and some anti-depressant drugs

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4
Q

what analgesics work by activating (or potentiating) descending inhibitory controls?

A

opioids

select tricyclic antidepressants

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5
Q

what analgesics work by targeting ion channels upregulated in nerve damage?

A

antiepileptics of several types such as GABA pentinoids

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6
Q

what is the WHO analgesic ladder?

A

1) paracetamol
2) NSAIDs (aspirin, diclofenac, ibuprofen, indometacin, naproxen)
3) weak opioid (codeine, tramadol, dextropropoxyphene)
4) strong opioid (morphine, oxycodone, hydromorphone, heroin, fentanyl)

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7
Q

combinations of which opioids are often used in moderate / severe pain?

A

1 + 2 (paracetamol and NSAIDs)

or

1 + 3 (paracetamol and weak opioid)

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8
Q

what mediates supraspinal anti-nociception?

A

descending pathways from brainstem

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9
Q

what regions of brain are involved in pain perception and emotion?

A

cortex, amygdala, thalamus, hypothalamus

these regions project to specific brainstem nuclei

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10
Q

what do the neurones of brainstem nuclei give rise to in the descending pathway?

A

efferent pathways that project to spinal cord to modify afferent input

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11
Q

what are three important brainstem regions in the regulation of pain?

A

the periaqueductal grey (midbrain)

locus ceruleus (pons)

nucleus raphe magnus (medulla)

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12
Q

what do endogenous opioids (enkephalins) or morphine cause excitation of?

A

PAG

they do this by the disinhibition or GABAergic interneurones

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13
Q

what areas of the brainstem do activated PAG neurones project to via the dorsolateral funiculus (DLF)?

A

nucleus raphe magnus

locus ceruleus (pons)

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14
Q

what does the NRM excite after coming in contact with PAG axons?

A

serotonin (5-HT)

enkephalins

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15
Q

what does the action of opioids on NRM and LC result in?

A

inhibition of nociceptive transmission in dorsal horn of spinal cord

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16
Q

opioid action is mediated by GPCR all of which signal to Gi/o to produce what three things?

A

1) inhibition of opening of Ca channels (presynaptic effect) which suppresses excitatory release from nociceptor terminals
2) opening of K+ channels (postsynaptic) which suppresses excitation of projection neurones
3) inhibition of adenylate cyclase

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17
Q

what subunit mediates the inhibition of Ca2+ channels and the opening of K+ channels?

A

Gi/oβγ subunit

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18
Q

which subunit mediates the inhibition of adenylate cyclase?

A

Gi/oα subunit

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19
Q

what opioid receptors are responsible for most of the analgesic action of opioids but also some major adverse effects?

A

μ (mu, aka MOP*)

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20
Q

what opioid receptors contribute to analgesia but activation can be proconvulsant?

A

δ (delta, aka DOP*)

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21
Q

what opioid receptors contribute to analgesia at spinal and peripheral level and activation is associated with sedation, dysphoria and hallucinations?

A

κ (kappa, aka KOP*)

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22
Q

what is a major respiratory effect of opioids?

A

apnoea

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23
Q

what is the mechanism behind opioids causing this respiratory affect?

A

blunting of medullary respiratory centre to CO2

this causes hypercapnic response; pain opposes this but natural sleep is synergistic

involves μ and δ receptors

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24
Q

what is a major cardiovascular effect of opioids?

A

orthostatic hypotension

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25
Q

what is the mechanism behind opioids causing this cardiovascular affect?

A

reduced sympathetic tone and bradycardia (via actions on medulla)

histamine-evoked vasodilation

morphine, but not all opioids cause mast cell degranulation which can trigger bronchospasm in asthmatics

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26
Q

what are major gastrointestinal effects of opioids?

A

nausea
vomiting
constipation
increased intrabilliary pressure

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27
Q

what is the mechanism behind opioids causing these GI effects?

A

action on CTZ (outside the BBB)

increased smooth muscle tone,
decreased motility, via enteric neurones - involves μ- and δ-receptors

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28
Q

what are major CNS effects of opioids?

A 
confusion 
euphoria 
dysphoria 
hallucinations 
dizziness 
myoclonus 
hyperalgesia (with excess use)
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29
Q

what is the mechanism behind opioids causing these CNS effects?

A

occurs to different degrees dependent upon the specific opioid drug and receptor subtypes activated

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30
Q

which opioids work in an agonistic fashion by prolonged activation of u-opioid receptors?

A 
morphine 
diamorphine 
codeine 
fentanyl 
pethidine 
buprenophine 
tramadol 
methadone 
etorphine
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31
Q

how is morphine metabolised and excreted?

A

metabolised in liver by glucuronidation at the 3 and 6 positions yielding M3G that is inactive and M6G that retains analgesic activity

excreted by kidney

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32
Q

how many morphine be administered?

A

IV - acute severe pain

IM, SC or oral - general wards

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33
Q

what administration method is most appropriate in chronic pain?

A

oral

either as immediate (oramorph) or sustained release (MST continus)

34
Q

what is the difference between diamorphine (3,6-diacetylmorphine, heroin) and morphine?

A

diamorphine is more lipophillic

35
Q

diamorphine has a rapid onset of action when administered what way?

A

IV (enters CNS rapidly)

36
Q

when is diamorphine used?

A

for severe post-operative pain (but it is banned in some countries)

37
Q

what is codeine (3-methoxymorphine)

A

a naturally occurring weaker opioid for mild / moderate pain

38
Q

how is codeine metabolised?

A

hepatic metabolism by demethylation to morphine by CYP2D6 and CYP3A4

39
Q

how is codeine administered?

A

orally

40
Q

what other affect other than analgesia does codeine have?

A

anti-diarrhoeal and antitussive

41
Q

what are the semi-synthetic derivatives of codeine which have higher potency?

A

oxycodone and hydrocodone

42
Q

how much more potent is fentanyl than morphine?

A

75-100 fold

43
Q

how is fentanyl administered?

A

IV to provide analgesia in maintenance anaesthesia

transdermal (and buccal) delivery in chronic pain states but not acute

44
Q

when is pethidine used?

A

in acute pain, particularly labour

45
Q

how is pethidine administered?

A

rapid onset when given IV, IM or SC but has short duration so not suitable for chronic pain

46
Q

why must pethidine not be used in conjunction with MAO inhibitors?

A

this combination would cause excitement, convulsions and hyperthermia

47
Q

phenylpiperidine is a class of opioid which contains what?

A

fentanyl

pethidine

48
Q

what is norpethidine?

A

neurotoxic metabolite (seizures)

49
Q

when is buprenophine (partial agonist) useful?

A

chronic pain with patient-controlled injections

has slow onset but long duration

50
Q

how is buprenophine administered?

A

injection or sublingually

51
Q

how does tramadol work?

A

weak u-receptor agonist, probably exerts significant analgesic action by potentiation of descending serotonergic (from NRM) and adrenergic (from LC) systems

52
Q

how is tramadol administered?

A

orally

53
Q

when should tramadol be avoided?

A

patients with epilepsy

54
Q

how does methadone work?

A

weak u-agonist of the phenylheptylamine class with additional actions at other sides in CNS, including potassium channels, NMDA glutamate receptors and some 5-HT receptors

55
Q

how is methadone administered?

A

orally, long term of action

56
Q

when can methadone be used?

A

treating patients with chronic pain in terminal cancer

assists in heroin withdrawal

57
Q

what is a drug 1000 fold more potent than morphine and is used in veterinary (not human) practice?

A

etorphine

58
Q

what are examples of opioid antagonists?

A

naloxone
naltrexone
alvimopan, methylnaltrexone

59
Q

how does naloxone work?

A

competitive antagonist at u-receptors

60
Q

when is naloxone used?

A

reverse opioid toxicity associated with overdose (may cause withdrawal)

newborn with opioid toxicity (eg respiratory depression) as result of administration of pethidine to mother during labour

61
Q

how is naloxone administered?

A

given incrementally IV

IM and SC routes if IV not practical

62
Q

why is the fact naloxone has a short half life important?

A

since opioid toxicity can recur to strong opioids which a longer duration of action

63
Q

what must you clinically do when administering naloxone?

A

monitor effects very carefully, titrating the individual dose and frequency to that required - do not leave patient unattended

64
Q

naltrexone works similar to naloxone but what is its advantage?

A

oral availability and much longer half life

65
Q

alvimopan and methylnaltrexone are also opioid antagonists but these do not enter CNS, what do they do instead?

A

reduce GI effects of surgical and chronic opioid agonist use

66
Q

what are examples of NSAIDs that are widely employed to reduce mild / moderate inflammatory pain?

A

ibuprofen

naproxen

67
Q

what is the mechanism behind how non selective NSAIDs have analgesic, antipyretic and anti-inflammatory actions?

A

they inhibit the synthesis and accumulation of prostaglandins by COX enzymes COX-1 and COX-2

68
Q

what are examples of non selective NSAIDs?

A 
aspirin 
ibuprofen 
naproxen 
diclofenac 
indometacin
69
Q

what are examples of COX-2-selective inhibitors?

A

etoricoxib
celecoxib
lumiracoxib

70
Q

the therapeutic benefit of NSAIDs largely derives from inhibition of COX-2 - true or false?

A

true - COX2 is induced locally at site of inflammation by various cytokines

COX1 is constitutively active

71
Q

NSAIDs can act both peripherally and centrally to do what?

A

suppress the decrease in the activation threshold of the peripheral terminals of nociceptors that is caused by prostaglandins

decrease recruitment of leukocytes that produce inflammatory mediators

if they cross the BBB, suppress the production of pain-producing
prostaglandins in the dorsal horn of the spinal cord (that, for example, reduce the action of the inhibitory neurotransmitter, glycine)

72
Q

what is a long term side effect of non selective NSAIDs?

A

gastrointestinal damage

(PGE2 produced by COX-1 protects against acid / pepsin environment)

also nephrotoxicity

73
Q

why is the use of selective COX-2 inhibitors limited?

A

they are prothrombotic

74
Q

what conditions cause severe and debilitating neuropathic pain?

A

trigeminal neuralgia
diabetic neuropathy
post-herpetic neuralgia
phantom limb pain

75
Q

what are treatment options for neuropathic pain?

A

gabapentin and pregabalin (antiepileptics)

amtitriptyline, nortryptilline and desipramine (tricyclic antidepressants)

carbamazepine

76
Q

how do gabapentin and pregabalin work?

A

these do not act via the GABAergic system but instead reduce the cell surface expression of a subunit (α2δ) of some voltage-gated Ca2+ channels (high-voltage-activated subgroup) which are upregulated in damaged sensory neurones

this presumably causes a decrease of neurotransmitters, such as glutamate and substance P, from the central terminals of nociceptive neurones

77
Q

when is gabapentin commonly employed?

A

migraine prophylaxis

78
Q

when is pregabalin useful?

A

painful diabetic neuropathy

79
Q

how do tricyclic antidepressants work?

A

act centrally by decreasing reuptake of noradrenaline

80
Q

how does carbamazepine work?

A

blocks subtypes of voltage-activated Na+ channel that are upregulated in damaged nerve cells

81
Q

carbamazepine is first line treatment in what?

A

to control pain intensity and frequency of attacks in trigeminal neuralgia

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