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Physiology of Analgesia Flashcards

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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
what is the mechanism behind opioids causing this cardiovascular affect?
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
26
what are major gastrointestinal effects of opioids?
nausea vomiting constipation increased intrabilliary pressure
27
what is the mechanism behind opioids causing these GI effects?
action on CTZ (outside the BBB) increased smooth muscle tone, decreased motility, via enteric neurones - involves μ- and δ-receptors
28
what are major CNS effects of opioids?
``` confusion euphoria dysphoria hallucinations dizziness myoclonus hyperalgesia (with excess use) ```
29
what is the mechanism behind opioids causing these CNS effects?
occurs to different degrees dependent upon the specific opioid drug and receptor subtypes activated
30
which opioids work in an agonistic fashion by prolonged activation of u-opioid receptors?
``` morphine diamorphine codeine fentanyl pethidine buprenophine tramadol methadone etorphine ```
31
how is morphine metabolised and excreted?
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
32
how many morphine be administered?
IV - acute severe pain IM, SC or oral - general wards
33
what administration method is most appropriate in chronic pain?
oral either as immediate (oramorph) or sustained release (MST continus)
34
what is the difference between diamorphine (3,6-diacetylmorphine, heroin) and morphine?
diamorphine is more lipophillic
35
diamorphine has a rapid onset of action when administered what way?
IV (enters CNS rapidly)
36
when is diamorphine used?
for severe post-operative pain (but it is banned in some countries)
37
what is codeine (3-methoxymorphine)
a naturally occurring weaker opioid for mild / moderate pain
38
how is codeine metabolised?
hepatic metabolism by demethylation to morphine by CYP2D6 and CYP3A4
39
how is codeine administered?
orally
40
what other affect other than analgesia does codeine have?
anti-diarrhoeal and antitussive
41
what are the semi-synthetic derivatives of codeine which have higher potency?
oxycodone and hydrocodone
42
how much more potent is fentanyl than morphine?
75-100 fold
43
how is fentanyl administered?
IV to provide analgesia in maintenance anaesthesia transdermal (and buccal) delivery in chronic pain states but not acute
44
when is pethidine used?
in acute pain, particularly labour
45
how is pethidine administered?
rapid onset when given IV, IM or SC but has short duration so not suitable for chronic pain
46
why must pethidine not be used in conjunction with MAO inhibitors?
this combination would cause excitement, convulsions and hyperthermia
47
phenylpiperidine is a class of opioid which contains what?
fentanyl | pethidine
48
what is norpethidine?
neurotoxic metabolite (seizures)
49
when is buprenophine (partial agonist) useful?
chronic pain with patient-controlled injections has slow onset but long duration
50
how is buprenophine administered?
injection or sublingually
51
how does tramadol work?
weak u-receptor agonist, probably exerts significant analgesic action by potentiation of descending serotonergic (from NRM) and adrenergic (from LC) systems
52
how is tramadol administered?
orally
53
when should tramadol be avoided?
patients with epilepsy
54
how does methadone work?
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
how is methadone administered?
orally, long term of action
56
when can methadone be used?
treating patients with chronic pain in terminal cancer assists in heroin withdrawal
57
what is a drug 1000 fold more potent than morphine and is used in veterinary (not human) practice?
etorphine
58
what are examples of opioid antagonists?
naloxone naltrexone alvimopan, methylnaltrexone
59
how does naloxone work?
competitive antagonist at u-receptors
60
when is naloxone used?
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
how is naloxone administered?
given incrementally IV IM and SC routes if IV not practical
62
why is the fact naloxone has a short half life important?
since opioid toxicity can recur to strong opioids which a longer duration of action
63
what must you clinically do when administering naloxone?
monitor effects very carefully, titrating the individual dose and frequency to that required - do not leave patient unattended
64
naltrexone works similar to naloxone but what is its advantage?
oral availability and much longer half life
65
alvimopan and methylnaltrexone are also opioid antagonists but these do not enter CNS, what do they do instead?
reduce GI effects of surgical and chronic opioid agonist use
66
what are examples of NSAIDs that are widely employed to reduce mild / moderate inflammatory pain?
ibuprofen | naproxen
67
what is the mechanism behind how non selective NSAIDs have analgesic, antipyretic and anti-inflammatory actions?
they inhibit the synthesis and accumulation of prostaglandins by COX enzymes COX-1 and COX-2
68
what are examples of non selective NSAIDs?
``` aspirin ibuprofen naproxen diclofenac indometacin ```
69
what are examples of COX-2-selective inhibitors?
etoricoxib celecoxib lumiracoxib
70
the therapeutic benefit of NSAIDs largely derives from inhibition of COX-2 - true or false?
true - COX2 is induced locally at site of inflammation by various cytokines COX1 is constitutively active
71
NSAIDs can act both peripherally and centrally to do what?
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
what is a long term side effect of non selective NSAIDs?
gastrointestinal damage (PGE2 produced by COX-1 protects against acid / pepsin environment) also nephrotoxicity
73
why is the use of selective COX-2 inhibitors limited?
they are prothrombotic
74
what conditions cause severe and debilitating neuropathic pain?
trigeminal neuralgia diabetic neuropathy post-herpetic neuralgia phantom limb pain
75
what are treatment options for neuropathic pain?
gabapentin and pregabalin (antiepileptics) amtitriptyline, nortryptilline and desipramine (tricyclic antidepressants) carbamazepine
76
how do gabapentin and pregabalin work?
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
when is gabapentin commonly employed?
migraine prophylaxis
78
when is pregabalin useful?
painful diabetic neuropathy
79
how do tricyclic antidepressants work?
act centrally by decreasing reuptake of noradrenaline
80
how does carbamazepine work?
blocks subtypes of voltage-activated Na+ channel that are upregulated in damaged nerve cells
81
carbamazepine is first line treatment in what?
to control pain intensity and frequency of attacks in trigeminal neuralgia

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