Session 8 Opioids Flashcards
What is nociception?
non-conscious neural traffic due to trauma or potential trauma to tissue
What is pain?
complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture
Describe the pain reflex (ending with post central gyrus)
- Cell damage / death
- Nociceptors stimulated
- Release of substance P and Glutamate
- Afferent nerve stimulated - 1st order neuron
- First order neurone synapses with 2nd order neurone in dorsal horn
- 2nd order neurone decussates
- Action potential ascends
- 2nd order neurone synapses with 3rd order neurone in thalamus
- 3rd order neurone projects to post central gyrus
We modulate pain through modulators. Where are these found a) peripherally and b) centrally?
a) substantia gelatinosa
b) periaqueductal grey
How do we modulate pain peripherally? (i.e. the pathway)
- tissue damage occurs
- project with alpha-delta and c fibres towards the dorsal horn
- this transmits to the thalamus and makes our body realise that we are experiencing pain
when tissue damage occurs, we also send inhibitory signals to the substantia gelatinosa (main modulator)
‘rubbing it better’ stimulates the substantia gelatinosa which then inhibits lamina 1 and lamina 5 and reduces the pain that’s projecting towards the thalamus
How do we modulate pain centrally?
- tissue damage occurs
- project with alpha-delta and c fibres to the dorsal horn
- this projects to the thalamus then the cortex
When the thalamus and cortex detect pain, the thalamus sends stimulatory signals towards the periaqueductal grey matter which then sends inhibitory signals to the dorsal horn - they do this by releasing endogenous opioids e.g. 5-HT and enkephalins
these endogenous opioids work on our endogenous opioid receptors which causes a reduction in pain
How do opioid GPCR work?
action = decrease cAMP –> hyperpolarisation and decreased substance P release + increased dopamine release
u (MOP) GPCR
location =
endogenous opioids =
effects =
location = supraspinal / GI tract
endogenous opioids = enkephalins and b-endorphins
effects = analgesia, depression, euphoria, dependence, respiratory sedation
delta (DOP) GPCR
location =
endogenous opioids =
effects =
location = widely distributed
endogenous opioids = enkephalins
effects = analgesia, inhibit dopamine, modulate u
k (KOP) GPCRs
location =
endogenous opioids =
effects =
location = spinal cord, brain and periphery
endogenous opioids = dynorphins
effects = analgesia, diuresis, dysphoria
Describe the WHO analgesic ladder
simple analgesia e.g. paracetamol and NSAIDS
weak opioid e.g. codeine
strong opioid e.g. morphine, fentanyl
What are the four general principles of Opioids (as a class)
- Exploit natural opioid receptors (either agonise or antagonise)
- Main therapeutic effects are via u-receptors
- Aim to modulate pain
- Also indicated in cough, diarrhoea and palliation
Which opioid’s are strong agonists?
Morphine
Fentanyl
Which opioid’s are moderate agonists?
Codeine
Which opioid is a mixed agonist/antagonist (partial agonist)?
Buprenorphine
Which opioid is an antagonist?
Naloxone
Morphine
Absorption =
Distribution =
Metabolism =
Elimination =
Absorption = PO (long term pain relief), IV, IM, SC, PR
- IV and SC - in acute pain relief
- significant first pass effect - 40% bioavailability
Distribution = rapidly enters all tissues but struggles to cross BBB
Metabolism = morphine + glucuronic acid –> M6G (main analgesic effect) + M3G (neuroexcitatory/euphoria side effect)
Elimination = renal
What receptor does morphine have a strong affinity for?
u receptors (minimal for k and d)
NB: complete activation of u
main actions of morphine?
analgesia and euphoria
side effects of morphine?
respiratory depression - medullary respiratory centre becomes less responsive to Co2
vomiting - as chemoreceptors are stimulated
GI tract - as morphine decreases motility (constipation), increases sphincter tone
miosis -constriction of pupils
histamine release - caution in asthmatics
Fentanyl
Absorption =
Distribution =
Metabolism =
Elimination =
Absorption = IV, epidural, intrathecal, nasal
* 80-100% bioavailability
Distribution = highly lipophilic, highly protein bound, high level of CNS crossing
Metabolism = hepatic (via CYP3A4)
Elimination = renal (very short half life)
Fentanyl compared to morphine? (receptors etc)
100 x more potent
higher affinity for u receptor
less histamine release, sedation and constipation
main actions of fentanyl?
analgesia
anaesthetic
side effects of fentanyl?
respiratory depression
constipation
vomiting
Codeine
Absorption =
Metabolism =
Elimination =
Absorption = PO, SC
Metabolism = codeine converted to morphine via CYP2D6
(CYP2D6 is inhibited by fluoxetine)
Elimination = renal! glucoronidation of morphine
Codeine vs morphine potency
codeine is only 1/10th of the potency of morphine (less potent)
main actions of codeine?
mild to moderate analgesia
cough depressant
side effects of codeine?
constipation
respiratory depression - worse in children so don’t give if aged under 12!
Buprenorphine
Absorption =
Distribution =
Metabolism =
Elimination =
Absorption = transdermal, buccal and sublingual
Distribution = very lipophilic
Metabolism = hepatic (via CYP3A4) then glucoronidation (prior to biliary excretion)
Elimination = biliary (safe in renal impairment)
* half life = 37 hours
Buprenorphine vs morphine
very high affinity for u receptor - low Kd
long duration of action
not easily displaced
lower Emax as its a partial agonist so lower efficacy
antagonist at k receptors
main actions of buprenorphine?
moderate to severe pain (chronic pain)
opioid addiction treatment
side effects of buprenorphine?
respiratory depression
low BP
nausea
dizziness
NB: side effects aren’t as bad as buprenorphine is a partial agonist
Naloxone
Absorption =
Distribution =
Metabolism =
Elimination =
Absorption = IV, IM, intranasal and PO * very LOW oral bioavailability as extensive first pass effect (i.e. very well absorbed in the gut) Distribution = rapid as very lipophilic Metabolism = hepatic * converted to naloxone-3-glucuronide Elimination = renal * duration of action is 30-60 minutes
Naloxone vs morphine in terms of affinity?
u>d>k
greater affinity than morphine but less than buprenorphine
main action of naloxone?
competitive antagonism of opioid
side effects of naloxone?
short half life so someone could go back into overdose quickly so need to give as a slow infusion so that the overdosed drug (morphine or heroin) can be metabolised
How do we build up a tolerance to opioids? (i.e. what are the mechanisms?)
- Phosphorylation and uncoupling
2. cAMP production
How does the phosphorylation and uncoupling mechanism lead to opioid tolerance?
without tolerance:
- u receptor coupled to G Protein
- give opioid which leads to decreased cAMP and therefore decreased pain
BUT on repeated exposure to opioid —>
- sensitivity of u receptor to the opioid is reduced
* so opioid wont bind as readily
OR
- Arrestin (a protein) binds to u receptor which means that G proteins become uncoupled and can no longer bind to the u receptor
* downstream process can’t occur - no decrease in cAMP and therefore no decrease in pain felt
How does the process of cAMP production lead to opioid tolerance?
Normally, opioid will decrease cAMP and decrease pain
BUT when opioid is removed, you can get a rebound effect within that cell:
cell becomes flooded with cAMP –> neuronal excitability occuring –> multisystemic withdrawal symptoms
this means that you need greater doses to minimise that period of time where your cells aren’t exposed to opioid to minimise the effect
What is a leading cause of opioid addiction / overdose?
Iatrogenic causes
