Session 8: Opioids Flashcards
What is nociception?
Non-conscious neural traffic du to trauma or potential trauma to tissue.
An example is withdrawing your hand from a hot plate. A reflexive response.
What is pain?
A complex, unpleasant awareness of sensation modified by experience, expectation, immedatie context and culture.
Explain the mechanism behind pain.
A nocireceptor is stimulated and this leads to release of substance P and Glutamate.
The afferent nerve is stimulated and will synapse in the dorsal horn.
Here at the level of the spinal nerve the 2nd order neuron will decussate via the ventral white commissure and then ascend.
2nd order will synapse in the thalamus and a third order neuron will take over and synapse in the primary sensory cortex.
Sharp vs dull pain (fibres)
Delta fibres are myelinated fibres responsible for sharp pain
C-fibres are demyelinated fibres responsible for dull aching pain.
There are two kinds of modulators of pain.
Which?
Substantia gelatinosa
Peri aqueductal grey
Where is substantia gelatinosa found?
Peripherally
Where is peri aqueductal grey found?
Centrally
Explain the substantia gelatinosa role in pain.
Tissue damage leads to stimulation of dorsal horn.
It also sends inhibitory signal to substantia gelatinosa.
How can the substantia gelatinosa be stimulated?
What effect will this have?
You can rub pain better. Rubbing causes stimulation of substantia gelatinosa and leads to reduction of pain.
Explain central modulation of pain.
Tissue damage sends signal up to the thalamus and the thalamus send stimulatory signal to both cortex and PAG.
Cortex will also send stimulatory signals to PAG.
PAG will then send inhibitory signals back to the spinal cord and dorsal horn by the use of endogenous opioids such as serotonin (5-HT) and Enkephalins which will act on opioid receptors.
This leads to a reduction in pain.
Give examples of endogenous opioid receptors.
They are GPCRs
μ-receptors (MOP)
δ-receptors (DOP)
K-receptors (KOP)
Where can each be found?
MOP - supraspinal and GI tract
DOP is in wide distribution
KOP found in spinal cord, brain and periphery.
What stimulates each receptor type?
MOP - Enkephalins and b-endorphins
DOP - Enkephalins
KOP - Dynorphins
Effects of stimulation of MOP
Analgesia
Depression
Euphoria
Dependence
Respiratory sedation
Effects of stimulation of DOP
Analgesia
Inhibition of dopamine
Modulation of MOP
Effects of stimulation of KOP
Analgesia
Diuresis
Dysphoria
Explain the WHO analgesic ladder.
Depending on pain you should start at the bottom of the analgesic ladder with giving simple analgesia such as paracetamol or NSAIDs.
If this doesn’t do the trick try weak opioids such as codeine.
If the patient is still in pain give strong opioids such as morphine or fentanyl.
However need to assess pain in each patient, of course you wouldn’t give only NSAIDs to a patient in extensive pain.
On which receptor do medicinal opioids usually act?
MOP
Use of opioids
Mostly to modulate pain
However can also be used in coughs (codeine in cough syrup), diarrhoea and palliation
Give two examples of strong opioid agonists.
Morphine
Fentanyl
Administration of morphine.
Oral (long term)
IV
IM
SC
PR
Explain the gut absorption of morphine.
It has a significant first pass effect of 40% oral bioavailability.
Distribution of morphine.
Not very lipophilic
However it does rapidly enter all tissues including foetal.
It does not readily cross the BBB
Metabolism of morphine.
Morphine conjugates with glucuronic acid to produce the active metabolites M6G and M3G.
Effects of the active metabolites of morphine.
M6G has an analgesic effect
M3G have neuroexcitatory and euphoric side effects
Elimination of morphine.
Renally
Pharmacodynamics of morphine.
Strong affinity for MOP receptors and minimal for KOP and DOP.
They have a complete activation of MOP.
Actions of morphine.
Analgesia
Euphoria
Side effects of morphine.
Respiratory depression (due to medullary resp centre less responsive to CO2)
Emesis
Constipation
CVS
Miosis (constriction)
Histamine release
Administration of fentanyl.
IV
Epidural
Intrathecal
Nasal
With an 80-100% bioavaiability
Distribution of fentanyl.
Highly lipophilic and highly protein bound
It also crosses the BBB readily
Metabolism of fentanyl.
Hepatically via CYP3A4
Elimination of fentanyl.
Half life of 6 minutes and renally excreted
Why is fentanyl a better option than morphine in kidney disease?
Both are excreted via kidneys but fentanyl is excreted less so.
Safer to use in CKD etc…
Pharmacodynamics in fentanyl compared to morphine.
100x potency in fentanyl and also a high affinity for MOP receptors than morphine.
The higher affinity means less side effects
Side effects in fentanyl.
Less histamine release, sedation and constipation due to the higher affinity.
However you still get respiratory depression, constipation and vomiting.
Give an example of a moderate agonist.
Codeine
Administration of codeine
Usually orally
Can be given subcutaneously as well but that is very rare.
Metabolism of codeine.
It is a prodrug and is metabolised by CYP2D6 into morphine.
How can the amount of morphine that accumulate from codeine be regulated?
By inhibition of CYP2D6 by example SSRIs like fluoxetine
Why do some people report a lot of side effects of codeine where some people say it barely had any effect?
Because there is a variable expression of CYP2D6 in people which means that it can be hard to know if it is going to work and in which doses.
Elimination of codeine.
Glucoronidation of morphine and renal excretion
Pharmacodynamics of codeine compared to morphine.
1/10 of potency
Actions of codeine
Mild to moderate analgesia
Cough depressant
Side effects of codeine.
Constipation
Respiratory depression
What is buprenorphine?
A mixed agonist-antagonist (sometimes called a partial agonist)
Administration of buprenorphine.
Transdermally (patch), buccal, sublingual
Distribution of buprenorphine.
Highly lipophilic
Metabolism of buprenorphine.
In liver by CYP3A4 and then glucoronidated before biliary excretion.
Elimination of buprenorphine.
Mainly biliary but also renally.
This means that it is safe to use in renal impairment.
Also has a long half-life of 37 hours
Pharmacodynamics compared to morphine.
High affinity of MOP receptors with a very low Kd.
A long duration of action and is not easily displaced, in fact it displaces other opioids such as morphine.
It has however a lower Emax as it is a partial agonist.
Also works as an antagonist for K receptors.
Actions of buprenorphine.
Moderate to severe pain
Opioid addiction treatment.
Side effects of buprenorphine.
Respiratory depression
Low BP
Nausea
Dizziness
Give an example of an opioid antagonist.
Naloxone
Administration of naloxone.
IV
IM
Intranasal
PO
Bioavailability of naloxone.
Very low oral bioavailability as it has an extensive first pass effect.
Around 90% is absorbed in the gut but after the first pass effect only around 2% is left to work.
Distribution of naloxone.
Rapid distribution and highly lipophilic
Also a rapid onset of action.
Metabolism of naloxone.
Hepatically by glucuronidation
Elimination of naloxone.
Renally excreted where the duration of action of naloxone is about 30-60 mins.
Pharmacodynamics of naloxone compared to morphine.
Has a higher affinity for opioid receptors than morphine leading to displacement.
However less affinity than buprenorphine
Action of naloxone.
Competitive antagonism of opioids.
Means it can be good in overdoses
Side effects of naloxone.
Short half-life
Slow infusion
Why is it important to be aware that the duration of action of naloxone is only 30-60 minutes?
Because it means that a drug addict can come into clinic, get naloxone -> they wake up and become conscious and upset that you ruined their high.
They refuse to stay at the hospital and walk away.
After 60 minutes the naloxone wears off and they can go back into overdose again.
Give the two broad mechanisms of opioid tolerance.
Phosporylation and uncoupling
cAMP production.
Explain the normal action of an opioid.
An opioid acts on a MOP receptor.
Decreased levels of cAMP and this leads to decreased pain.
Explain the effect of phosporylation and uncoupling.
Persistent use of an opioid can lead to intracellular phosphorylation which will deactivate the MOP receptor.
Peristent use can also lead to other proteins called arrestins bind to the receptor to uncouple the G protein.
Both of these leads to less of an effect of opioid.
The person now needs more of an opioid to get a similar effect
Explain opioid tolerance and cAMP production.
When the opioid is bound this leads to less cAMP.
However when the stimulus is then removed more cAMP will be produced to compensate.
This leads to neuronal excitability and the withdrawal symptoms that we see in opioid tolerance.
Give examples of withdrawal symptoms.
Aggitation
Sweating
Anxiety
Emesis
Diarrhoea
All can be attributed to neuronal excitability
Which receptor is mainly responsible for overdose?
MOP
Most common cause of death due to OD.
Respiratory depression
OD effects
Dependence
Vomiting
Constipation
Hypotension and bradycardia
Decreased sex drive
Miosis
Histamine release
Drowsiness
Respiratory depression
Most common tx of OD
Naloxone infusion
In which people should you be cautious about prescribing opiates?
Manual labourers and those who drive for a living
Elderly
Bedbound
Asthmatics (histamine release)
Biliary tract obstruction
Resp disease
Renal impairment
Pregnancy
Contraindications of opioids. (when not to give!)
Hepatic failure
Acute respiratory distress
Comatose
Head injuries
Raised ICP
Explain opioid use in palliative care.
Buprenorphine, diamorphine, fentanyl, morphine and oxycodone are all used in palliative care.
They are used to relieve pain and shortness of breath.
However they can have side effects such as nausea and constipation (especially in bed bound)
Read the last few pages of the lecture as they give some info on epidemics and how opioids are controlled.
