S3: Opiod Analgesics Flashcards
What is pain?
Pain is subjective and difficult to define. it tends to be a sensation associated with tissues damage such as injury, inflammation as well as brain/nerve injury.
Difference nociceptive pain and neuropathic pain
- Nociceptive pain is caused by tissue damage and or inflammation, where there is triggering of the nociceptor a-delta fibres or C fibres.
- Neuropathic pain is caused by damage to the nerve itself, the body or axon could be damaged, may also be caused by brain damage.
Why is chronic pain clinically important?
Chronic pain is very disabling and a lot of people suffer from it and it therefore is a massive cost to our healthcare system.
Demonstrating this is the fact there are several analgesics in the top 10 mot prescribed drugs in the UK>
List some analgesics drugs
- Opioids
- NSAIDs
- Tricyclic antidepressants
- Anti-convulsant (Na+ channel blockers)
- Ca2+ channel blockers
- Cannabinoids
Difference opiates and opiods
- Opiates are substances that come from the poppy somniferum (opium poppy) and these include morphine and codeine
- Opioids are endogenous substances as well as synthetic substances that produce morphine like effects. Endorphins and Enkephalin are examples of endogenous opioids.
Describe opioid receptors
- G protein couples receptors (one protein that spans membrane 7 times).
- They are all linked to the Gi/Go alpha subunit. They work to switch off adenylate cyclase and thus decrease levels of cAMP and PKA.
- There are 3 subtypes of the opiod receptor, mew, delta and kappa giving us MOP, DOP and KOP.
- The MOP receptors are often associated with actions of morphine and linked to analgesia.
Describe the pain pathway and our natural pain killing system
- Nociceptive afferent from periphery projecting to dorsal horn of the spinal cord. It will then synapse onto a secondary afferent to thalamus and be directed up to cortex giving perception of pain.
- There is also the descending inhibitory pain pathways that stimulate cells in the periaqueductal grey matter which will project down the the nucleus raphe magnus in the brain stem and excite the neurons here.
- The axons from raphe nucleus will project down to the dorsal horn and excite inhibitory interneurons to release enkephalin which will bind to Mu receptors (MOP) on the C and A delta fibres carrying pain signals from nociceptors.
- Activation of Mu receptors prevents the primary afferents from stimulating the secondary afferents (second order neurones) and therefore no signal sent up spinothalamic tract and no signals to brain. Hence no pain felt.
How does stress affect pain?
Stress induced analgesia will activate the descending pathways (inhibitory) in order to survive!
Where are the 3 main places opiods act at?
- The periphery e.g. in the hand.
- The dorsal horn.
- Descending inhibitory pathways..
Why are opioids such good analgesics?
Opioid receptors are always found where pain signalling is. The opioid receptors when stimulated in the periphery or dorsal horn (laminae II) it will reduce neuronal firing and conduction of nociceptive signals to the brain.
Hence these signals don’t get to the brain and the pain isn’t perceived.
How are NSAIDs different to opioids?
They both reduce synaptic transmission but with different mechanisms. NSAIDs work by inhibiting COX enzyme.
Describe the cellular mechanism of our pain pathway
We have a nociceptive fibre entering the dorsal horn and synapsing with a secondary afferent. The nociceptive fibre conducts AP (stimulated by pain stimulus e.g. burn) to open VGCC which then causes a efflux of NT into the synapse to bind to the excitatory post synaptic receptor and stimulate the superficial dorsal horn neurone. The dorsal neurone will then send information up our spinal cord which will be perceived as pain.
Explain the cellular mechanism of opioids on presynaptic terminal (nociceptive fibre)
There is binding of our drug or endogenous compound to the opioid receptor found on the presynaptic terminal. The Gi pathway will be stimulated which inhibits adenylate cyclase and as a result two things occur:
- The inhibition of Ca2+ channels. Inhibition of vgCa2+ (N type) at the synaptic bouten means that the APs going down the axon that depolarise the synaptic bouten that would normally open the vgCa2+ now will not open. This means that there is less influx of calcium and less intracellular calcium so not as much NT will be stimulated and released into the synaptic cleft. Less NT will therefore bind to its excitatory post-synaptic membrane receptor to carry of the impulse to the brain.
- Opening of K+ channels. When K+ channels are activated it will lead to K+ efflux from the cell. This will cause the membrane potential to get more negative and hyperpolarise this makes it more difficult for the bouten to depolarise and the vgCa2+ will be harder and even more less likely to open.
- These both lead to a reduction in synaptic transmission.
Explain the cellular mechanism of opioids on postsynaptic terminal (dorsal horn neurone)
Opioid receptors found on the post synaptic membrane if activated can also open K+ channels which will make it hyperpolarised and reduce the post-synaptic neuronal firing as it is harder to reach threshold.
- There is then fewer impulses to the brain so the brain will not perceive pain.
Explain why opioids also switch on neuronal areas involved in producing analgesia e.g. increase descending inhibition
Opioids also switch on our anti-nociceptive descending pathways e.g. in periaqueductal grey matter and nucleus raphe magnus.
- Under normal circumstances, the inhibitory interneurone will be inhibiting the descending anti-pain pathway e.g. releasing GABA so we can feel pain.
- The opioid receptors are found on these inhibitory interneurons, therefore if they are activated vgCa2+ will become less active and there will be more K+ efflux!
Because of this, it will reducing firing in the interneurone and remove the inhibitory effect on the descending anti-pain pathway.
- Therefore the anti-pain pathway switches on and will start signalling down and reducing pain.
- This process is called disinhibition.
List effects of opioids
- Pain relief
- Euphoria
- Respiratory depression
- Cough
- Vomiting
- Pupillary contriction
- GI
- CVS
Describe the euphoric effect of opioids
Opioids give people a sense of well being and relief of stress. It is extremely addictive and it is not only a analgesic tool but it help reduce anxiety in distressed patients.
- This euphoric feeling caused by opioids is thought to be due to increasing dopamine transmission. The reward pathways are associated with dopamine.
- Under normal circumstances, this inhibitory interneurone will release GABA which will bind to GABA receptors on the dopaminergic pre-synaptic membrane. This binding will have an inhibitory affect on the pre-synaptic neurone and will dampen down dopamine release.
- If you take give opioids, these will bind to opiate receptors on the GABAergic inhibitory interneurone synaptic membrane. The receptors are Gi linked so will reduce adenylyl cyclase which will mean less cAMP is formed and less PKA activated. As a result, more vgCa2+ will be closed and membrane more hyperpolarised due to K+ efflux. Hence, there will be less GABA release and less activation of the GABA receptor on the dopaminergic neurone.
- This means that there will be less inhibition of the neurone so it will release more dopamine. In the reward areas of the brain this will lead to euphoria.
Describe how opiods can cause respiratory depression
This is the main cause of death from opioid overdose.
- Opioid receptors are found in the respiratory areas of the brain such as the pre-botzinger complex (this area sets respiratory rate pattern) as well as the brain stem and medullary nuclei chemoreceptors.
- Stimulation of the opioid receptors in these areas will suppress these neurones, this will therefore suppress respiratory pattern (a suppressed driving of respiration). Because opioid receptors are also found at the nuclei chemoreceptor region, suppression here will change the chemoreceptor sensitivity to arterial PCO2.
- Normally as arterial PCO2 increased, the chemoreceptors would signal for increased ventilation to increase to blow off the CO2, but because they are less sensitive this doesn’t occur properly and CO2 will accumulate.
- This can cause respiratory failure.
How do opioids cause a cough?
Opioids suppress the cough reflex, hence codeine is used in cough medicines.
How do opioids cause vomiting?
pioids will stimulate the chemoreceptor trigger zone (found in area postrema) and this will be sensed as a toxin and vomiting will be triggered. If you’re taking opioids for medicinal purposes you will be given an anti-emetic at the same time. Morphine is often given with metoclopramide (an anti-emetic).
How do opioids cause pupillary constriction?
Opiates cause pupil to constrict so you get a pinpoint pupil, this can be a defining feature of opioid overdose. This is because opioids stimulate the oculomotor nerve and increase parasympathetic activity causing the pupil to constrict.
It is an important diagnostic feature for overdose as most other coma/respiratory depression will cause pupil dilation.
How do opioids affect the GI system?
Opioids will increase GI tone and decrease motility. This causes constipation and reduces absorption of other drugs. Loperamide is an opioid and used for diarrhoea but doesn’t cross the BBB so we don’t get the other side effects of opioids. Here we can see opioids being very useful.
Why must be avoid opiods in acute asthmatics?
They cause histamine release from mast cells. Opioids can stimulate this causing an inflammatory like response, local redness, itching and rash. If this response goes systemic, the histamine will cause bronchoconstriction (bad in asthmatics) and can cause hypotension. We must avoid opioids in acute asthmatics as it can be very dangerous. If given, it must be in low doses and monitored in asthmatics.
Can NSAIDs and Opioids be given together?
Yes because they have different mechanisms to target pain.
