S3: Opiod Analgesics

Question 1

What is pain?

Answer 1

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.

Question 2

Difference nociceptive pain and neuropathic pain

Answer 2

• 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.

Question 3

Why is chronic pain clinically important?

Answer 3

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>

Question 4

List some analgesics drugs

Answer 4

• Opioids
• NSAIDs
• Tricyclic antidepressants
• Anti-convulsant (Na+ channel blockers)
• Ca2+ channel blockers
• Cannabinoids

Question 5

Difference opiates and opiods

Answer 5

• 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.

Question 6

Describe opioid receptors

Answer 6

• 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.

Question 7

Describe the pain pathway and our natural pain killing system

Answer 7

• 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.

Question 8

How does stress affect pain?

Answer 8

Stress induced analgesia will activate the descending pathways (inhibitory) in order to survive!

Question 9

Where are the 3 main places opiods act at?

Answer 9

1. The periphery e.g. in the hand.
2. The dorsal horn.
3. Descending inhibitory pathways..

Question 10

Why are opioids such good analgesics?

Answer 10

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.

Question 11

How are NSAIDs different to opioids?

Answer 11

They both reduce synaptic transmission but with different mechanisms. NSAIDs work by inhibiting COX enzyme.

Question 12

Describe the cellular mechanism of our pain pathway

Answer 12

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.

Question 13

Explain the cellular mechanism of opioids on presynaptic terminal (nociceptive fibre)

Answer 13

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:

1. 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.
2. 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.

Question 14

Explain the cellular mechanism of opioids on postsynaptic terminal (dorsal horn neurone)

Answer 14

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.

Question 15

Explain why opioids also switch on neuronal areas involved in producing analgesia e.g. increase descending inhibition

Answer 15

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.

Question 16

List effects of opioids

Answer 16

• Pain relief
• Euphoria
• Respiratory depression
• Cough
• Vomiting
• Pupillary contriction
• GI
• CVS

Question 17

Describe the euphoric effect of opioids

Answer 17

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.

Question 18

Describe how opiods can cause respiratory depression

Answer 18

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.

Question 19

How do opioids cause a cough?

Answer 19

Opioids suppress the cough reflex, hence codeine is used in cough medicines.

Question 20

How do opioids cause vomiting?

Answer 20

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).

Question 21

How do opioids cause pupillary constriction?

Answer 21

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.

Question 22

How do opioids affect the GI system?

Answer 22

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.

Question 23

Why must be avoid opiods in acute asthmatics?

Answer 23

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.

Question 24

Can NSAIDs and Opioids be given together?

Answer 24

Yes because they have different mechanisms to target pain.

Question 25

Describe the absorption and metabolism of the three main opioids (codeine, methadone and diamorphine) and there

Answer 25

Codeine and diamorphine once taken into the body will be metabolised to morphine, methadone on the other hand is a synthetic compound that is an agonist of opioid receptors.
These drugs tend to be weak bases with a pKa of about 8. Because of this there is poor stomach absorption because the drugs will accept protons and become charged so they cannot cross the cell membrane and get into the blood. Absorption occurs more in intestine where it is more alkaline and the drugs donate their protons and become neutral and more lipophilic.

Question 26

Describe the bioavailability of opioids

Answer 26

Opioids also have a high first pass metabolism. Due to both of these reasons the bioavailability of the drug tends to be quite low (20-30%) when taken orally. Hence these drugs tend to be given i.v. or i.m.

Question 27

Describe metabolism of morphine

Answer 27

So lets say we now have morphine in the body, it will be further metabolised by cytochrome P450 enzymes into an active form (morphine-6-glucuronide) and an inactive form (morphine-3-glucuronide).
As they are broken down by P450 enzymes we must be aware of other drugs the individual is taking because these may be inhibiting or inducers of P450 enzymes as this will have a big effect on morphine metabolism.
These drug interactions could be dangerous as morphine needs to be at the right level in the body due to its many potential side-effects.

Question 28

How is diamorphine given?

Answer 28

tit is a pro-drug and more lipid soluble, so giving i.v. it will get into the brain much faster and person will get a quicker “hit”

Question 29

How is methadone given?

Answer 29

Is taken orally and has a long half-life so person only needs one hit (they don’t need to top up constantly), it has less powerful effects but is an agonist of Mu so prevents withdrawal symptoms.

Question 30

How is codeine given?

Answer 30

It is far less potent than diamorphine and methadone and often taken orally. It is a mild analgesic and often combined with NSAIDs!

Question 31

Why must you be careful giving opioids to a patient with kidney failure?

Answer 31

Opioids are excreted by the kidney so they could get a build up of opioids in their body and cause an overdose.

Question 32

What does Nalaxone do?

Answer 32

It is an antagonist that has affinity but not efficacy. Naloxone blocks opioid receptors and can be used to reverse morphine-induced symptoms. If a person has overdosed there will be lots of stimulation of opioid receptors, we can give Naloxone and this can block the receptors and compete with opioid in order to reverse the overdose effects by preventing stimulation of the receptors. It has higher affinity for the receptors but no efficacy.

Question 33

Is methadone a full agonist?

Answer 33

Yes. it had high affinity and efficacy.

Question 34

What is Buprenorphine?

Answer 34

Buprenorphine is a partial opioid agonist, they have high affinity but have medium efficacy. They are useful in helping with withdrawal of heroin and as they have a long duration of action if a person then takes heroin on top it will produce little effect because the Buprenorphine will be bound.
Hence it is used for heroin addiction.

Question 35

What are the three features of opioid poisoning?

Answer 35

• CNS depression/Coma
• Pinpoint pupils
• Respiratory depression

Question 36

List some other clinical signs for opioid poisoning

Answer 36

• Low respiratory rate (4/min)
• Low BP
• Low body temp
• Needle marks
• Flaccid muscles
• Decreased bowel sounds
• Decreased bladder sounds