Opioid Analgesics Flashcards
Is pain objective or subjective?
Subjective
What are the two components of pain?
- Physiological
- Psychological
What is another name for the physiological perception of pain?
Nociception
Give two scenarios where the psychological aspect of pain becomes apparent
- Phantom limb pain
- Intractable pain
Which divisions of the nervous system do opioids affect?
- CNS
- PNS
What type of effect do opioids have on the CNS?
Psychoactive
What theory does the action of opioids in the PNS conform with?
The ‘gate theory’ of pain
To where in the CNS are pain signals initially transmitted to?
The substantia gelatinosa
Where is the substantia gelatinosa found?
The dorsal horn of the spinal cord
What can happen to pain signals within the substantia gelatinosa?
They can be modulated
What neurotransmitter is responsible for relaying pain signals within the substantia gelatinosa?
Substance P
How do opioids exert their effects at the spinal level?
Inhibit the release of Substance P from the nerve terminals in the substantia gelatinosa
What natural part of the pain pathway do opioids mimic to an extent?
Descending inhibitory nerves from the thalamus
What do the inhibitory descending nerves from the thalamus do?
Use inhibitory interneurones to block the release of Substance P within the substantia gelatinosa
How does rubbing an injury make it ‘better’?
Stimulation of mechanoreceptors that can have an inhibitory effect on pain transmission via the substantia gelatinosa
What are the 3 main types of endogenous opioid peptides?
- Enkephalins
- Endorphins
- Dynorphins
What is the pre-cursor molecule for enkephalins?
Proenkephalin
What is the pre-cursor molecule for endorphins?
POMC
What else is POMC a pre-cursor for?
- α-MSH
- ACTH
What is the pre-cursor molecule for dynoprhins?
Prodynorphin
What are the two main types of enkephalins?
- Met-enkephalin
- Leu-enkephalin
What is the main type of endorphin?
β-endorphin
What are the three types of opioid receptors?
- μ-opioid receptors
- δ-opioid receptors
- κ-opioid receptors
Where are μ-opioid receptors generally found?
Supraspinal i.e. in the brain
What effect does binding to μ-opioid receptors have?
Analgesia
Where are κ-opioid receptors mostly found?
Spinal cord
Where are δ-opioid receptors found?
They are widely distributed
What type of receptor are all opioid receptors?
GPCRs
Receptors at which location within the synapse are most important in pain control?
Presynaptic receptors
What effect does binding to μ-receptors have?
Opening of K⁺ channels and increased efflux of K⁺
What is the result of increased efflux of potassium?
Decreased excitability
What is the result of binding to κ-receptors?
Decreased influx of Ca²⁺ via channels
What is the result of binding to δ-receptors?
Decreased adenylate cyclase activity leading to decreased cAMP synthesis
Are the effects of the receptor sub-types limited to only one subtype?
No - each subtype can exert all of the effects i.e. cause increased efflux ok potassium, decrease calcium influx and decrease cAMP
What do all the effects of the opioid receptors have on the intracellular calcium?
Reduced entry of Ca²⁺
What is the result of decreased entrance of calcium ions?
Less release of neurotransmitter (Substance P) vesicles into the synaptic cleft
What receptor causes most of the opioid side-effects?
μ-receptors
What side-effects does μ-receptor binding have?
- Nausea
- Vomiting
- Constipation
- Drowsiness
- Miosis
What are the two big problems of long-term opioid use?
- Dependance
- Tolerance
What does dependence mean in terms of opioid use?
If opiods are removed the patient sufferes from withdrawal symptoms
What does tolerance mean with respect to opiate use?
A higher dose is needed to achieve the same effect
What is the danger of opiates tolerance?
Users need a higher dose to the point where it risks respiratory depression and death
The risk of respiratory depression has what consequence on opiate prescribing?
Monitoring is required
What effect can opiates have on the CVS?
Can cause hypotension
What side-effect can be caused by κ-receptor binding?
Dysphoria
What are the type of opioid receptor binding drugs?
- Agonists
- Partial agonists
- Agonist/antagonist
- Antagonist
Give an opioid receptor agonist
Morphine (the gold standard)
Give an opioid receptor partial agonist
Buprenorphine
Give an opioid receptor agonist/antagonist
Nalbuphine
How do opioid receptor agonist/antagonists work?
They exert an agonistic effect at one receptor sub-type and cause an antagonistic action at another
Give an opioid receptor antagonist
Naloxone
What can naloxone be used for?
Reversal of opioid induced respiratory depression
What is the half-life of morphine?
~4 hours
What is the oral bioavailability of morphine?
25%
What is the half-life of diamorphine (heroin)?
5 minutes
What is the half-life of methadone?
~24 hours
What is the oral bioavailability of methadone?
90%
What is another opioid with a good oral bioavailability?
Codeine
Does morphine enter Phase 1 metabolism?
No - it already has hydroxyl groups so enters straight into Phase 2 metabolism
To what metabolites is morphine metabolised to?
- Morphine-6-glucuronide
- Morphine-3-glucuronide
Why does morphine have a ‘slightly extended half-life’?
Morphine-6-glucuronide is still an active molecule
How are morphine metabolites excreted?
In the urine
What is the result of urinary excretion of morphine metabolites?
Urine can be screened for opioid use
Despite its short half-life of 5 minutes, why is heroin the opiate of choice for substance misusers?
Becuase its structure allows for rapid entry across the blood-brain barrier where it is the metabolised to morphine after which it has the usual ~4 hour half life
What are the clinical uses of opioids?
- Analgesia
- Anaesthesia
What sort of pain are opioids used to treat?
Moderate to severe pain (particularly pain with a visceral origin)
What are the indications for morphine?
- Analgesia (particularly terminal illness)
- Diarrhoea
What are the indications for diamorphine?
Analgesia (in terminal illness only due to its tendency to cause dependence)
What are the indications for methadone?
Maintenance in opiod dependence
What are the indications of tramadol?
Analgesia
What are the extra-opioid effects of tramadol?
5-HT and NA re-uptake inhibition (minor anti-depressant side-effects)
What type of drug is morphine?
A pro-drug
What is codeine metabolised to?
Morphine
What converts codeine to morphine?
CYP2D6
What is the clinical significance of CYP2D6?
It has significant genetic polymorphism meaning some people cannot metabolise codeine to morphine and so receive no benefits
What is codeine used for?
Mild analgesia
What is the route of administration of morphine?
Oral
What is the indication of fentanyl?
Anaesthesia
Why does fentanyl work as an anaesthetic agent?
It has up to 100x the potency of morphine
What is the indication for pethidine?
Analgesia in labour
What is the route of administration of pethidine?
IM
What is the dangerous side-effect of pethidine?
It is metabolised to not pethidine which can cause convulsions
What are the indications for naloxone?
- Opioid toxicity
- Respiratory depression
- Treatment of dependence
What are the medico-legal implications of opioid prescribing?
May are controlled drugs e.g. morphine, diamorphine and pethidine
