S9 L1 Opioids Flashcards
What is the difference between nociception and pain?
Nociception → non conscious neural traffic due to trauma or potential trauma to tissue
Pain → complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture
How is pain ‘felt’?
1- Damage to tissue - release bradykinin, prostaglandins and serotonins
2- Nociceptors stimulated
3- Release of substance P and glutamate
4- Afferent nerve stimulated - Aδ fibres or Ac fibres
→ Aδ- sharp pain
→ Ac- unmyelinated, dull pain, more stimuli require to generate same response
5- Enters dorsal horn and synapses on lamina 1 or 5 on 2nd order neurones
6- Fibres decussate
7- Action potential ascends in spinothalamic tract
8- Synapse in the thalamus on 3rd order neurones
9- Project to post central gyrus (primary sensory cortex- pain felt)
How can we modulate pain?
Modulators in the central and peripheral system
Peripherally → Substantia gelatinosa
Centrally → Peri aqueductal grey
How is pain modulated peripherally?
- Tissue damage → Aδ and Ac fibres to lamina 1 and 5 → project to thalamus etc…
- Inhibitory signals also sent to the substantia gelatinosa (in the dorsal horn)
- ‘Rub it better’ → Activates Aβ fibres which stimulate the substantia gelatinosa → Inhibitory projections to lamina 1 and 5 in dorsal horn - reduced amount of pain to the thalamus
How is pain modulated centrally?
- Tissue damage → Aδ and Ac fibres….. DH…. thalamus…. cortex
- Periaqueductal grey found in midbrain- thalamus and cortex act on PAG- Stimulate it
- PAG sends inhibitory signals via nucleus raphe magnus in the medulla to the dorsal horn to reduce the amount of pain from the dorsal horn going to the thalamus
→ Inhibitory signals through endogenous opioids and 5-HT
What are the endogenous opioids?
Enkephalins, Endorphins and Dynorphins
Act on opioid receptors = G protein coupled receptors
Three receptor subtypes - MOP/µ, DOP/δ and KOP/K
Which is the most important opioid receptor clinically?
MOP/µ
Found in the brainstem and thalamus
Responsible for therapeutic and adverse effects
How do the opioid receptors work?
GPCR
- Agonist binds
- Activate inhibitory G protein
- Leads to decrease in cAMP, via inhibition of adenylate cyclase
- Efflux of potassium
- Hyperpolarisation of the membrane (→ less AP)
- Decrease substance P and GABA release
- Increase dopamine release
What is opioid tolerance?
- Phosphorylation and uncoupling
2. cAMP production
How does phosphorylation and uncoupling lead to tolerance?
- Normally → opioid binds to µ receptor attached to G protein → ↓cAMP → ↓pain
- Opioid binding also leads to intracellular phosphorylation by intracellular kinase → begin to modulate µ receptors
→ Facilitate Arrestin binding → displacement of G protein
→ Opioid unable to bind as effectively so doesn’t have the same effect - Therefore opioid binding → don’t get same ↓cAMP → don’t get same ↓pain
How does cAMP production lead to tolerance?
- Normally → opioid binds to µ receptor attached to G protein → ↓cAMP → ↓pain
- Over period of time → remove opioid? → rebound effect → ↑↑↑cAMP inside cells
- Therefore
→ ↓amount of time between opioid doses
→ ↑dose- require more opioid to get the same ↓cAMP and ↓pain
Also ↑cAMP leads to ↑neuronal excitability - withdrawal symptoms (cramping, sweating, diarrhoea vomiting, extreme agitation) → important to treat to prevent death
What are the general principles of opioid receptors?
- Exploit natural opioid receptors either by agonising or antagonising them
- Main therapeutic effects via µ-receptors
- Aim to modulate pain
- Also indicated in cough, diarrhoea and palliation
What are the different classes of opioids?
Strong agonists Moderate agonist Mixed agonist/antagonists/ partial agonists Antagonist Others
What is the WHO analgesic ladder?
For chronic pain
Start with simple analgesia gradually increase strength
Simple analgesia → weak opioid → strong opioid
(neuropathic pain treated slightly differently)
What is the pharmacokinetics of morphine?
Strong agonist
→ Absorption
- Taken PO, IV, IM, SC, PR
- Gut absorption erratic
- Significant first pass effect - 40% oral bioavailability
→ Distribution
- Lipophilic - rapidly enters al tissues including foetal
- Struggles to cross the BBB - no protein binding
→ Metabolism
- Morphine + glucaronic acid → M6G (therapeutic effect) + M3G (neuronal excitability)
→ Elimination
- Renally
What is the mechanism of action of morphine?
Strong affinity to µ-receptors
Complete activation of µ-receptors
What does morphine result in?
Analgesia → inability to feel pain
Euphoria → feeling or state of intense excitement
What are the adverse effects of morphine?
- Respiratory depression → ↓sensitivity of medullary respiratory centre to CO2 → ↑CO2 no ↑RR →CO2 toxicity
- Emesis → chemoreceptor effect
- GI tract → ↓GI motility + ↑sphincter tone → constipation
- Cardiovascular
- Miosis
- Histamine release - caution in asthmatics - mast cell release
What is the pharmacokinetics of fentanyl?
Strong agonist → Absorption - IV, Epidural, Intrathecal, Nasal - 80-100% bioavailability → Distribution - Highly lipophilic, highly protein bound - High levels of CNS crossing BBB → Metabolism - Hepatic via CYP3a4 → Elimination - Half life 6 minutes - Renally excreted
What is the mechanism of action of fentanyl?
High affinity for µ receptors (100x potency of morphine)
Less histamine release, sedation and constipation
What does fentanyl result in?
Analgesia - unable to feel pain
Anaesthetic - unable to feel sensations
What are the adverse effects of fentanyl?
Respiratory depression
Constipation
Vomiting
What is the pharmacokinetics of codeine?
Moderate agonist → Absorption - PO, SC administration → Metabolism - Codeine → morphine via CYP2D6 - CYP2D6 inhibited by fluoxetine - SSRI - Variable expression across population (low CYP2D6 less effective) → Elimination - Glucoronidation of morphine and renal excretion
What is the mechanism of action of codeine?
Pro-drug
1/10th potency of morphine
Binds to µ receptor
What does codeine result in?
Mild-moderate analgesia
Cough depressant
What are the side-effects of codeine?
Constipation- prescribe a laxative alongside
Respiratory depression - worse in children (avoid in <12s)
What is the pharmacokinetics of buprenorphine?
Mixed agonist-antagonist → Absorption - Transdermal, Buccal, sublingual → Distribution - Very lipophilic → Metabolism - Hepatic via CYP3A4 - Glucoronidation before biliary excretion → Elimination - Biliary >renal - Safe in renal impairment - Half life 37 hours
What is the mechanism of action of buprenorphine?
Very high affinity for µ receptor- low Kd
Long duration of action
Not easily displaced
Lower E(max) as partial agonist, lower efficacy
Antagonist at K receptors
What is the result of buprenorphine?
Moderate to severe pain relief - doesn’t have to be taken orally
Opioid addiction treatment
What are the side effects of buprenorphine?
Respiratory depression
Low BP
Nausea
Dizziness
What is the pharmacokinetics of naloxone?
Antagonist → Absorption - IV, IM, Intranasal, PO - Very low oral bioavailability as extensive first pass effect - Rapid onset of action → Distribution - Rapid distribution as very lipophilic → Metabolism - Hepatic → naloxone-3-glucuronide - Renally excreted → Elimination - Duration of action 30-60mins
What is the mechanism of action of naloxone?
Affinity µ > δ > K
Greater affinity than morphine- displaces it
Affinity less than buprenorphine - unable to displace it
Competitive antagonism of opioid
What are the side effects of naloxone?
Short half like
Slow infusion → slowly displaces morphine, gradually reduce overdose
→ Avoid patient going into respiratory depression, bolus would displace morphine, short 1/2 so quickly wears off then rebind to receptor- overdose
Why do we need to consider overdose?
Growing problems
Large number of iatrogenic addicts → prescription addiction
1 in 4 will develop addiction
9.6% rise in drug related deaths 2016-2017
67.8% caused by opiates
What are the effects of overdose?
µ receptor responsible for most severe side effects
Variable effects of doses - become chronic opioid users requires higher dose to get same effect
Respiratory depression most serious- common cause of death (↓CO2 response so ↑CO2 level→ No ↑RR → apnoea → death)
- Dependence, vomiting, constipation, hypotension and bradycardia, decreased sex drive, histamine release, miosis, drowsiness, respiratory depression → apnoea
How is overdose treated?
Naxolone infusion as treatment
When prescribing opioids what special considerations do we need to make?
- Manual labourers/ Drivers → can make you drowsy
- Elderly
- Bedbound
- Asthmatics
- Biliary tract obstruction
- Respiratory disease
- Renal impairment
- Pregnancy
What are the contraindications of opioid use?
- Hepatic failure
- Acute respiratory distress
- Comatose
- Head injuries
- Raised ICP
What is palliative prescribing?
Symptoms control in the last year of life
Difficult area of prescribing - many think it increases the chance of death
Buprenorphine, diamorphine, fentanyl, morphine and oxycodone used
Tend to ignore the special considerations
When are opioid used in palliative prescribing?
Pain
SoB - unable to blow off CO2 so breathing fast, reduce sensitivity of medulla to CO2- decrease RR
What side effects need to be manage in palliative care?
Nausea
Constipation → prescribe laxatives alongside
What are the different types of palliative prescribing?
Months to weeks
→ Long acting background level of pain control
→ Short acting top up dose for extra
Days to hours
→ Continuous subcut infusion - standard dose every couple of hours
→ Top up doses as needed
What classification of prescription drugs are opioids?
Controlled drugs- Misuse of Drugs legislation Aims to prevent - Misuse - Illegal obtainment - Harm being caused Benefits of medial use vs risk of harm Prescribed must included - Date and prescribers address and full name - Patients address and name - Form of the drug- tablets, syrup, capsules, patches, ampoules - Units- mgs, mls etc - Total volume- in word and figures - Clearly defined dose
