Lecture 17- Opioids Flashcards
define nociception
Nociception – ‘non-conscious neural traffic due to trauma or potential trauma to tissue’
- E.g. when we touch something hot
define pain
is the neural processes of encoding and processing noxious stimuli.
outline pain pathway
- Damaged tissue release bradykinin and prostaglandins etc
- Nociceptors stimulated
- Release of Substance P (agonises local inflammatory response) and Glutamate
- Glutamate stimulates Adelta fibres (sharp pain) or C fibres (unmyelinated and transmit dull pain)
- Afferent nerve stimulated enter spinal cord in the dorsal horn and synapse with second order neurone
- Fibres decussate at the same level of entry
- Action potential ascends (spinothalamic)
- Synapse in thalamus
- Project to Post central gyrus (primary somatosensory cortex)

where can we modulate pain
peripherally and centrally
where is pain modulate peripherally and centrally
- Peripherally: Substantia Gelatinosa
- Centrally: Peri aqueductal grey
different mechanisms used
Peripheral modulation
- Within the substantia gelatinosa in the dorsal horn
- Lamina 1 and 5 are where pain fibres transmit
- E.g.
- Stimulation of Adelta + C fibres due to tissue damage
- Enters lamina 1 and 5
- Ascends the spinal cord via the spinothalamic tract and projects to the thalamus
- Receive pain sensation in the primary somatosensory cortex
- The tissue damage also sends inhibitory signals to the substantia gelatinosa- technically would make it feel as painful as possible
- How do we modulate this? By ‘rubbing it better’
- Ab fibres are activated by rubbing the tissue and send stimulatory signals to the substantia gelatinosa
- Send inhibitor signals to lamin 1 and 5, reducing amount of pain received by the thalamus

Central modulation
- Pain received by the thalamus and then cortex (primary somatosensory cortex)
- Both the thalamus and cortex can stimulate the periaqueductal grey matter
- Which then sends inhibitory signals to the dorsal horn and reduce the amount of pain being send from the DH to the thalamus.
- Via endogenous opioids and 5-HT (serotonin)

Endogenous opioids
Enkephalins, Endorphins and Dynorphins
opioid receptor
- Opioid receptors= G protein receptors
- Three receptor subtypes
- MOP/μ – most important clinically
- DOP/δ
- KOP/Κ
MOP receptor (u)
- Found predominantly brainstem and thalamus
- Also in spinal cord and GI tract
- Responsible for therapeutic and adverse effects
outline how opioid GPCR receptors decrease pai felt
- Agonist (opioid) binds to GPCR e.g. MOP receptor
- Leads to decrease in cAMP
- Efflux of potassium
- Hyperpolarisation of membrane
- Decreases substance P and GABA release
- Increases dopamine release
Opioids as a class
- Use opioids to exploit natural opioid receptors either by agonising or antagonising them
- Main therapeutic effect via u-receptors (MOP)
- Aim to modulate pain
- Also indicated in cough, diarrhoea and palliation
- Many different examples
Opioid tolerance
- Many mechanisms
- Can start to develop after a single dose
- 2 main proposed mechanisms
opioid tolerace mechanisms
- Phosphorylation and uncoupling
- cAMP production
Phosphorylation and uncoupling
- Opioid binds to MOP receptor and activates G protein
- Causes decreased cAMP within cell
- Decreased pain in the body
- However … as opioid starts to bind we get intracellular phosphorylation of MOP receptor by kinases within the cell and these start to modulate the MOP receptor
- Modulation means that proteins like Arrestin can bind and displaces G protein…
- Or it means the opioid may not have the same effect on the MOP receptor…
- Therefore don’t get decrease cAMP
- Therefore don’t get decrease in pain

cAMP production
- Opioid binds causing decreased cAMP and decreased pain
-
However… over a period of time when opioid is removed we get rebound effect massively increasing amount of camp in the cell, therefore increased pain
- Can cause neuronal excitability which causes withdrawal symptoms
- Therefore… have to give higher and higher dose of opioid in order to achieve same decrease in cAMP and pain

WHO analgesic ladder
- For chronic pain (not as useful for acute pain)
- Want to aim to keep lowest dose and weaker opioid for as long as possible
- Start with simple analgesia e.g. paracetamol and NSAIDS
- Then use weak opioids e.g. codeine
- Then move to strong opioids e.g. morphine, fentanyl

simple analgeisa
paracetamol, NSAIDS
weak opiod
codeine
strong opioid
tramadol, buprenorphine, methadone, diamorphine, fentanyl, hydromorphone, morphine
opioids do not work for …
Nerve pain: Neuropathic drugs used e.g. shingles
- Anticonvulsants
- Tricyclics
- Serotonin/NA reuptake inhibitors
name 2 strong MOP(u) receptor agonists
morphine and fentanyl
name a moderate MOP receptor agonisrs
codeine
name a mixed agonist-antagonist of MOP receptor
buprenorphine
name an MOP receptor antagonists
naloxone
uses of morphine (oral/IV/IM/PR)
- Analgesia – severe pain
- Long-standing pain when weaker painkillers no longer work
Pharmacokinetics of morphine
- Absorption
- PO,IV,IM,SC,PR
- Gut absorption erratic
- Significant first pass effect- 40% oral bioavailability
- Distribution
- Rapidly enters all tissues (lipophilc) including foetal
- Struggles to cross blood- brain barrier (no protein binding)
- Metabolism
- Morphine + glucuronic acid–> M6G +M3G
- M6G- main analgesic effect
- Morphine + glucuronic acid–> M6G +M3G
- Elimination
- Renally
Mode of action of morphine
- Strong agonist of U (MOP) receptor
- Complete activation of U
- Decrease in cAMP
- Decrease in pain
Adverse drug response of morphine
- Resp depression
- Emesis
- GI tract
- Increases sphincter tone
- Reduces GI motility
- CVD
- arrhythmias
- Miosis
- Histamine release- caution in asthmatics
- Euphoric effect
- Dizziness
Contraindication of morphine
- Renal impairment
- Head injury
- Acute resp depression
- Heart failure secondary to chronic lung disease
- Raised ICP
- Risk of paralytic ileus
- Pregnancy
Drug-drug interactions (many) of morphine
Alcohol- both depressant effects on CNS
uses of fentanyl (IV, epidural, interthecal and nasal)
- Analgesia
- Anaesthetic
Compared to morphine…fentanyl is
- 100x potency
- Higher affinity for U (MOP) receptor
- Less histamine release, sedation and constipation
Pharmacokinetics fentanyl
- Absorption
- IV, Epidural, Intrathecal, Nasal
- 80-100% bioavailability
- Distribution
- Highly lipophilic, highly protein bound
- High level of CNS crossing
- Metabolism
- Hepatic via CYP3A4
- Elimination
- Half life 6 minutes
- Renally excreted
Mode of action fentanyl
- Strong agonist of U (MOP) receptor
- Complete activation of U
- Decrease in cAMP
- Decrease in pain
Adverse drug response fentanyl
- Respiratory depression
- Constipation
- vomiting
Contraindication fentanyl
- head injury
- raised ICP
- acute resp depression
Drug-drug interactions (many) fentanyl
- alcohol
- st john’s wart
uses of codein (oral, SC)
- Mild- moderate analgesia
- Cough depressant
Pharmacokinetics codeine
- Absorption
- PO, SC administration
- Metabolism
- Codeine–> Morphine via CYP2D6
- CYP2D6 inhibited by some drugs
-
Variable expression
- Either not enough (no effect) or too much (toxicity)
- Elimination
- Glucoronidation of morphine and renal excretion
Mode of action codeine
- Moderate agonist to MOP receptor
- Decrease in cAMP
- Decrease in pain
Adverse drug response codeine
- Constipation (very bad)
- Prescribe laxative alongside
- Respiratory depression (worse in children)
Contraindication codeine
- Head injury
- Acute resp depression
- ICP
- UC
- Known ultra-rapid codeine metabolisers
Drug-drug interactions (many)
- Alcohol
- CYP2D6 inhibitors
- Fluxetine
- Buprenorphine
buprenoprhine uses
- Moderate- severe pain
- Opioid addiction treatment
Pharmacokinetics buprenorphine
- Absorption
- Transdermal, Buccal, sublingual
- Distribution
- Very lipophilic
- Metabolism
- Hepatic via CYP3A4
- Then glucoronidation before biliary excretion
- Elimination
- Biliary > Renal
- Safe in renal impairment
- Half life 37 hours – give patches
Mode of action buprenorphine
- Partial agonists to mu (MOP) receptor, meaning it only partially activates opiate receptors
- Also weak kapp receptor antagonist and delta receptor agonists
- Compared to morphine:
- Very high affinity for μ receptor
- Low Kd
- Long duration of action
- Not easily displaced
- Difficult to reverse effect
- Lower E(max) as partial agonist, lower efficacy à less side effect
- Antagonistic κ receptors
Adverse drug response buprenorphine
- Respiratory depression
- Low BP
- Nausea
- Dizziness
Contraindication buprenorphine
- Hepatitis
- Liver problems
- Alcohol intoxication
- Biliary and gall bladder problems
Drug-drug interactions (many) buprenorphine
- Amiodarone
- amlodipine
naloxone uses
- Rapidly reverse opioid overdose
Pharmacokinetics naloxone
-
Absorption
- IV, IM, Intranasal, PO
- Very low oral bioavailabilty 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
Mode of action naloxone
- Competitive antagonism of opioid – MU or MOP receptor
- Blocks effect of other opioids e.g. morphine
- Therefore increase in cAMP, increase pain, less of a high
naloxone compared to morphine:
- Affinity μ>δ>κ
- Greater affinity than morphine
- Affinity less than buprenorphine
Adverse drug response
- Short half life
- Must give as slow infusion (gradual displacement of morphine)
- If given in a rapid bolus will rapidly wear off the effect of morphine, however then the effects of morphine may become toxic again rapidly because its not been metabolised/excreted yet
Contraindication naloxone
- Pts known to be hypersensitive
- Cardiac problems- caution
Drug-drug interactions nalxoone
- Codeine
- Tramadol
- Opium
- Morphine (good)
overdose epidemic
- Growing problem
- Large number of iatrogenic addicts
- 1 in 4 will develop addiction
- 9.6% rise in drug related deaths 2016à2017
- 67.8% caused by opiates

How is overdose mediated
- U (MOP) receptor
- As you take more and more you need to take more to get relief
- Variable effects of doses
- Main cause of death is resp depression- acidosis
- Naloxone= treatment
- Be a vigilant prescriber

Special considerations
- Manual labourers/Drivers
- Elderly
- Bedbound
- Asthmatics
- Biliary tract obstruction
- Respiratory Diseases
- Renal impairment
- Pregnancy
Contraindications
- Hepatic failure
- Acute respiratory Distress
- Comatose
- Head injuries
- Raised ICP
which opioids are used for palliative prescriving
- Buprenorphine, diamorphine, fentanyl, morphine and oxycodone
- Difficult area of prescribing
- Tend to ignore special considerations
palliative prescribing of opioids
- Difficult area of prescribing
- Tend to ignore special considerations
- Indications: Pain, Shortness of breath
- Manage side effects: nausea, constipation
- Last Months to Weeks of life
- Long acting background level of pain control
- Short acting top up doses for extra
- Last Days to Hours of life
- Continuous subcutaneous infusion
- Top up doses as needed

Opioids as controlled drugs
- Controlled under Misuse of Drugs Legislation
- Aim to prevent
- Misuse
- Illegal obtainment
- Harm being caused
- Benefit of medical use vs Risk of harm

How to prescribe opioids
- Start low and titrate up
- Remember paracetamol element
-
Must include:
- Date and prescribers address and Full name
- Patients address and name
- Form of the drug- tablets, syrup, capsules, patches, ampoules etc
- Units- mgs, mls etc
- Total volume- in words and figures
- Clearly defined dose
