2.3 Opioids Flashcards
Draw the Steps involved in pain pathway
page 50/353 of regional book
Analgesics Sites of action / mechanism / examples
Transduction
Transduction:
act at the site of injury
and prevent action of
inflammatory mediators
NSAIDs Antihistaminics Membrane-stabilising agents Opioids Bradykinin and serotonin antagonists Local anaesthetics
Analgesics Sites of action / mechanism / examples
Transmission
Transmission:
alter nerve conduction
Local anaesthetics
Analgesics Sites of action / mechanism / examples
Modulation:
Modulation:
modify spinal and supraspinal modulation
Intrathecal and epidural opioids
α2 Agonists NMDA antagonists:
ketamine,
magnesium,
tramadol
Analgesics Sites of action / mechanism / examples
Perception:
Perception:
act centrally to reduce perception
Parenteral opioids
α2 Agonists
General anaesthetics
Analgesics Sites of action x4
Transduction
Transmission
Modulation
Perception
Opioid receptors are what type
Opioid receptors are a
group of G protein–coupled receptors
with .
what are their ligands
opioids as ligands
Name endogenous opioids
The endogenous opioids are dynorphins, enkephalins, endorphins and nocioceptin.
Are receptors localised to central tissues
Opiate receptors are distributed widely in the brain, spinal cord and peripheral tissues.
Name the opioid receptors
OP1 - Kop
OP2 - Dop
OP3 - Mop
OP4 - Nop
Receptor Endogenous Desirable Undesirable
OP1
OP1
(KOP/Ќ)
Dynorphin
β- Endorphin
Analgesia
Dysphoria, psychomimetic effects, dieresis
KOP inhibits descending inhibitory pathways, hence is anti-analgesic
Receptor Endogenous Desirable Undesirable
OP2
OP2
(DOP/δ)
Enkephalin
β- Endorphin
Supraspinal and spinal analgesia,
sedation
Constipation,
physical dependence
Receptor Endogenous Desirable Undesirable
OP3
OP3
(MOP/μ)
Enkephalin
β- Endorphin
Supraspinal and
spinal analgesia,
sedation Respiratory depression, bradycardia, miosis, urinary retention, pruritis, nausea and vomiting, constipation, physical dependence
Where is MOP
MOP is present
in para-aqueductal grey (PAG) of brain
and
descending inhibitory control pathway,
and mediates most of the
actions of opioids.
It augments descending inhibition
(reducing pain or
providing analgesia).
Receptor Endogenous Desirable Undesirable
OP4
OP4
(NOP)
Nociception
Nil
Anti-analgesia
Is the sigma receptor and Opioid receptor
The effects of sigma (σ) receptor are
not antagonised by naloxone,
and hence this receptor is
not classified as an
opioid receptor anymore.
Activation of opioid receptor
by an opioid molecule produces:
3 effects
- Hyperpolarisation by K+ efflux
- Inhibition of Ca+ influx,
preventing neurotransmitter release - Inhibition of adenylate cyclase
Site and action Effects Example
Presynaptic
Site and action
1 Inhibition of adenylate cyclase
(needed for Ca+ influx)
2 Inhibition of Ca+ influx
3 Facilitation of K+ efflux
(hyperpolarisation)
Effects
Failure of excitatory neurotransmitter
release (glutamate) at dorsal horn
Example
KOP and NOP:
prevent Ca+ influx
MOP, DOP: facilitate
K efflux
Site and action Effects Example
Post-synaptic
Post-synaptic
Facilitation of K+ efflux
(hyperpolarisation)
Failure of action potential generation
MOP, DOP: facilitate
K+ efflux
Opiate refers
Opiate refers to only the alkaloids in opium and the natural and semisynthetic derivatives of opium.
The term opioid
The term ‘opioid’ includes all
naturally occurring or synthetic drugs
that have stereospecific actions at
opioid receptors,
the effects of which can
be antagonised by naloxone.
TABLE 2.11 Classification of opioids by synthesis
Endogenous
Natural
Endogenous Semi-synthetic Fully synthetic Opioid-like drugs
Endorphins
Enkephalin
Dynorphine
Nociception
Morphine
Codeine
Thebaine
Semi-synthetic
Fully synthetic
Opioid-like drugs
Semi-synthetic
Heroin Hydromorphone Hydrocodone Oxymorphone Oxycodone Buprenorphine Dextrometharphan
Fully synthetic
Pethidine Fentanyl Alfentanyl Remifentanyl Sufentanil
Opioid-like drugs
Tramadol
Opioids by action @ receptor
MOP
agonist
partial
antagonist
MOP (μ)
Agonist
Morphine, pethidine, methadone,
fentanyl, alfentanyl,
remifentanyl sufentanil
Partial agonist
Buprenorphine
Antagonist Naloxone Naltrexone Pentazocine Nalorphine
Opioids by action @ receptor
DOP
agonist
antagonist
DOP (δ)
ag
Morphine (μ > δ) Pentazocine
Nalorphine
antag
Naloxone
Naltrexone
What is tolerance
context of opioids
Tolerance and dependence are induced
by chronic exposure to opioids.
Tolerance means that
higher doses of opioids
are required to
produce the same effect,
reducing the maximum response attainable.
what is responsible for tolerance
It is mainly due to
receptor desensitisation.
Does tolerance develop to adverse effects of opioids
Tolerance develops to most of the
adverse effects as well,
like dysphoria, itching, urinary retention and respiratory depression,
does tolerance occur to adverse effects the same rate
is there any side effects that do not display tolerance
but occurs more slowly to the
analgesia and
other physical side effects.
However, tolerance does not develop to constipation or miosis.
How is analgesic efficacy determined
Analgesic efficacy is determined
by calculating the
‘number needed to treat (NNT)’.
NNT is defined as the
average number of patients
who need to be treated (with analgesic drug)
to prevent one additional bad outcome
(pain).
What is it the inverse of
It is defined as the inverse of the absolute risk reduction.
NNT =
1 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ (proportion of patients with at least 50% pain relief with analgesic – proportion of patients with at least 50% pain relief with placebo)
How can analgesics be compared
Various analgesics have been compared in the
Oxford league table of analgesic efficacy.
Codeine 60 mg is least efficacious,
while selective COX-2 inhibitors are most efficacious.
Opioids and their metabolites
Drug
Morphine
Enzyme system
Morphine
UGT2B7
Morphine-6-glucuronide
(10% but active)
Morphine-3-glucuronide
(80% but inactive)
Moprhine
Active metabolite
Actions
M6G: analgesia
M3G: hyperalgesia
Opioids and their metabolites
Drug
Diamorphine
Enzyme system
Active metabolite
Actions
Diamorphine
Ester hydrolysis
6-Monoacetylmorphine (MAM)
and
morphine
Morphine is active component
Opioids and their metabolites
Drug
Pethidine
Enzyme system
Active metabolite
Actions
Pethidine
CYP3A4
Norpethidine
50% analgesic action;
neurotoxicity
Opioids and their metabolites
Drug
Codeine
Enzyme system
Active metabolite
Actions
Codeine
CYP2D6
Morphine, nor codeine Morphine:
analgesia
Opioids and their metabolites
Drug
Tramadol
Enzyme system
Active metabolite
Actions
Tramadol
CYP2D6
O-desmethyltramadol (M1 metabolite)
Analgesia
Inactive metabolite of fentanyl
What is proparacetamol
norfentanyl is an inactive metabolite of fentanyl;
propacetamol is a prodrug of paracetamol.
Conversion of Morphine PO into diff routes / drugs
Take 10 pO
IV morphine
IM
S/C
S/C diamorphine
Periop doses +-/
Route Ratio (as compared to oral morphine)
Example
Oral morphine 1 : 1 30 mg
Intravenous morphine 1 : 3 10 mg
Intramuscular morphine 1 : 2 15 mg
Subcutaneous morphine 1 : 2 15 mg
Subcutaneous diamorphine 1 : 4
(as diamorphine has two molecules of morphine)
7.5 mg
Perioperative doses ± 20%
Epidural dose of Morphine
Intrathecal
Compared to PO dose
Epidural dose of morphine is 1 : 10 of oral (up to 5 mg),
while intrathecal is 1 : 100 (100–200 mcg).
Morphine Important facts
What type of pain is morphine very effective against
vs
what type less effective
Salient features of morphine are as follows.
Particularly effective for visceral pain,
while less effective for sharp pain.
How does morphine cause N+V
where what receptors
Nausea and vomiting:
stimulation of CTZ
(5-HT3 and dopamine receptors).
Morphine
What side effects of rapid release
by what effect
How is this reversed
Can cause histamine release if
administered rapidly or in large doses,
resulting in bronchospasm and hypotension;
take naloxone.
Morphine
When do patients experience more severe pruritis
how is it mediated
How is it treated
What other meds can be used to Rx
Is there anything noveau used
Pruritus when given intrathecally or epidurally.
It is not histamine mediated
treated with naloxone.
Ondansetron, propofol and
antihistaminics have been used.
Recent peripherally acting antagonists such as methylnaltrexone have been used to reverse peripheral side effects without reversing centrally mediated analgesia.
Morphine
What effect can it have on the eye
How is this mediated
How is it reversed
Meiosis
through stimulation of
Edinger–Westphal nucleus;
reversed by atropine.
Morphine
How can it affect fluid balance
Can induce antidieresis by
increasing antidiuretic hormone secretion,
resulting in water retention and hyponatremia.
Morphine
What affect can it have on ventilation
How is this mediated
Chest wall rigidity
mediated by interaction with
dopaminergic and GABAergic
pathways in substantia nigra and striatum.
Difficulty in ventilation can result following administration of opioids at induction:
take with muscle relaxants
PK
PO
How is morphine prepared
How does this affect its absorption
How does this affect onset
Whats PO bioavail
why
Morphine is a weak base,
hence it is absorbed from the small bowel.
This delays absorption and results in slow onset of oral dose.
Oral bioavailability is 30% because of
high first-pass metabolism in liver.
Morphine
IV
IM
Bioavail
Speed onset
How is absorption S/C route
Why
Intravenous and intramuscular
bioavailability are higher
and onset is faster
(10 and 30 minutes, respectively).
Because of low lipid solubility,
its absorption from the subcutaneous
route is slow and so is usually avoided.
Neuraxial morphine issues
why
Neuraxial morphine is
associated with rostral spread
and
delayed respiratory depression.
How is morphine metabolised
To what
What are their relative proportions
It is metabolised by
UGT2B7 to
active
morphine-6-glucuronide
(M6G)
(10%–30%)
and
an
inactive morphine-3-glucuronide
(M3G)
(70%– 90%).
What is the active metabolite of morphine
What is its potency vs Morphine
How is its PK differ
What is an issue with the inactive metabolite
M6G is
two to four times as potent as morphine,
is more hydrophilic,
stays in the brain for a
longer period and
undergoes enterohepatic circulation.
M3G may be associated
with morphine induced
hyperalgesia
Morphine disposition in susceptible populations
Age < 3 months
Patient group
Characteristic
Effect and implication
Age < 3 months
Reduced conjugation
and renal excretion ability
Prolonged duration,
so be cautious;
prefer shorter acting
opioids (fentanyl > morphine)
Morphine disposition in susceptible populations
Patient group
Elderly
Characteristic
Effect and implication
Elderly
Reduced Lean mass
and hepatic blood flow
Increased sensitivity
Reduce doses
Morphine disposition in susceptible populations
Patient group
Characteristic
Effect and implication
High body
mass index
High body mass index
Lean body weight < total body weight
Higher chances of obstructive sleep apnoea
Calculate doses according to lean body weight
Careful use of sedatives and opioids in view of
obstructive sleep apnoea
Morphine disposition in susceptible populations
Liver failure
Patient group
Characteristic
Effect and implication
Liver failure
Reduced metabolism and
increased elimination half-life
Increased sensitivity (along with encephalopathy)
Cautious use in small titrated doses
Morphine disposition in susceptible populations
Patient group
Renal failure
Characteristic
Effect and implication
Renal failure
Accumulation of M6G metabolite
(renally excreted)
Uraemic encephalopathy may increase sensitivity
