Analgesia: Opioids Flashcards
what are opioids most commonly used for?
perioperative analgesia
why are opioids less commonly used for chronic pain management?
poor oral bioavailability of opioids
in what pain states are opioids less effective?
neuropathic (e.g. brachial plexus avulsion where there is significant nerve damage)
what are the main pharmacological effects of opioids in mammals?
analgesia
sedation
excitation
bradycardia
respiratory depression
nausea and vomiting
decreased GI motility
varied urinary effects
antitussive
minimal effect on inotropy
effects on the pupil
when is excitation most often seen following opioid administration?
in pain free animals when giving as a premed
when does opioid induced bradycardia have most effect?
when the patient is anaesthetised
why do opioids cause respiratory depression?
depresses bodies response to rising CO2 so that respiratory drive now comes from lack of oxygen which is physiologically abnormal
when are nausea and vomiting most commonly seen following opioid administration?
when used as a premed in pain free animals
what are the main urinary effects seen with opioids?
increased or decreased micturition
reduced sensitivity to urge to urinate
what is inotropy?
heart contractility
what are the effects of opioids on the pupil in dogs?
miosis
what are the effects of opioids on the pupil in cats?
mydriasis
how do opioids have effect within the body?
mimic naturally occurring opioid peptides (neurotransmitters)
what are the endogenous naturally occurring opioid peptides?
beta-endorphin
leucine and methionine enkephalins
dynorphins
where are opioid receptors mostly found?
brain and spinal cord
what are the main opioid receptors found in the brain and spinal cord?
mu
kappa
delta
NOP
what does NOP stand for?
nociceptin opioid peptide
what is the endogenous ligand for the NOP receptor?
nociceptin
what are the subtypes of the delta opioid receptors?
delta 1
delta 2
where are delta opioid receptors located?
brain
peripheral sensory neurones
what is the function of delta opioid receptors?
analgesia
antidepressant
convulsant
physical dependence
what can be modulated by delta opioid receptors?
mu-opioid receptor-mediated respiratory depression
what types of kappa opioid receptor are there?
kappa 1
kappa 2
kappa 3
where are kappa opioid receptors located?
brain
spinal cord
peripheral sensory neurones
what is the function of kappa opioid receptors?
analgesia
anticonvulsant
depression
dissociation/hallucinogenic
diuresis
miosis
dysphoria
neuroprotection
sedation
stress
what opioid receptor provides the most effective analgesia?
mu
what types of mu receptor are there?
mu 1
mu 2
mu 3
where are mu opioid receptors found?
brain
spinal cord
peripheral sensory neurones
intestinal tract
what are the functions of mu 1 receptors?
analgesia
physical dependance
what are the functions of mu 2 receptors?
respiratory depression
miosis
euphoria
reduced GI motility
physical dependance
what are the functions of mu 3 receptors?
possible vasodilation
where can morphine be obtained from?
directly extracted from opium which is taken from the fried latex of poppy seed pods
how are opioids such as methadone and pethidine produced?
synthetically developed
where do all commercially available opioid drugs act?
opioid receptors
what information will suggest how an opioid drug will act?
receptors or receptor subtypes they act at
mechanism of action at these receptors
pharmacokinetics
species differences
what does the pharmacokinetics of a drug describe?
what the body does with the drug, how they are taken up by the body, transported and broken down
what are the main mechanisms of action at opioid receptors?
full agonist
partial agonist
mixed agonist-antagonist
antagonist
what mechanism of action at an opioid receptor provides the most effective analgesia?
full agonist
what type of opioids provide the most effective analgesia?
full mu agonist
what drugs are examples of full agonists?
methadone
fentanyl
what drugs are examples of partial opioid agonists?
buprenorphine
what drugs are examples of mixed agonist-antagonist?
butorphanol
what drug is an example of an opioid antagonist?
naloxone
what is the difference between full and partial agonists?
full agonists bind to and activate a receptor with the maximum response that an agonist can elicit at that receptor
partial agonists bind to and activate a receptor but only have partial efficacy even if they bind to all receptors
what does the potency of a drug describe?
how much of a drug is required to have an effect
what does the efficacy of a drug describe?
how much effect of the drug is seen at full receptor occupancy
why do the formulation concentrations of methadone and buprenorphine differ so much?
due to differences in potency - buprenorphine is more potent so requires less mg/kg to see effect
why is methadone better for severe pain than buprenorphine?
methadone is more effective than buprenorphine
describe the efficacy and potency of fentanyl
highly effective and potent making overdose likely
what are the routes of administration for opioids?
IM
SC
IV
OTM
transdermal
epidural/spinal
(not all by all routes)
what opioid cannot be administered by IV injection?
pethidine
why must pethidine not be administered IV?
risk of allergic reaction
what route of administration of opioids gives poor bioavailability?
oral
why does oral administration of opioids lead to poor bio-availability?
significant first pass metabolism of opioids by liver so are broken down before reaching site of action
what route of administration of buprenorphine may be less efficacious in cats?
SC
why does oral transmucosal administration of opioids provide better bioavailability than oral?
bypass of liver due to absorption across oral mucous membranes rather than swallowing
why are opioids limited in use for chronic pain?
not useful when administered orally due to poor bioavailablity
what are the advantages and disadvantages of IV administration of opioids?
rapid onset, reliable uptake, painless with no volume restriction
need IV access
what are the advantages and disadvantages of IM administration of opioids?
reliable uptake
painful, especially high volumes
what are the advantages and disadvantages of SC administration of opioids?
easy to perform
unreliable uptake
what are the advantages and disadvantages of OTM administration of opioids?
easy to perform
only certain opioids (buprenorphine in cats)
what are the advantages and disadvantages of transdermal administration of opioids?
good for chronic use
no licenced products
what are the advantages and disadvantages of epidural/spinal administration of opioids?
very effective analgesia for right cases (usually intraoperative analgesia)
no licenced opioids, technically difficult
what needs to be considered when planning what analgesic to use?
efficacy
duration of action
potential for adverse events
what must be balanced when deciding whether to use a more efficacious opioid?
need for severe pain management balanced against potential side effects
what controls the effect of a drug irrespective of how it acts?
concentration of drug at the site of action
what does the onset of action of a drug depend on?
route of adminstration - how long the drug will take to get to its site of action and will it all arrive at a similar time (e.g. IV fast and bolus)
potency - how much needs to be bound before effect is seen
how quickly the drug is removed form the receptors
when is peak effect of a drug seen?
when all the drug is sitting in a receptor
how long is the duration of action of fentanyl?
ultra short - 20mins
what are ultra short acting opioids used for?
intraoperative bolus
short term infusion (CRI)
what are the short acting opioids?
butorphanol, pethidine
how long do short acting opioids such as butorphanol last for?
2 hours
how long do medium acting opioids such as methadone last for?
2-4 hours
what are the medium acting opioids?
methadone
morphine
what are the longer acting opioids?
buprenorphine
how long do longer acting opioids like buprenorphine last for?
6 hours
what are short, medium and longer acting opioids used for?
general use for acute, pre, peri and post operative pain
part of a multimodal analgesia regimen
what may medium and longer acting opioids be used for that short acting would not?
painful patient (e.g. RTA)
what must be considered if the patient will require opioid treatment for more than a few hours?
frequency of re-dosing and the chance of opioid accumulation
what effect does dose have on duration of action?
higher dose = duration of action increased
what is the fomulation of all currently vet licensed opioids?
immediate release - what you give is what you get
what are the 4 main misconceptions around opioid administration?
opioids cause mania in cats
opioids cannot be re-dosed within expected duration of action
respiratory depression can occur
opioids cannot be combined with other classes of analgesic drug
how can the common misconception that opioids cause mania in cats be challenged?
only seen at very high doses and in pain free patients (e.g. as part of a premed)
how can the common misconception that opioids cannot be re-dosed within their expected duration of action be challenged?
if analgesic effect has worn off the patient can be redosed
how can the common misconception that opioids cause respiratory depression be challenged?
less significant than in humans
mostly an issue under GA when the patient should have a controlled airway and could e ventilated anyway
how can the common misconception that opioids should not be combined with other classes of analgesic drug be challenged?
great for multimodal analgesia
don’t usually give different opioids together though
what opioids are ultra short acting full mu agonists?
fentanyl
alfentanil
sufentanil
remifentanil
what species is fentanyl licenced for?
dogs
cats
horses
rabbits
what opioids are medium acting full mu agonists?
morphine
methadone
pethidine
what species is methadone licenced for?
dogs
cats
what species is morphine licensed for?
dogs
cats
horses
what opioids are longer acting partial mu agonists?
buprenorphine
what species is buprenorphine licensed for?
dogs
cats
rabbits
what opioids are short acting mixed kappa agonist mu antagonists?
butorphanol
what species is butorphanol licensed in?
dogs
cats
rabbits
why are opioids controlled drugs?
due to risk of abuse by humans rather thn clinical safety
what is a significant advantage of opioids?
can re-dose until desired effect is achieved
wide safe dosage range
what do side effects of opioids relate to?
potency
what opioids have the greatest likelihood of side effects?
those with the greatest analgesic efficiency
when are side effects of opioids more likely?
when the animal is not in pain
what are the useful clinical effects of opioids?
analgesia
sedation
antitussive (less evidence then in humans)
what are the main side effects of opioids that cause concern?
respiratory depression
bradycardia
is opioid mediated respiratory depression usually clinically significant in awake patients?
no - only really seen under GA
what is bradycardia following opioid administration mediated by?
vagus nerve
what can vagally mediated bradycardia following opioid administration be treated with?
anticholinergic
what is an example of an anticholinergic that may be used to treat vagally mediated bradycardia following opioid administration?
atropine
glycopyrrolate
is atropine licensed for veterinary use to treat vagally mediated bradycardia following opioid administration?
yes
is glycopyrrolate licensed for veterinary use to treat vagally mediated bradycardia following opioid administration?
no
what may low dose anticholinergic cause when given for vagally mediated bradycardia following opioid administration?
worsening of brady cardia
what may high dose anticholinergic cause when given for vagally mediated bradycardia following opioid administration?
tachycardia
what is the ideal way to treat vagally mediated bradycardia following opioid administration?
atropine IM
what should you do if the patient remains bradycardic following administration of an anticholinergic to treat vagally mediated bradycardia?
give more
what should you do if the patient becomes tachycardic following administration of an anticholinergic to treat vagally mediated bradycardia?
wait!
what are the less concerning side effects of opioids?
sedation (sometimes desirable)
excitation
gut stasis
nausea and vomiting (patient dependent)
when may sedation following opioid administration be an issue?
if drugs are accumulating when the patient has been given opioids for a longer period
how can sedation following long periods of opioid dosing be avoided?
decrease frequency of dosing
what can be done to reduce the risk of excitation as a side effect of opioid administration?
IM
titrate opioid dose to pain level
what must be balanced when considering gut stasis as a side effect of opioid administration?
pain also leads to gut stasis so must be balanced
list the analgesic efficacy of opioids from most to least effective
fentanyl
methadone and morphine
pethidine
buprenorphine
butorphanol
when is morphine more likely to be used than methadone clinically?
CRI
what are the main side effects of fentanyl?
some dose dependent respiratory depression
likely to induce bradycardia
when is fentanyl most useful?
CRI as short acting
how effective is methadone compared to morphine?
equi or more efficatious
is nausea and vomiting increased or decreased with methadone compared to morphine?
reduced
is methadone linked to histamine release when given IV?
no concerns
why may morphine be better in a CRI than methadone?
may be less accumulative
what are the respiratory and CVS side effects of methadone?
minimal
how does methadone interact with NMDA receptors?
antagonist - helps with chronic pain and prevention of upregulation of pain response
what is the role of an NMDA receptor antagonist?
bind to glutamate binding sites on NMDA and prevent release of calcium
where are NMDA receptors found?
CNS
what limits pethidine post operative use?
short acting
what is the issue with giving pethidine IM?
painful - large volume
what is the issue with giving pethidine IV?
histamine release caused
why may there be pain on buprenorphine injection?
multi-dose formulation uses preservative which stings and not palatable OTM in cats
what route may buprenorphine be less effective?
SC
what is the onset of action of buprenorphine?
delayed for analgesia and sedation
where should buprenorphine be stored?
in with controlled drugs and usage recorded
what schedule is buprenorphine?
3
what schedule are all other opioids?
2
what is the analgesic efficacy of butorphanol like?
questionable
short-lived and likely to require high doses
what is a disadvantage of using butorphanol if patient is more painful than thought?
may interfere with any subsequent full agonist administration
what is the sedation provided by butorphanol like?
good
is butorphanol subject to controlled drugs regulations?
no
what is naloxone used for?
specific antagonist so can reverse effects of an opioid (e.g. if significant side effects)
what must be done if naloxone is given?
alternative analgesia provided as analgesia reversed
what are the key areas of perioperative analgesia planning?
plan based on patients current and anticipated pain
provide analgesia before it is needed
pain score regularly
consider multimodal analgesia
what is preventative analgesia?
provision of analgesia before it is needed
when selecting an opioid for premed of a patient with moderate to severe pain (e.g. fracture repair) which would you chose?
methadone
when selecting an opioid for premed of a patient with moderate pain (e.g. ex lap) which would you chose?
methadone
pethidine
when selecting an opioid for premed of a patient with mild pain (e.g. castration) which would you chose?
buprenorphine
when selecting an opioid for premed of a patient for sedation only which would you chose?
butrophanol
what must be balanced when choosing which opioid to use?
side effects against analgesia needed
when selecting an opioid for intraoperative management of moderate to severe pain which would you chose?
methadone
fentanyl (bolus or CRI)
epidural (morphine)
when selecting an opioid for intraoperative management of moderate pain which would you chose?
methadone
fentanyl (bolus or CRI)
when selecting an opioid for intraoperative management of mild pain which would you chose?
unnecessary
what are alternative options to additional opioids for intraoperative analgesia?
regional or local anaesthetic techniques
adjunctive drugs (ketamine/alpha 2)
what is the benefit of using local / regional anaesthetic techniques during anaesthesia?
increased CVS stability
MAC sparing
what are the main considerations for postoperative analgesia?
optimal route of administration
dosing intervals
what is the dosing interval for methadone?
4-5 hours
what is the dosing interval for buprenorphine?
every 6 hours
what can be done to prevent accumulation of methadone if being administered repeatedly over days?
increase time interval to 12-18 hours
describe the opioid ladder
mild post op pain: buprenorphine and NSAIDs
more invasive techniques: buprenorphine and NSAIDs with adjunctive techniques
Moderate pain: methadone, NSAIDs and adjunctive analgesia
severe pain: CRI with morphine
if this is inadequate switch to fentanyl or add additional drug like dexmed, ketamine or lidocaine
what is the benefit of a CRI for severe pain management?
avoids peaks and troughs in analgesia which occur with bolus dosing
