Analgesia Flashcards
why are opioids less commonly used for chronic pain management?
due to poor oral bioavailability
which class of analgesia is not often used for chronic pain management?
opioids
why are opioids a good choice as a perioperative drug?
They give good sedation and analgesia
What effect can opioids have at high doses?
excitation
what effect do opioids have on the heart?
bradycardia
what effect do opioids have on respiratory drive?
cause respiratory depression
what effects do opioids have on the GI system?
nausea and vomiting (premed), decreased GI motility
what effects do opioids have on the urinary system?
various urinary effects - bladder less sensitive to urge to urinate
which class of analgesic can have antitussive effects?
opioids
what effect do opioids have on inotropy?
minimal effect
what effects do opioids have on the eyes?
effects on the pupil - miosis in dogs (and most mammals), mydriasis in cats
what are the pharmacological effects of opioids in mammals?
analgesia
sedation
excitation
bradycardia
respiratory depression
nausea and vomiting, decreased GI motility
various urinary effects
antitussive
effects on pupil (miosis/mydriasis)
what type of system is the opioid system?
endogenous
what are the 3 families of naturally occurring opioid peptides (neurotransmitters)?
beta-endorphin
leucine and methionine - enkephalins
dynorphins
where are the opioid receptors mainly found?
in the brain and spinal cord
what are the 4 types of opioid receptor?
mu
kappa
delta
NOP (nociceptin opioid peptide) receptor
what are the subtypes of the delta opioid receptor?
delta 1 and 2
where are the delta opioid receptors found?
brain
peripheral sensory neurones
what is the function of the delta opioid receptors?
analgesia
antidepressant effects
convulsant effects
physical dependence
may modulate mu opioid receptor-mediated respiratory depression
what are the subtypes of the kappa opioid receptor?
k1, k2, k3
where are the kappa opioid receptors located?
brain
spinal cord
peripheral sensory neurones
what is the function of the kappa opioid receptors?
analgesia and sedation
anticonvulsant effects
depression
neuroprotection
dissociative/hallucinogenic effects
dysphoria
diuresis
miosis
stress
what are the subtypes of the mu opioid receptor?
mu 1, mu2, mu3
where are the mu opioid receptors located?
brain
spinal cord
peripheral sensory neurones
intestinal tract
what are the functions of the mu1 opioid receptors?
analgesia
physical dependence
what are the functions of the mu2 opioid receptors?
respiratory depression
miosis
euphoria
reduced GI motility
physical dependence
what are the functions of the mu3 opioid receptors?
possible vasodilation
where do opioid drugs act?
at the opioid receptors
what common opioid drugs are full agonists?
methadone and fentanyl
what common opioid is a partial agonist?
buprenophine
what common opioid is a mixed agonist-antagonist?
butorphanol
what is the antagonist for opioids?
naloxone
which opioids are associated with analgesia?
mu agonists
which opioids provide the most effective analgesia?
full mu agonists
why are full agonists effective analgesic agents?
they bind to and activate a receptor with the maximum response that an agonist can elicit at that receptor
why are partial agonists less effective than full agonists?
they bind to and activate a receptor but only have partial efficacy, even if they bind to all receptors
what is potency?
the amount of drug required to see a given effect
what is efficacy?
the relative ability of a drug-receptor complex to produce a maximum functional response
which is more potent out of methadone and buprenorphine?
buprenorphine
which is has better efficacy, methadone or buprenoprhine?
methadone
by which routes can opioids be administered?
IV
orally
subcut
IM
oral transmucosal (buccal)
why is pethidine not administered IV?
can induce allergic reactions
what route of opioid administration is less efficacious in cats?
subcut buprenorphine
why do opioids have poor oral bioavailability?
very significant first pass metabolism
what are the advantages of administering opioids IV?
rapid onset of action
reliable uptake
painless - drug volume unimportant
what are the disadvantages of administering opioids IV?
need IV access
what is the advantage of administering opioids IM?
reliable uptake
what is the disadvantage of administering opioids IM?
painful, particularly if administering large volumes
what is the advantage of administering opioids SC?
easy to perform
what is the disadvantage of administering opioids SC?
unreliable uptake
what is the advantage of administering opioids OTM?
easy to perform
what is the disadvantage of administering opioids OTM?
only certain opioids (cats and buprenorphine)
what is the advantage of administering opioids transdermally?
good for chronic use
what is the disadvantage of administering opioids transdermally?
no licensed products
what is the advantage of administering opioids epidural/spinal?
very effective analgesia for the right cases (mostly intraoperative)
what is the disadvantage of administering opioids eipdural/spinal?
no licensed opioids for this
technically difficult
what does the onset of action of a drug depend on?
route of administration
what is the peak effect of a drug?
the time it takes for a drug to reach the maximum concentration after administration of a drug that needs to be absorbed
which opioids are ultra-short-acting?
fentanyl (mins)
unlicensed - alfentanil, sufentanil, remifentanil
which opioids are short-acting (2hrs)
butorphanol
pethidine
which opioids are medium-acting (2-4hrs)
methadone and morphine
which opioids are longer-acting (6hrs)
buprenorphine
what has the main effect on duration of action of an opioid?
dose given
what are the 4 most common misconceptions surrounding opioid administration to animals?
opioids cause mania in cats
opioids cannot be re-dosed within their expected ‘duration of action’
respiratory depression can occur
opioids cannot be combined with other classes of analgesic drug
why is ‘opioids cause mania in cats’ a misconception?
only occurs at really high doses and generally in pain-free cats e.g. overdosing at pre-med
why is ‘opioids always cause respiratory depression’ a misconception?
it is a significant issue in humans but with vet patients it is mostly an issue with patients who are anaesthetised where there is airway control and we can ventilate if necessary
which other drug cannot be given with opioids?
tramadol (and other opioids)
which opioid is a partial mu agonist?
buprenorphine
which opioid is a kappa agonist?
butorphanol
what do side effects of opioids mostly relate to?
potency - those with greatest analgesic efficacy have the greatest likelihood of side effects
when are side effects of opioids less likely to be seen?
when the animal is in pain
how do opioids cause bradycardia and how can this be treated?
vagally mediated
can be treated with anticholinergics (atropine, glycopyrrolate)
what can occur with low IV doses of anticholinergics to treat bradycardia?
might promote a worsening of the bradycardia
what can occur with high IV doses of anticholinergics to treat bradycardia?
tachycardia
how should you manage accumulation of opioids in the body?
decrease frequency of dosing
why can management of gut stasis with opioid use be tricky?
pain causes reduced gut motility but so do opioids
list the common opioid drugs in order of analgesic efficacy (least to most)
butorphanol
buprenorphine
pethidine
methadone and morphine
fentanyl
when might morphine be a better choice clinically than methadone?
if a CRI is needed
what are the effects of fentanyl?
dose-dependent respiratory depression
bradycardia
useful for CRI as very short-acting
what are the advantages of methadone compared to some other opioids?
equi-or more efficacious analgesia and reduced nausea/vomiting compared to morphine
minimal CVS and respiratory side effects
why is pethidine rarely used in practice?
short acting - limits post-operative use
large volume - painful IM
histamine release if given IV
methadone is just better lol
why is buprenorphine painful on injection and not palatable to cats?
multi-dose preparation has preservative
which schedule 3 opioid should be kept in a locked cupboard?
buprenorphine
does butorphanol have good analgesic efficacy?
no - if any it is short lived, likely to require higher doses than given clinically
does butorphanol give good sedation?
yes
why is butorphanol attractive to practitioners?
not subject to controlled drugs regulations
what must be considered when using naloxone?
analgesic effect of opioid will also be reversed - need to provide alternative
what is the advantage of using intra-operative local analgesia?
spares inhalational agent in CVS unstable patients
what dosing interval should be used for methadone if being administered repeatedly over several days?
12-18 hours to prevent accumulation
which opioids are used for CRI?
morphine, fentanyl if morphine inadequate
how do local anaesthetics work (broadly)?
by preventing an action potential in the nerve, preventing nerve conduction
what causes an action potential?
voltage-dependent opening of Na+ and K+ channels in the cell membrane
what does the Na/K pump do?
pump ions against their concentration gradient to maintain an electrical gradient
how is the membrane depolarised?
rate of Na+ entry exceeds K+ exit
how is the action potential generated
depolarisation sets off a Na+ positive feedback whereby more voltage=gated Na+ channels open and the membrane becomes more depolarised - if a threshold is reached, an AP is generated
how does the membrane repolarise?
when Na+ channels become inactivated and a special set of K+ channels open and K+ leaves the axon
where are voltage operated Na+ channels present?
in all excitable tissues
what do local anaesthetics do to the sodium channels?
block them, therefore blocking nerve conduction
what effect are local anaesthetics said to have?
membrane stabilising effect
what are the main types of nerves in the body?
motor, sensory and autonomic
what are the different types of sensory nerves?
proprioceptors, mechanoreceptors and nociceptors
what are the types of autonomic nerves?
preganglionic B
postganglionic C
why are larger diameter axons more resistant to LA block?
they are more heavily myelinated
which axons are more resistant to LA block?
larger diameter axons - more heavily myelinated
which axons are more susceptible to LA block?
c fibres (unmyelinated)
Aδ fibres (thinly myelinated)
why is there a nociceptive block before proprioceptive/mechanoreceptive/motor blockade?
C fibres and Aδ (nociceptive) fibres are preferentially blocked
which types of linkage can a LA have in structure?
ester or amide
what is the basic structure of a LA drug?
an aromatic group (lipophilic) with a basic side chain/tertiary amine (hydrophilic)
with an ester OR amide linkage
why is the side chain important in LAs?
only the uncharged form can penetrate lipid membranes and enter the nerve cell
what is the pKa of LAs?
weak bases (pKa 8-9)
how does the pKa affect onset of action of LAs?
the higher the pKa, the slower the onset of action
why are LAs less effective in inflamed tissue?
a greater proportion of the drug will be ionised and therefore less drug can penetrate the nerve membrane to bind to the sodium channel
list lidocaine, bupivicaine, procaine and ropivacaine in order of toxicity (least to most)
procaine
lidocaine
bupivacaine
ropivacaine
what is the relationship between LA toxicity and potency?
toxicity increases as potency increases
what affects the duration of action of LAs?
ease of penetration and amount of drug reaching sodium channels (lipid solubility)
strength of binding to the sodium channels
speed of removal (dependent on tissue perfusion)
metabolism of LA (ester vs amide)
what is the easy way to remember ester vs amide?
ester - no i in the name before the -caine
amide - i in the name before the -caine
how stable are ester linkages?
relatively unstable
how are ester linkages broken down?
rapidly broken down by pseudocholinesterase - hydrolysis of the ester link
which LA linkage is more stable?
amide linkage
how are LAs with amide linkage metabolised?
subject to biotransformation with conjugation in the liver
do ester or amide linkages have a longer half life?
amide linkages
what is formed as a product of ester hydrolysis?
PABA
what can production of PABA result in?
allergic reactions
how is PABA formed?
as a product of ester hydrolysis
does the CSF contain esterases?
no
what breaks down the amide link?
cytochrome P450 enzymes
what can affect breakdown of amides?
hepatic disease can prolong or inhibit metabolism
which drugs can increase breakdown of amides?
barbiturates - induce enzymes
which drugs can inhibit breakdown of amides?
drugs which inhibit P450 enzymes e.g. midazolam
why are local anaesthetics often made into a salt solution?
they are poorly water soluble
why can LAs sometimes sting on injection?
often are made into a hydrochloride salt solution which lowers the pH
which formulations can lidocaine come in?
sterile solutions for parenteral use
aerosols for nasal/airway use
topical patches
what is baricity?
the weight of one substance compared with the weight of an equal volume of another substance
why do LAs for epidural have high baricity?
to avoid spread high into the epidural space
what is added to epidural LAs to make them heavier?
glucose
what is the baricity comparator substance for spinal anaesthesia?
cerebrospinal fluid
why is adrenaline commonly added to LAs?
vasoconstrictor - reduces speed of systemic absorption and therefor prolongs duration of action
how does adrenaline prolong effects of LAs?
reduces the speed of systemic absorption
what are the benefits of adding adrenaline to LAs?
prolongs duration of action
reduced risk of toxicity
reduces bleeding at the injection site
what state must a drug be in to be systemically active?
unbound and unionised
what is the relationship between plasma protein binding, concentration and pH?
percentage binding decreases as concentration rises or pH falls
what is the significance of plasma protein binding with LAs and patients with liver failure?
reduced plasma proteins in patients with liver failure
which species is lidocaine licensed for?
dogs, cats, horses
what is the onset of action of lidocaine?
2-5 minutes
what is the duration of action of lidocaine?
20-40 minutes
which has a lower cardiotoxicity, lidocaine or bupivacaine?
lidocaine
which species is bupivacaine licensed for?
none - has to be used under cascade, owner needs to provide consent to use it
what is the duration of action of bupivacaine?
6 hours
which has a longer onset of action, lidocaine or bupivacaine?
bupivacaine
what is contained in EMLA?
mixture of lidocaine and prilocaine in a cream
how can maximum absorption of EMLA be achieved?
cover with an occlusive dressing
how long does it take to see the full effects of EMLA?
30-45 mins
what is EMLA commonly used for?
IV catheterisation
is EMLA licensed in veterinary species?
no
what are the main types of toxicity caused by local anaesthetics?
neurotoxicity
CVS toxicity
can local anaesthetics be re-dosed?
no
why should local anaesthetics always be drawn up into the smallest possible syringe?
essential to give accurate dose, especially in smaller patients
what type of toxicity is seen at lower concentrations of local anaesthetic?
CNS toxicity
what is seen in CNS toxicity with regards to local anaesthetic use?
generalised CNS depression that is proportional to the (unbound) drug -
minor behavioural changes
muscle twitching and tremors
tonic-clonic convulsions
CNS depression/respiratory depression and death
how can we treat CNS toxicity due to LAs?
symptomatic treatment - BDZs to control seizures, O2 suppplementation, intubation and controlled ventilation if required
what CVS signs are seen with LA toxicity?
hypotensions and dysrhythmias
how does LA toxicity cause hypotension?
depression of myocardial contractility
direct relaxation of vascular smooth muscle
loss of vasomotor sympathetic tone
which common LA typically causes dysrhythmias?
bupivacaine
how are dysrhythmias caused by LA toxicity?
lipophilicity means rapid entry to sodium channels during systole
drug remains bound to the sodium channel during diastole
presents as re-entrant arrhythmias
how can CVS toxicity as a result of LA use be treated?
symptomatically
anticholinergic for bradycardias
fluid therapy with inotropic support if needed
consider intralipid IV (‘mop up’ thr LA)
how can LA toxicity be prevented?
don’t exceed ‘safe’ max dose
if greater volume needed, dilute with saline
use appropriately sized syringes for accuracy
use appropriate size needles to minimise tissue trauma
aspirate before injection to confirm not in blood vessel
which LA blocks can RVNs carry out?
any that don’t enter a body cavity
which LA blocks can RVNs not carry out?
epidural/pleural catheter
what is epidural anaesthesia?
injection of anaesthetic drug into the epidural space
what is spinal anaesthesia?
injection of an anaesthetic drug into the sac of CSF surrounding the spinal cord and nerves
in which animals is epidural anaesthesia more difficult to perform?
in obese and pregnant patients
any other patients where anatomical landmarks are affected
how can epidural injection be made easier to perform accurately?
use of U/S or x-ray
what are some of the contraindications for epidural injection?
skin infection at puncture site
sepsis
coagulation impairments
can anaesthetics used for epidurals have preservatives in?
no - must be sterile and preservative-free
what else might be added to an epidural injection?
opioids
medetomidine
ketamine
what are the possible side effects of an epidural block?
hypotension
hypothermia
urinary retention
infections
slowed hair regrowth
what is the difference between local and regional anaesthesia?
size of affected area
local - small discrete area e.g. infiltration
regional - blocks a larger area
there is cross-over
what are some examples of loco-regional anaesthesia?
blocks - ophthalmic, dental, limb nerve blocks
intravenous regional anaesthesia
intra-articular
wound soaker catheters
which topical LAs are licensed?
only the laryngeal spray for feline intubation
where can infiltration be carried out?
anywhere on the body provided there is enough tissue to infiltrate
is infiltration local or regional anaesthesia?
local
give some examples of infiltration
testicular for castration
ovarian ligament
around a skin tumour to be excised
incisional line block
ring block of distal limb/tail
intraperitoneal
how is infiltration usually carried out?
injected in a V shape or reverse pyramid into the area of interest
can RVNs perform infiltration blocks?
not any that require entry into a body cavity (but could act as the VS’s hands under direction)
what are the pros of initiating NSAID therapy for chronic pain (e.g. OA) in dogs?
quick onset of action - non-pharmacological methods take long time
extensive evidence base to support analgesic efficacy, effective doses and re-dosing interval
licensed in dogs and cats for short and long-term treatment
why is it important to manage chronic pain in patients?
chronic pain is maladaptive and of no benefit to the animal
the feeling of pain comprises the sensory discriminative aspect being processed by the brain and then interpreted with both physical and emotional components
pain is a significant welfare issue
what is nociceptive pain?
pain originating from tissues which are not part of the nervous system
what is neuropathic pain?
pain originating from tissues in the nervous system
what is released when nerves are damaged?
cholecystokinin
what does cholecystokinin do?
antagonises opioid-mediated analgesia
why are opioids less effective in patients with neuropathic pain?
cholecystokinin is released by nerve damage, which antagonises opioid mediated analgesia
which type of analgesics are less effective against neuropathic pain?
opioids
how do most NSAIDS work?
by inhibiting prostaglandin production from arachidonic acid by inhibiting the COX enzyme
where do most NSAIDs work?
in the periphery
where can NSAIDs work in the CNS?
in the dorsal horn by inhibiting COX (precise mechanism of action unknown)
what do the adverse effects associated with NSAID administration relate to?
the protective functions that prostaglandins have in the body
bow easily the NSAID can leave the circulation and cross into the tissues
what are the 2 types of prostaglandins?
consititutive - ‘housekeeping’
inducible - those induced by inflammation
what leads to the side effects of NSAIDs?
blocking of the protective functions provided by the constitutive prostaglandins
which COX isoenzyme produces which type of prostaglandin?
COX-1 isoenzyme - constitutive
COX-2 isoenzyme - inducible
why are the newer NSAIDs advantageous in terms of patient safety?
they are more COX-2 specific and have less effect on the constitutive (protective) prostaglandins
what do all the veterinary NSAIDs with a peri-operative license have in common?
they all show COX-2 selectivity
how can renal side effects of NSAIDs be reduced?
prescribing those with a degree of COX-2 selectivity
what GI functions do prostaglandins have?
maintenance of mucosal blood flow
bicarbonate and mucous secretion
epithelialisation
what GI side effects can NSAID use lead to?
GI ulceration and bleeding
what do prostaglandins regulate in the renal system?
GFR
renin release
sodium excretion
why should we be wary of giving NSAIDs under anaesthesia?
blockade of the vasodilatory PGs may cause a decreased GFR at times of low circulating blood volume (e.g. hypotension, hypovolaemia) - can induce kidney failure
what renal side effects can NSAIDs lead to?
water retention and oedema
hypertension
may impair GFR in patients with renal disease of hypotension
may cause renal ischaemia in patients with hypotension
what are the hepatic side effects of NSAID use?
NSAID therapy will usually induce liver enzymes in normal dogs - link to hepatopathy?
what are the CNS side effects of NSAID use?
may see idiosyncratic dullness and lethargy in cats
what is important to consider in terms of haemostasis and NSAIDs?
older NSAIDs that are unspecific for COX can affect clotting
do newer NSAIDs affect blood clotting?
they will prolong markers of blood clotting if given for long courses (30-90 days) but these are not linked to clinical signs of bleeding
how can we reduce the risk of side effects with chronic NSAID use?
do not exceed licensed dose
do not give 2 NSAIDs concurrently
do not give with corticosteroids
do not give to hypotensive/dehydrated patients
warn owners about risks of NSAIDs
when is GI ulceration more likely with NSAID use?
if the animal has pre-existing GI ulceration, liver disease and/or is geriatric
why do we not commonly combine NSAIDs with gastroprotectants?
there is limited evidence to support combining with gastroprotectants/antacids/H2 antagonists
why should we not administer NSAIDs to patients with hypotension?
prostaglandins are essential in maintaining renal blood flow and GFR during hypotension
what signs should we tell owners to look for when administering NSAIDs?
vomiting/diarrhoea
signs of blood in the faeces
dullness
anorexia
which parameters should be monitored in animals on NSAID therapy (gold standard)?
clinical examination and history
haematology and biochemistry
urinalysis
blood pressure
when should patients be re-checked after starting NSAID therapy?
re-check regarding side effects 1-2 weeks after starting treatment (side effects most likely to occur in first 2 weeks)
how often should high-risk patients on NSAIDs be monitored?
NSAIDs should be avoided in high-risk patients
how often should medium-risk patients on NSAIDs be monitored?
rechecked monthly +/- blood work/blood pressure/urinalysis
which patients are medium-risk for side effects due to NSAID use?
those with concurrent disease in a target organ)
how often should low-risk patients on NSAIDs be monitored?
should be re-checked every 3-6 months
what are some other treatment options if NSAIDs are not efficacious alone/poorly tolerated?
NSAID cycling - swap drugs (only one licensed in cats at present)
introduction of analgesic adjunctive therapies e.g. gabapentin
non-pharmacological therapies e.g. diet, weight management, physiotherapy, acupuncture
