Pain Management: Opioids Flashcards
opiate
any of the narcotic alkaloids found in the poppy
including morphine, codeine, and thebaine.
opioid
any substance, endogenous or synthetic, that produces morphine-like actions which can be blocked by naloxone.
thebaine is the precursor to (3)
precursor for oxycodone, hydromorphone, oxymorphone
3 classes of opioids
morphine like
meperidine like
methadone like
derivatives of morphine: full agonists (3)
heroin
hydromorphone
oxymorphone
derivatives of morphine: partial agonists (2)
codeine
hydrocodone
opioid antagonist examples
naltrexone
naloxone
buprenorphine
mixed agonist antagonist
buprenorphine: acts as an agonist at one subtype of opioid receptor and an antagonist at another.
meperidine class
fentanyl
sufentanil
alfentanil
heroin is morphine with
two acetyl groups added to it
diacetyl morphine
the active ingredient in heroin is
morphine
why do people with opioid use disorder prefer heroin to morphine?
the 2 acetyl groups make heroin get into the brain faster than morphine does because it is much more lipophilic.
fentanyl vs heroin
more potent
more lipophilic
gets into the brain faster
which type of receptors do opioids work through?
G protein coupled receptors
true or false: endogenous and exogenous opioids both work through G protein coupled receptors
true
the opioid receptors
mewe
delta
kappa
ORL1
Which type of G protein do all 4 of the opioid receptors couple to?
Gi
opioid receptors are expressed both
pre synaptically an post synaptically
opioid receptors are coupled to calcium channels on which side of the synapse?
pre synaptic terminal
when calcium enters the pre synaptic terminal,
the axon terminal releases its neurotransmitter into the synaptic cleft.
what happens when you activate opioid receptors on pre synaptic terminals?
By activating the Gi protein, inhibiting calcium channels and keeping Ca from entering the pre synaptic terminal, which stops NT release. (halting pain transmission)
opioid receptors are coupled to potassium on which side of the synapse?
post synaptic side
Opioid receptors on the post synaptic side do what?
open potassium channels, causing K to flood out of the neuron.
pre synaptic and post synaptic mechanism act to
shut down pain transmission at the level of the synapse
By activating the opioid receptors on the presynaptic and postsynaptic terminals,
neuron is inhibited from transmitting a pain signal to another neuron
effects of opioids on the CNS(7)
analgesia euphoria sedation resp depression cough depression n/v pupillary constriction
gold standard for treating moderate to severe pain, especially for nociceptive/inflammatory pain
opioids
because of ____, you can keep increasing the dose of opioids
tolerance
diagnostic tool for diagnosing an opioid overdose
pupillary constriction (armyosis)
opioid effects on GI tract (4)
increased tone, decreased motility
delay in gastric emptying
constipation
increase in intrabiliary pressure
opioids: pruritis
histamine release from mast cells
immune suppression: opioids
occurs with long term use.
Reduced hypothalamic pituitary adrenal (HPA) access and direct effects on immune cells themselves. immune cells have mew opioid receptors.
opioids: endocrinopathies
chronic long term use
decrease circulating sex hormones. can lead to osteroporosis
opioids: hyperalgesia
extreme response to pain from chronic prescribing of opioids
pure agonists: morphine like
Scientific name
phenanthrenes
example of morphine like pure agonists (phenanthrenes) 7
morphine codeine oxycodone oxymorphone hydromorphone etorphine dimorphine
examples of meperidine-like phenylpiperidines
meperidine fentanyl alfentanyl sufentanyl remifentanyl
example of methadone-like (diphenylheptanes)
methadone
loperamide
tramadol
tapentadol
mixed agonists-antagonist (4)
buprenorphine
butorphanol
nalbuphine
pantazocine
buprenorphine and butorphanol
receptors
partial agonists at mew opioid receptors
antagonists at kappa opioid receptors
nalbuphine and pentazocine
Antagonize/agonize where?
antagonist at mew receptors
agonist at kappa receptors
mixed agonist-antagonist can be used
as analgesics
mainstay treatment for chronic moderate/severe nociceptive or inflammatory pain
pure agonists
opioids in neuropathic or functional pain
no efficacy
opioids having no clinically relevant ceiling effect to analgesia is related to
tolerance with repeated administration
true or false - morphine is superior to other mu agonists
false
variation exists among all pure agonist
MoA morphine
pre and post synaptic
activation of mu, kappa, and delta.
pre synaptic - block calcium channels and reduce NT release
post synaptic - open K channels, cause hyperpolarization of post synaptic neuron, leading to a decrease in cell firing.
PO bioavailability of morphine
25%
low
low bioavailability of morphine means
you have to give a much higher dose po to achieve the same effect that you would IV
M6G
the active metabolite of morphine
M3G
neurotoxic metabolite of morphine
if metabolism of morphine is changed, we have to be careful about M3G.
renal impairment and morphine
you will have a buildup of m6G and m3G.
toxicity.
half-life of morphine
~2 hr
adverse effects of morphine
resp depression N/V dizziness mental clouding dysphoria pruritis constipation urinary retention hypotension
Contraindications for morphine are related to (4)
impaired liver function
impaired response function
asthma
hypotension
drug:drug interactions with morphine
any drugs with major significance relating to additive effects of morphine.
half lives of oxy, hydromorphine, oxymorphone, codeine
relatively short
which opioid is preferred for those with renal insufficiency and why?
hydromorphone as it does not have a lot of active metabolites.
notable side effect of hydromorphone
chest pain
codeine metabolism
phase I via CYP2D6
converts to morphine
ultrametabolizers of codeine
cyp2d6
codeine poisoning
converting to morphine at dangerous levels
may be seen in breastfed infants
meperidine class drug example
fentanyl
half life of meperidine
short
meperidine as compared to morphine
less constipation
more lipophilic and gets to the brain quicker, doesn’t effect peripheral tissues.
meperidine for chronic pain
not recommended because of the metabolite toxicity
med that is contraindicated with meperidine
MAOI
Meperidine and tachycardic patients
contraindicated. can raise HR further
routes of admin for fentanyl
paraenteral
transdermal
transmucosal
potency of fentanyl
high, about 100x morphine potency
half life of fentanyl
high
lipophilicity of fentanyl
high
which makes it a good candidate for transdermal route.
why isn’t there po fentanyl?
it goes through significant first pass effect and does not reach systemic circulation
T or F: fentanyl and its congeners are devoid of active metabolites
true
carfentanyl potency
1000x morphine
100x fentanyl
why is fentanyl safe to give those with renal impairment?
lack of active metabolites
advantages of fentanyl (4)
speed of analgesia in the setting of spontaneous breakthrough pain (given transmucosal)
transdermal
preferred to morphine in renal insufficiency
less prone to constipation
who cannot be prescribed transdermal or oral transmucosal fentanyl?
opioid naive patients
transdermal fentanyl is inappropriate for what kind of pain?
acute, intermittent, or mild
transmucosal fentanyl is always dosed
in the lowest dose in an opioid tolerant patient
methadone is
a long acting agonist
half life of methadone
20-35 hours
does methadone have active metabolites?
no
opioids safe for renal impaired patients
hydromorphone
fentanyl
methadone
EKG changes with methadone
possibility of QTc interval prolongation
neuropathic pain and methadone
more effective than other opioids
why does methadone produce less tolerance?
because it antagonizes NMDA receptors, altering glutamate levels in the CNS. tolerance does not develop at the same rate.
why is methadone usable for neuropathic pain?
because it antagonizes NMDA receptors, altering glutamate activity.
pharmacokinetic drug:drug interactions of methadone
many drugs induce or inhibit CYP3A4
methadone itself induces 3A4
pharmacodynamic drug:drug interactions of methadone
- anything that may cause CNS depression
- anything that may cause QTc prolongation
what are the two opioids that are lipophilic enough to be given transdermally?
buprenorphine
fentanyl
which 2 opioids are not available PO?
buprenorphine
fentanyl
which 4 opioids can be given extended release?
hydromorphone
morphine
oxycodone
oxymorphone
which opioids can be given as suppositories?
hydromorphone
morphine
which 2 opioids are not offered injectable?
codeine
oxycodone
which is the only opioid that is given transmucosally?
fentanyl
which opioids stand out for breakthrough pain?
fentanyl
methadone
opioid tolerance
progressive loss of effect with sustained administration of an opioid receptor agonist
tolerance can be up to
30-fold
tolerance to a particular opioid is comprised of either
- tolerance unique to that opioid
- tolerance that extends to other opioid agonists
cross tolerance
tolerance that extends to other opioid receptor agonists
different responses to an opioid develop tolerance at different rates, ie:
tolerance to respiratory depression happens quickly, while tolerance to constipation never really happens.
tolerance to a drug is combatted with
higher doses
watch for adverse effects
opioid induced tolerance (4) characteristics
progressive decrease in efficacy
increased dose decreases pain
adverse effects with increased dosing
*decreased sensitivity to opioid analgesics(
opioid induced hyperalgesia (4) characteristics
paradoxical increase in sensitivity to painful stimuli
increased dose increases pain
may be a different pain altogether
increased sensitivity to pain
why is methadone spot blank on equianalgesic chart?
because tolerance is nonlinear in methadone. you’ll need to see a chart specific to methadone.
what is the issue with equianalgesic tables?
- single dose studies in opioid naive patients with acute pain
- variables such as bioavailability are not taken into account
- undirectional vs bidirectional equivalencies *pay attention to sedation when going from one drug to another
when changing from IR to ER
start with the same daily total dose
if changing from one opioid to another, what must you do with the new dose?
reduce the new med dose by 25-50% to begin with
breakthrough pain types (4)
spontaneous
incidental volitional
incidental nonvolitional
end of dose
volitional pain
pain under the patients control. ie raising arm after shoulder surgery would cause volitional pain
Non volitional pain
unpreventable pain. ie coughing after surgery
management of spontaneous, volitional, and volitional breakthrough pain
IR opioid PRN
management of end of dose breakthrough pain
increase the dose or frequency of the around the clock analgesic
breakthrough pain dosinf
10-15% total daily dose of the same opioid
management of volitional pain
consider premeditating 30-45 min in advance of anticipated pain trigger
what medications might you consider in the case of spontaneous or non volitional pain that comes on quickly
transmucosal fentanyl
or
PO methadone
onset of analgesia is directly related to
lipophillicity
oral transmucosal fentanyl black box warning
- only dosed by titration, beginning with 100 mcg
- use only in opioid tolerant individuals
opioid receptor antagonists
naloxone
naltrexone
methylnaltrexone
alvimopan
short acting opioid receptor antagonist
naloxone
long acting opioid receptor antagonist
naltrexone
naloxone and naltrexone are antagonists of
mu kappa and delta
naloxone is given ____ while naltrexone is given ____
naloxone - IM, IV, intranasal
naltrexone - oral
naloxone and naltrexone block ____ and exacerbate ____
block stress induced analgesia
exacerbate clinical pain
what rebound effects do you need to monitor for after use of naloxone
htn
tachycardia
ventricular arrhythmias
what can naloxone and naltrexone also reverse
gi immotility/constipation
opioid receptor antagonists that do not cross the BBB
and what does this mean?
methylnaltrexone
alvimopan
adverse effects may be reversed but analgesia will not ie you can relieve constipation without reversing pain control
buprenorphine can be abused and require naloxone. how many attempts of naloxone may it take?
3-4
Suboxone SL
how it works
you’ll only feel the agonist, not the antagonist part.
it’s buprenorphine and naloxone.
if you crush it and inject it, you can’t get high bc the naloxone blocks it.
