Opioid Pharmacology

what was the archetypal ‘dangerous drug’ feared by lay people and physicians?
morphine

what has clinical experience, especially in the management of cancer pain, shown about morphine?
that fears are unfounded?

what is the dose range of morphine for cancer pain?
can vary from 15mg to 15g/ day

draw the aciton of opioids and nsaids in pain relief
draw the aciton of opioids and nsaids in pain relief

what are the opioid receptors called?
μ
κ
σ
δ

what are the effects of the μ opioid receptor?
– analgesia (mostly supraspinal)
– respiratory depression
– euphoria
– sedation
– parasympathetic stimulation, miosis

what are the effects of the κ opioid receptor?
– spinal analgesia
– dysphoria / sedation
– miosis

what are the effects of the σ opiooid receptor?
dysphoria, hallucinations

what are the effects of the δ opioid receptor?
various subclinical effects

what are the CNS effects of opioids?
1. analgesia and reduced affective response to pain
2. euphoria/dysphoria
3. sedation/ hypnosis/ narcosis
4. respiratory depression, reduced sensitivity to CO2
5. cough suppression
6. miosis, mediated via parasympathetic pathways
7. nausea / vomitus- chemoreceptor trigger zone
8. truncal rigidity- especially fentanyl
9. addiciton in non-medical setting

what are the CVS effects of morphine?
some bradycardia
orthostatic hypotension

what are the GI effects of morphine?
– increased smooth muscle tone
– increased sphincter tone
– antisecretory
– proabsorptive

what are the GU effects of morphine?
increased smooth muscle tone (bladder, ureter)
increased tone of bladder sphincter muscle

what are the neuroendocrine effects of morphine?
histamine release

what are the indications for opioid use?
analgesia
anesthesia
acute pulmonary edema
cough
diarrhea

what are the ROA of opioids?
oral
rectal
subQ
IV
certain derivatives: intranasal, buccal, transmucosal, transdermal

what is the gold standard opioid agonist?
morphine 3-5h

what is the short acting opioid agonist?
meperidine 2-3h

what is the ultrashort in emergency opioid agonist?
fentanyl 20-30 min

what is are the opioid agonists used in anesthesiology?
sufentanyl
alfentanyl
remifentanyl

what is the long acting opioid agonist?
fentanyl 9h terminal elimination half life
methadone 25h

what is the most abused opioid agonist?
heroin (illegal in US)

what is the ‘weak’ opioid agonist?
codeine

what are the other opioid agonists?
oxycodone
hydrocodone

what are the partial opioid receptor agonist?
tramadol
nalbuphine
buprenorphine

which partial opioid agonists have a ceiling effect?
tramadol
buprenorphine, buccal

what are the opioid antagonists?
naloxone
naltrexone
alvimopan

what is the half life of naloxone?
60-100m

what is the half life of naltrexone?
up to 48h

what are the features of alvimopan?
antagonist of peripheral opioid receptors

what are the antitussive opioids?
dextromethorphane
levopropoxyphene

what are the antidiarrheal opioids?
loperamide

what is apomorphine?
structural derivative of morphine, but little or no binding to opioid receptors

what are the PK of apomorphine?
subQ
injection pen

what are the PD of apomorphine?
centrally acting dopaminergic drug

what is the use of apomorphine?
1. adjunct tx of Parkinson’s
2. powerful emetic drug
3. alternative medicine, tx of addiciton

what are the PK features of the fentanyl patch?
constant flow rate into epidermis (2.5 μg/cm^2/h)
variable diffusion/perfusion into systemic circulation

what are the clinically relevant half lives of fentanyl?
– t1/2 initial= 20-30 min
– t1/2 terminal= 9h
– t1/2 transdermal patch= 17h

what is the dose conversion of fentanyl vs PO morphine?
current recommendation: 1:100
probably adequate: 1:70

what are the problems with transdermal fentanyl?
– apply patch to hairless skin
– ensure steady skin temperature
– apply patches to 3 different sites, alternatively

is morphine taken solely to control pain addictive?
no

what are the categories of pain?
1. Nociceptive:
– traumatic
– inflammatory
– colicky
– vascular
2. Neuropathic
– deafferentiation
– sympathetically maintained

what causes superficial nociceptive pain?
pinch
scratch
venous puncture
= easy to localize

what causes deep nociceptive pain?
muscle, bone, joint injury
= often difficult to localize, especially with severe pain

what causes visceral nociceptive pain?
colicky pain
tumor pain
=difficult to localize, especially with severe pain

what is the emotional quality of superficial nociceptive pain?
little or none

what is the emotional quality of deep or visceral nociceptive pain?
upsetting
intimidating
horrifying
devastating

what is the autonomous response to superficial nociceptive pain?
mydriasis
nausea
vomiting
collapse
shock

what is the prognosis for acute pain?
disease/ injury will heal soon

what is the prognosis for chronic pain?
disease / injury will not heal any time soon

what is the prognosis for chronic pain syndrome?
self perpetuating condition
originating lesion is secondary

what is the goal of treatment of acute pain?
reduce pain to tolerable levels

what is the goal of treatment of chronic pain?
ensure normal quality of life

what is the onset of analgesia in acute pain?
quick onset is important

what is the duration of analgesia in acute pain?
adjusted to clinical situation

what are the onset and duration of analgesia in chronic pain?
continous analgesia

what is the role of sedation in acute pain?
may be useful

what is the role of sedation in chronic pain?
unwanted (with very few exceptions)

what are the adverse effects to consider in acute pain management?
relevant in cases of predisposition

when are AE relevant in chronic pain?
always relevant

what is the ROA in acute pain?
often IV

what is the ROA in chronic pain?
preferably oral, rectal, transdermal

what are the drugs and doses used in acute pain?
standard protocols

what are the drugs and doses used in chronic pain?
drugs according to WHO, doses always individualized

what is the dosage interval in acute pain?
on recurrence of symptoms

what is the dosage interval in chronic pain?
by the clock at constant intervals

when is co-medication important in acute pain?
relevant in case of predisposition

when is co-medication important in chronic pain?
mostly required

what is the order of drugs to give per WHO recommendations for pain?
1. peripheral NSAID
2. Weak partial opioid + NSAID
3. Strong Opioid + NSAID

what are the WHO rules for pain management?
by the mouth
by the clock
by the ladder

what is the objective of the WHO guidelines for chronic pain management?
analgesia sufficient to restore quality of life

what are the rules to follow for NSAID according to WHO guidelines for pain management?
– use sufficient dose
– don’t combine NSAID analgesics
– preventive= antiulcer like ranitidine

what are the rules to follow for partial/weak opioids according to WHO guidelines for pain management?
one partial agonist only don’t combine with strong opioid
-preventive: antiulcer + laxative

what are the rules to follow for strong opiods according to WHO guidelines for pain management?
– use one strong opioid
– provide rescue medication
– preventive:
–1st week: antiemetic
— continuously: laxative, antiulcer

what is the incidence of NSAID induced GI bleed?
NSAID induced GI complications occur in 2-4 % of patients under prolonged tx, estimated cost in US is 4 billion/year

how many NSAID associated hospitalizations per year?
80K

how many NSAID associated deaths / year in USA?
8K

how many NSAID associated hospitalizations in CA/year?
3897

how many NSAID associated deaths in CA/year?
365

how much ASA used in USA per year?
10-20K tons

NSAIDs kill almost as many people per year as what?
AIDS
Multiple Myeloma

what NSAIDs carry a low risk of GI bleed?
Acetaminophen
Ibuprofen RR~2

what NSAIDs carry an intermediate risk of GI bleed?
ASA RR~3, 1:111 per year of tx
diclofenac

what NSAIDs carry a high risk of GI bleed?
piroxicam RR~13
indomethacin 1:33/year
ketoprofen RR~30

what is the history of NSAIDs?
BC: extracts from bark of willow tree
1800s: salicin, synth of ASA
1971: PGs
1976: COX
1988: COX1 cloned
1991: COX2 cloned
1996: meloxicam (mobic), Rofecoxib (Vioxx), celecoxib (celebrex)

what is the incidence and Tx of constipation as an AE of opioids?
80-100%
laxatives, alvimopan

what is the tx of urinary retention as an AE of opioids?
muscarinic drugs/ alpha blockers

at the onset of treatment, what is the incidence and tx for nausea/emesis as an AE of opioids?
20-60%
antiemetics

what is the tx for pruritus at the onset of opioid therapy?
antihistamine

what are the side effects of opioid therapy at onset?
nausea/emesis
pruritus
dizziness
euphoria
dysphoria
confusion
neuro/psychomotor imbalance
respiratory depression

what are the mechanisms of opioid induced respiratory depression?
1. direct depression of respiratory center neurons
2. sedation, anesthesia

what is important to remember about respiratory depression in opioid therapy?
1. pain is a powerful stimulus of respiration
2. sedation precedes any serious respiratory deoression

what should one consider as tx in case of opioid overdose?
mechanical ventilation or naloxone

what are the opioid receptors in epithelia? and their function?
μ
δ
κ
increase mucosal absorption
decrease secretion

what are the opioid receptors in smooth muscle?
mainly μ
increase SMC tone

what are the opioid receptors in the spinal cord?
δ

what are the opioid receptors in the brain?
μ
δ

what is the mechanism of opioid induce nausea/vomitus?
direct effect on chemoreceptor trigger zone in area postrema

what is important to consider in opioid induced nausea?
1. rapid drug invasion aggravates nausea
2. vagal tone plays a role
3. inform patient of partial tolerance
4. preventive tx with metoclopramide
5. no ondansetron

what are the mechanisms of opioid induced urinary retention?
relaxation of detrussor muscle
constriction of sphincter muscle

what is the effect of anticholinergic drugs on opioid induced urinary retention?
aggravate the problem

what are the treatments to increased detrussor tone in opioid induced urinary retention?
parasympathomimetics:
carbachol
betanechol

what are the tx to relax sphincter tone in opioid induced urinary retention?
alpha 1 blockers:
prazosin
terazosin

what is the incidence of iatrogenic opioid addiction?
0.04%

what are the hypothetic determinants of iatrogenic opioid addiction?
– frequent change between states of analgesia/pain
– repeated euphoria induced by rapidly injected opioid
– history of addiction

what are the observations related to opioid dose in study about iatrogenic opioid addiciton?
-slow and moderate development of tolerance
– withdrawal symptoms are inconsistent, moderate, easy to manage

what is the pattern and severity of opioid therapy in chronic pain?
constant opioid medication
constant plasma levels
patient awake and active

what is the pattern and severity of opioid therapy in acute severe pain?
acute trauma, post op:
short term or on demand treatment with intermediate potency opioids for hours- days

what is the pattern and severity of opioid therapy in ICU treatment?
like polytruama, assisted ventilation:
high dose
high potency
continuously for days-weeks,
patient sedated/anesthetized

what is the pattern of opioid consumption in addiciton?
no pain
user expects and craves euphoria
intermittent intake of increasing doses
high potency
rapid onset

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