Opioids Flashcards
What does opioid produce
analgesia
what does opioid not produce?
- Loss of touch
- Loss of proprioception
- Loss of consciousness
opium chemical structure

What is the relationship b/w cholinergic system and opioid analgeisa?
positive modulator
drug enhances cholinergis system
physostigmine
drug antagonzies cholinergic
atropine
Ventilatory effects can be exaggerated by other drugs
- Amphetamines
- Phenothiazines
- MOA’s
- Tricyclics
- benzos
opioid breathing pattern
slow deep breathing
opioid OD triad
- Miosis
- Hypoventilation
- Coma
- Hypotension and seizures develop if arterial hypoxemia persists
opioid OD treatment
- Mechanical ventilation
- Supplemental oxygen
- Antagonist
reflex coughing
Provocation” of coughing – cause unclear?
•Imbalance of sympathetic and vagal nerve innervation
•Stimulation of juxtacapillary irritant receptors?
Fentanyl, sufentanil and alfentanil
• Not seen with morphine or hydromorphone
opioids causing reflex coughing
Fentanyl, sufentanil and alfentanil
•Not seen with morphine or hydromorphone
Opioid WITHDRAWAL ABSTINANCE SYNDROME
•Initial symptoms - yawning, diaphoresis, lacrimation
•Insomnia and restlessness are common
•Cramps, nausea, vomiting and diarrhea peak at 72 hours,
then decline in the next 7-10 days
During withdrawal, tolerance is quickly lost
what receptors activated during long term opioid use?
NMDA
Down regulates spinal glutamate receptors
Opioid, what kind of tolerance and what kind of dependence?
Pharmacodynamic tolerance and physical dependence
What kind of tolerance happens b/w opioids?
Cross-tolerance can occur between all opioids
opioid.
relationship b/w dependence and tolerance
Tolerance without physical dependence possible, but not vice
versa
During tolerance, what is upregulated and what is downregulated?
Receptor desensitization and down regulation; up regulation of cAMP
•2-3 weeks (MSO4)…much quicker with more potent drugs
Opioid. what is exception for tolerance
Everything except…miosis and bowel motility
effects produced by morphine
Produces
•Analgesia, euphoria, sedation and decreased concentration
•Nausea, body warmth, pruritis (nose), dry mouth, extremity heaviness
Increases pain threshold, modifies perception of noxious
stimulation
What kind of pain does morphine relieves?
Effective against visceral, muscles, joints, etc.
•Against slow dull pain
- when given preemptively.
Morphine onset
Onset 15-30 mins; slow compared to other opioids (e.g. fentanyl)
Morphine lipid, only small portion reaches CNS d/t
- Poor lipid solubility
- High degree of ionization at physiologic pH
- Protein binding
- Rapid conjugation by the liver
Morphine metabolites
75% morphine-3-glucuronide (inactive), morphine-6-glucuronide 5-10% (active), normorphine and codeine
Morphine, mpaired renal function can result in
accumulation and
unexpected respiratory depression
Morphine Decrease in plasma concentration primarily through
metabolism
Morphine
Plasma concentration higher in:
- Elderly
- Neonates (clearance decreased first 4 days of life)
Metabolite of Morphine
duration of action
morphine-6-glucuronide
•Longer duration of action than morphine
Metabolites of morphine
analgesic potency
Higher analgesic potency (65—fold higher than morphine)
meperidine analogues
Fentanyl, sufentanil, alfentanil and remifentanil
What is meperidine mainly used for? What is it structually similar to?
Structurally similar to atropine, mild antispasmodic effects
What receptor does meperidien work on? How?
Mu-receptor agonist
Mu1 receptors fxn
- analgesia (supraspinal and spinal)
- euphoria
- myosis
- bradycardia
- urinary retention
mu2 receptor fxn:
- analgesia (spinal)
- depression of ventilation
- physical dependence
- constipation
Kappa receptors:
results in inhibition of neurotransmitter release:
- Analgesia (supraspinal and spinal)
- dysphoria, sedation
- myosis
- diuresis
- lesser extent-hypoventilation and high intensity pain
-
Agonist-antagonist often act principally on K receptors
- low abuse potential
delta receptors
What kind of ligand does it respond to?
responds to endogenous ligands known as enkaphlins: May serve to modulate Mu receptor activity
- analgesisa (supraspinal and spinal)
- respiratory depression
- physical dependense
- urinary retention
- constipation
Allodynia –
perception of non-noxious stimuli as pain
Analgesia
absence of pain perception
Anesthesia
absence of all sensation
Anesthesia dolorosa –
pain in an area that lacks sensation
Dysesthesia –
unpleasant sensation with or without a stimulus
Epicritic
non-noxious sensation
Hypoalgesia –
diminished response to noxious stimulation
Hyperalgesia
exaggerated response to noxious stimulation
Hyperesthesia
increased response to mild stimulation
Hyperpathia
persistence of a sensation after the stimulus
Hypoesthesia
reduced cutaneous sensation
Neuralgia
pain in the distribution of a nerve or group of nerves
Nociception
neural response to traumatic or noxious stimuli
Paresthesia
abnormal sensation perceived without a stimulus
Protopathic
noxious sensation
Radiculopathy
functional abnormality of one or more nerve roots
Two distinct classes of opium
- phenanthrenes
- benzylisoquinoline

What is included in phenanthrenes
morphine, codeine, thebaine
what is included in benzulisoquinolines
papaverine (control spasm to decrease cerebral ischemia), noscapine
Modifications to morphine molecule result in
codeine and heroin…
SYNTHETIC OPIOIDS contains what structure
Contain a phenanthrene nucleus
• Synthesized rather than modified
Opioid PO absorption
Modestly absorbed orally
• Some undergo significant first-pass effect
synthesized opioid derivatives
• Morphine – levorphanol
• Methadone
• Benzomorphan – pentazocine
• Phenylpiperidine – meperidine, fentanyl
what are the fentanyls and they are different in what?
Fentanyl, sufentanil, alfentanil and remifentanil
• Different with regards to potency, rate of equilibrium in the plasma, and site of action
Opioid receptors are
G protein-coupled receptors
Opioid receptor Principle effect
Principle effect is to decrease neurotransmission
Opioids mimic the actions of
of endogenous ligands
• Enkephalins, endorphins and dynorphins
name the endogenous ligands
Enkephalins, endorphins and dynorphins
Where are opioid receptors located?
spine, brain and periphery
Pre synaptic
– inhibit release of acetylcholine,
dopamine, norepinephrine and Substance P
Post synaptic –
increased K+ conductance = decreased function
May regulate functions of what other ion channels
NMDA
Opioids do not work by:
- Block nerve impulses
- Alter responsiveness of afferent nerve endings to noxious stimulation
Where are opioid receptors in the brain?
- Periaqueductal gray
- Locus ceruleus
- Rostral ventral medulla
Where are opioid receptors in spinal cord?
Primary afferent and interneurons of the dorsal horn
Four types of opioid receptors
Mu
Kappa
Delta
Sigma
Opioid Small dose effects terminated through?
• Effects of multiple doses and infusions terminated by?
- Small dose effects terminated through redistribution
• Effects of multiple doses and infusions terminated by metabolism
Most opioids are metabolized in? Exceptions?
How are metabolites of opioids?
the liver • Exception is remifentanil
• Some opioids have active metabolites
Opioids Excreted primarily by
the kidneys
Opioids COMMON CV SIDE EFFECTS
In healthy patients, bradycardia with sustained
B/P
Impairment of SNS response (orthostatic hypotension)
- Venous pooling
- Histamine release
Does not sensitize the heart to catecholamines
Synergism with other drugs often causes myocardial effects
- Benzodiazepines
- Nitrous oxide
Cardiac protectant effect
• Enhances myocardial resistance to oxidative and ischemic stresses through Sigma and kappa receptors
Opioids COMMON RESPIRATORY EFFECTS
- Opioids produce a _____ depression of ventilation
• Via ____and _____ receptors in the brainstem
- Interfere with _____ and _____ ventilatory centers
• Regulate ____ and ______ of breathing
- Decreased responsiveness to _____
• By decreasing _____ release in the_____center of the brain
• Shift to the _____ in the CO2 response curve - Decreased ____ accompanied by compensation in ____
- Bronchial effects
• Decrease ______
• Increase _______ - _____ smooth muscle
- _____ release
- Factors that affect depression of ventilation:
- ___
- ____
- ____
- Opioids produce a dose-dependent depression of ventilation
• Via mu and delta receptors in the brainstem
- Interfere with pontine and medullary ventilatory centers
• Regulate rate and rhythm of breathing
- Decreased responsiveness to CO2
• By decreasing acetylcholine release in the medullary center of the brain
• Shift to the right in the CO2 response curve - Decreased RR accompanied by compensation in TV
- Bronchial effects
• Decrease ciliary action
• Increase airway resistance
• Bronchial smooth muscle • Histamine release
- Factors that affect depression of ventilation:
- Advanced age
- Natural sleep
- Pain
Opioid cough suppression
Depression of medullary cough centers
Codeine (bulky substitution on number 3 carbon position)
Dextromethorphan – dextrorotary – cough suppression without analgesia or respiratory depression
Opioid Common CNS effects\
- Opioids are not ____; ____ possible
- Most effective for ___ and ____ pain*
- Sedative and ____ effects; a sedated patient is not pain free
- Analgesic effects are two-fold:
• Inhibit ____ transmission of ____ information
• Activate ____ pathways - ____ cerebral blood flow, and possibly ____*
- Used cautiously in head trauma patients
- Alter ___
- ____
- Depression of ____
• Increased sensitivity when ____ is compromised
-Do not alter effects of ____drugs
Miosis due to action on autonomic nervous system component of _____ of oculomotor nerve
- Can be antagonized by atropine
- Severe _____can result in presence of morphine
- Opioids are not anesthetics; awareness possible
- Most effective for visceral and dull pain*
- Sedative and euphoric effects; a sedated patient is not pain free
- Analgesic effects are two-fold:
• Inhibit ascending transmission of nociceptive information
• Activate descending pathways - Decrease cerebral blood flow, and possibly ICP*
- Used cautiously in head trauma patients
- Alter wakefulness
- Miosis
- Depression of ventilation
• Increased sensitivity when BBB is compromised
-Do not alter effects of neuromuscular blocking drugs
Miosis due to action on autonomic nervous system component of Edinger-Westphal nucleus of oculomotor nerve
- Can be antagonized by atropine
- Severe arterial hypoxemia can result in presence of morphine
muscle rigidity
Opioids have no effect on nerve conduction
Skeletal muscle hypertonus ”truncal rigidity”
• Following large doses of opioid (phenylpiperidine)
• Related to mu receptors acting on dopamine and GABA channels
- Evidence supports resistance due to laryngeal musculature contracture
- Treat with NMB or naxolone
Morphine induces _____ that precedes analgesia
• In up to ______of patients
Assumption that ____occurs when ______ is relieved…
Morphine induces sedation that precedes analgesia
• In up to 60% of patients
Assumption that sleep occurs when pain is relieved…
Opioids on biliary tract and treatment of complication
Opioids cause spasm of biliary smooth muscle and the sphincter of Oddi
• Glucagon 2mg, IV will reverse smooth muscle spasm •
Does not antagonize analgesic effects
Morphine can contract of pancreatic ducts
- Increase in amylase and lipase levels
- Mimics acute pancreatitis
- decreased gastric motility, propulsive activity and emptying time
• Can increase risk of aspiration or delay drug absorption
- Opioid-induced constipation
• Can be debilitating in chronic users
Methylnaltrexone can antagonize effects
Opioids nausea and vomiting
Stimulation of ________ trigger zone in the _____
- _____receptors
- ______receptors
Increased ______ and delayed _______
NV not common in _____ patients
• ______ effect?
Stimulation of chemoreceptor trigger zone in the medulla
- Serotonin type 3 receptors
- Dopamine type 2 receptors
Increased GI secretions and delayed gastric emptying
NV not common in recumbent patients
• Vestibular effect?
genitourinary side effects
Opioid-induced augmentation of detrusor
muscle tone results in urgency, but tone of urinary sphincter enhanced, making voiding difficult
opioid induced cutaneous changes
- Morphine causes blood vessels to dilate
• Warm, flushed skin
- Histamine release – not an allergy
- Conjunctival erythema
- Pruritis
opioid PLACENTAL TRANSFER
Readily cross the placenta
• Result in neonatal depression
• Morphine greater than meperidine
Chronic use can cause neonatal physical dependence
• Naxolone may precipitate neonatal abstinence syndrome
Opioid drug interactions
Cholinergic system is a positive modulator of opioid analgesia
- Physostigmine – enhances
- Atropine – antagonizes
Ventilatory effects can be exaggerated by other drugs:
- Amphetamines
- Phenothiazines
- MOA’s
- Tricyclics
Long term effect of opioids use?
Long-term opioid use activates NMDA receptors • Down regulates spinal glutamate receptors
Codeine, what kind of opioid?
Naturally occurring opioid
chemical structure difference b/w codeine and morphine and significance?
(methyl for hydroxyl at 3 carbon)
• limits first-pass hepatic metabolism – can be given orally
Codeine
How much % is demythylated into what?
approximately 10% O-demethylated into morphine
• Accounts for most of its analgesic ability
codeine t1/2
3-3.5 hours
what other codeine metabolite might have some analgesic effect?
codeine-6-glucuronide may have some analgesic effects
How is codeine used to treat pain?
Weak opioid not used for treatment of severe pain • Usually combined with acetaminophen
codeine dosing
- 15 mg – oral cough suppressant
- 60 mg = 650 mg of aspirin
- 120 mg IM = 10 mg morphine
Codeine side effect
- Mild physical dependence
- Minimal sedation, nausea, vomiting and constipation
- Dizziness possible
- Unlikely to produce apnea
- Not recommended IV secondary to histamine and hypotension
When was meperidine first synthesized? what does meperidine have on its structure?
Synthesized in 1939 – phenylpiperdine ring
What type of receptor does meperidine work on?
Mu-receptor agonist
Meperidine CLINICAL USES
What receptor does meperidine work on?
In high dosese, what side effects?
Decreased significantly over the years Anti-shivering postoperatively
• Stimulation of kappa receptors
In high doses
• Negative cardiac inotropic effects
• Histamine release
meperidine potency compared to morphine
1/10 as potent as morphine
meperidine DOA
2-4 hours
meperidine In equal analgesic doses, it produces similar _____ to morphine
Sedation, euphoria, nausea, vomiting, depression of ventilation
What Limits meperidine oral usefulness
Extensive first pass metabolism by liver
How’s meperidine metabolized?
- 90% demethylization to normeperidine
- 10% hydrolysis to meperidinic acid
Meperidine excretion
Excretion is principle elimination route
- pH dependent (more acidic, greater fraction of drug excreted unchanged)
- Decreased renal function can result in accumulation of metabolites
meperidine side effects
May cause increase in heart rate, mydriasis • Modest atropine-like effects
• HIGH doses decrease myocardial contractility
Delirium and seizures
• Reflects an accumulation of normeperidine (high CNS effects)
May elicit serotonin syndrome in patients taking MAO inhibitor or fluoxetine
Promptly crosses the placenta, may exceed maternal concentrations Less biliary tract spasm
Withdraw develops more rapidly and is shorter in duration
Normeperidine:
- _____as active as meperidine
- Elimination half-time ____
• ____hours in renal failure
- Increased sensitivity in ____
• _____ plasma protein = _____ circulating volume
- May be involved in meperidine ____ – seen in patients
receiving drug for ____days (related to accumulation)
- _______ cannot be recommended
- Eventually undergoes _______ to meperidinic acid
- 1⁄2 half as active as meperidine
- Elimination half-time 15 hours
• >30 hours in renal failure
- Increased sensitivity in elderly
• Decreased plasma protein = increased circulating volume
- May be involved in meperidine delirium – seen in patients
receiving drug for 3+ days (related to accumulation)
- PCA cannot be recommended
- Eventually undergoes hydrolysis to meperidinic acid
Fentanyl is ________opioid analgesic in anesthesia
most widely used
Fentanyl has ____ structure
Phenylpiperidine ring
Fentanyl ____ x more potent than morphine
75-125
Fentanyl ________ onset and _______ duration of action
- Lipid ________
- _______terminates effect of single dose*
Rapid onset and shorter duration of action
- Lipid soluble
- Redistribution terminates effect of single dose*
fentanyl ______responsible for large first pass uptake
Lungs responsible for large first pass uptake
Fentanyl Extensively metabolized by ____ and _______
• Pharmacologic activity of metabolites is _______
Extensively metabolized by N-dealkylation and hydroxylation
• Pharmacologic activity of metabolites is minimal
fentanyl Elimination half-time is _____ than morphine
• ______ Vd – more than ______% leaves the plasma in less than __ minutes
Elimination half-time is longer than morphine
• Large Vd – more than 80% leaves the plasma in less than 5 minutes
Fentanyl
Elderly
- _____ elimination time due to________
- Age-related decreases in
___
___
___
___
Elderly
- Prolonged elimination time due to decreased clearance
- Age-related decreases in hepatic blood flow, microsomal enzyme activity, and albumin production (highly protein-bound)
Fentanyl ____ does not significantly prolong elimination half-time
Cirrhosis does not significantly prolong elimination half-time
Fentanyl context sensitive half-time increases with infusion >____hours • Reflects _____ and _____ into _____
Context sensitive half-time increases with infusion > 2 hours • Reflects redistribution and saturation into inactive tissue sites
Fentanyl clinical use:
Block ______ to surgical response
• ____IV dose prior to induction of anesthesia
Analgesia
- _____IV dose provide analgesia
- Sudden changes in level of surgical stimulation
Block sympathetic stimulation to surgical response • 1-3 ug/kg prior to induction of anesthesia
Analgesia
- 1-3 ug/kg IV provide analgesia
- Sudden changes in level of surgical stimulation
Fentanyl
Surgical anesthesia as sole anesthetic _______ (dose) to produce surgical anesthesia
_____ hemodynamics, ______cardiac depressant effect, ____histamine
Recall?, respiratory ______post op, lack of ____ to surgical stim at any dose
Surgical anesthesia as sole anesthetic
50-150 ug/kg to produce surgical anesthesia
Stable hemodynamics, lack of cardiac depressant effect, no histamine
Recall?, respiratory depression post op, lack of response to surgical stim at any dose
Fentanyl
Oral ______
• Peds – ____ min prior to induction ______(dose); preop sedation
Oral Transmucosal
• Peds – 45 min prior to induction 15-20 ug/kg; preop sedation
fentanyl transdermal
• _____related pain; produce ___, ____ concentration x __ days
• When applied preop and left in place x ___ hr, reduces ______
Transdermal
• Cancer related pain; produce long, stable concentration x 3 days
• When applied preop and left in place x 24 hr, reduces IV requirements
Fentanyl
SIDE EFFECTS
Similar profile to_____
“Secondary____”
• May reflect release from _____uptake
_____ evoke histamine release; hypotension ____
Bradycardia is ____ prominent
• Carotid sinus ____ control
Associated with modest ____ in ICP d/t ______?
Seizure activity; myoclonus
• Inhibition of _____
Marked synergism with ____and ____
SIDE EFFECTS
Similar profile to morphine
“Secondary Peaks”
• May reflect release from pulmonary uptake
Does NOT evoke histamine release;
hypotension unlikely
Bradycardia is more prominent
• Carotid sinus baroreceptor control
Associated with modest increases in ICP
• Vasodilatory?
Seizure activity; myoclonus
• Inhibition of inhibitory neurons
Marked synergism with propofol and versed
Sufentanyl
_____analogue of fentanyl
Potency is _____times that of fentanyl
Thienyl analogue of fentanyl
Potency is 5-10 times that of fentanyl
Sufentanyl clinical uses
Analgesia
• _____dose produces longer analgesia and less respiratory depression than fentanyl
Induction
• Doses required for laryngoscopy may cause chest wall rigidity*
Analgesia
• .1-.4 ug/kg produces longer analgesia and less respiratory depression than fentanyl
Induction
• Doses required for laryngoscopy may cause chest wall rigidity*
Sufentanyl PK
_____ protein binding compared to fentanyl
- Alpha 1 _____
- Enhanced effects in ____
______ terminates effects
- _____ lipid soluble
- ____ Vd
Significant first pass ______
Extensive protein binding compared to fentanyl
- Alpha 1 glycoprotein
- Enhanced effects in neonates
Rapid redistribution terminates effects
- Highly lipid soluble
- Increased Vd
Significant first pass pulmonary uptake
Sufentanyl PK
Rapidly metabolized by _____ and _____
- ____ metabolites are inactive
- ______ – _____ sufentanil
Clearance sensitive to _____
Normal ____ function important to clearance
Rapidly metabolized by N-dealkylation and O-demethylation
- N-dealylation metabolites are inactive
- O-demethylation – desmethyl sufentanil
Clearance sensitive to hepatic blood flow
Normal renal function important to clearance
Alfentanyl
_____ potent than fentanyl; ____ duration of action
____ onset of action after IV administration
- ___ fraction of unionized drug
- ____ volume of distribution
Less potent than fentanyl; shorter duration of action
Rapid onset of action after IV administration • High fraction of unionized drug
• Small volume of distribution
Alfentanyl
PHARMACOKINETICS
_____ onset and _____ due to prompt on-sight equilibration
- ___% of the drug exists in nonionized form at physiologic pH
- Principally bound by _____
Metabolized by ___ independent pathways
- _____ to _____
- _____ to _____
Vd ____ than fentanyl
PHARMACOKINETICS
Rapid onset and offset due to prompt on-sight equilibration
- 90% of the drug exists in nonionized form at physiologic pH
- Principally bound by alpha 1 glycoproteins
Metabolized by two independent pathways
- Piperdine N-dealkylation to noralfentanil
- Amide N-dealkylation to N-phenylpropionamide
Vd less than fentanyl
alfentanyl clinical uses
Dosing
• _____ IV – blunts stimulation of laryngoscopy
• _____ IV – catecholamine response to noxious stimulation
- __-___ ug/kg IV – produces unconsciousness (induction)
- combo with inhaled anesthetic ___-____ug/kg/hr
Dosing
• 15 ug/kg IV – blunts stimulation of laryngoscopy
• 30 ug/kg IV – catecholamine response to noxious stimulation
- 150-300 ug/kg IV – produces unconsciousness (induction)
- combo with inhaled anesthetic 15-150 ug/kg/hr
Alfentanyl
SIDE EFFECTS / COMPLICATIONS
Associated with:
• ____ significant decrease BP
• Diminished incidence of ____
- Acute ____
- Avoid in untreated _____patients
SIDE EFFECTS / COMPLICATIONS
Associated with:
• More significant decrease BP
• Diminished incidence of nausea and vomiting
- Acute dystonia
- Avoid in untreated Parkinson’s patients
Remifentanyl
Selective ___receptor agonist
• Potent ____ fentanyl
• Blood-brain equilibration like _____
Although it is a phenylpiperdine derivative:
• Structurally different because of ____
Very synergistic with ____
Benefits include:
• _____
• _____
• _____
• _____
Selective mu agonist
• Potent like fentanyl
• Blood-brain equilibration like alfentanil
Although it is a phenylpiperdine derivative:
• Structurally different because of ester linkage
Very synergistic with Propofol
Benefits include:
• Brief action
• Titratable
• Does not accumulate
• Rapid recovery
remifentanyl CLINICAL USES
Cases requiring___&_____analgesic effect
- ____ block
- Direct _____
- _______
Anesthesia Induction
• ______bolus, followed by and infusion of _____ for _____ minutes prior to induction agent
Analgesia
• ______ IV or _____ug/kg/min
Sedation
• ______ in combination with midazolam ___mg
CLINICAL USES
Cases requiring transient profound analgesic effect
- retrobulbar block
- Direct laryngoscopy
- Tracheal intubation
Anesthesia Induction
• 1 ug/kg bolus, followed by and infusion of .5-1 ug/kg/min for 10 minutes prior to induction agent
Analgesia
• .25-1.0 ug/kg IV or .05 – 2. ug/kg/min
Sedation
• .05-.1 ug/kg/min in combination with midazolam 2 mg
remifentanyl PK
____ Vd
_____ clearance (will accumulate ____ than other opioids)
• PK ____ in obese and IBW patients
Context sensitive half-time is ____minutes
Metabolized by ______
- ____ active metabolites
- Not affected by________ deficiency
- PK ____ by renal or hepatic failure
Small Vd Rapid clearance (will accumulate less than other opioids)
• PK similar in obese and IBW patients
Context sensitive half-time is 4 minutes
Metabolized by non-specific plasma esterases
- No active metabolites
- Not affected by pseudocholinesterase deficiency
- PK unchanged by renal or hepatic failure
Remifentanyl
SIDE EFFECTS
It is important to administer a ________for postoperative analgesia
Can induce “______” activity
Other effects:
• _____
• _____
• _____
_____ – secondary to acute opioid tolerance
• ____ and ____ can block this
SIDE EFFECTS
It is important to administer a longer acting opioid for postoperative analgesia
Can induce “seizure like” activity
Other effects:
• Nausea and vomiting
• Depress ventilation
• Decrease systemic BP
Hyperalgesia – secondary to acute opioid tolerance
• Ketamine and magnesium can block this
HYDROMORPHONE
A derivative of ______ (____) • ___ times more potent
• Slightly ____ duration of action
Less ____ than morphine
- ___ onset
- ___ sedation
- ___ euphoria
Effective alternative to treat ______ pain
Can cause ___ and ____
HYDROMORPHONE
A derivative of morphine (1926)
- 5 times more potent
- Slightly shorter duration of action
Less hydrophilic than morphine
- Faster onset
- More sedation
- Less euphoria
Effective alternative to treat moderate - severe pain Can cause agitation and myoclonus
METHADONE
_____ opioid
• ____ opioid in ____ pain settings
• Attractive for ____ and _____
_____ terminal half-life
• Requires ____ dosing
_____ variation among individuals
METHADONE
Synthetic opioid
• Oral opioid in chronic pain settings
• Attractive for withdrawal and drug suppression
Long terminal half-life
• Requires infrequent dosing
Large variation among individuals
methadone opioid withdrawal
Can substitute for _____ at ____ the dosage
• ____mg IV, produces postoperative analgesia >___ hours
Can substitute for morphine at 1⁄4 the dosage
• 20 mg IV, produces postoperative analgesia > 24 hours
methadone
SIDE EFFECTS
Similar to ____
• Depression of ___
- ____
- _____
- _____spasm
___ and ____ effects less
SIDE EFFECTS
Similar to morphine
• Depression of ventilation
- Miosis
- Constipation
- Biliary tract spasm
Sedative and euphoric effects less
methadone
TREATMENT OF CHRONIC PAIN
____ abuse potential
____ antagonist activity may be beneficial for _____ pain
Principle disadvantage is ____ and ____ half-life
• Drug can accumulate and cause ______
TREATMENT OF CHRONIC PAIN
Low abuse potential
NMDA antagonist activity may be beneficial for neuropathic pain
Principle disadvantage is prolonged and unpredictable half-life
• Drug can accumulate and cause depression of ventilation
Tramadol
Synthetic _____ analog
Can be given ___, ___ or ____ for ____ pain
- Weak/moderate ___ agonist
- ___ potent than morphine
- Useful for ___ treatment – less ___
• Enhances function of ____ inhibitory pathways
Metabolized by _____
• Metabolite _____has _____ analgesic effects
TRAMADOL
Synthetic codeine analog
Can be given orally, IM or IV for moderate to severe pain
- Weak/moderate Mu agonist
- Less potent than morphine
- Useful for chronic treatment – less addictive
• Enhances function of descending inhibitory pathways
Metabolized by CYP 450
• Metabolite O-desmethyltramadol has modest analgesic effects
Tramadol
DISADVANTAGES
Interacts with _____ Drug-related ____ (may lower ____)
High incidence of ______
______may interfere with analgesic component
• Reuptake of _____
DISADVANTAGES
Interacts with Coumadin anticoagulants Drug-related seizures (may lower seizure threshold) High incidence of nausea and vomiting
Ondansetron (Zofran) may interfere with analgesic component
• Reuptake of 5-hydroxytryptamine
Heroin
____ opioid
Originally claimed to have ____ qualities
Differs from ____ in that it rapidly penetrates the ___where it is hydrolyzed to active metabolites
- ____
- _____
Compared to morphine
• More ___ onset
• Less ____
• Greater liability for _____
Synthetic opioid
Originally claimed to have no addictive qualities
Differs from morphine in that it rapidly penetrates the CNS where it is hydrolyzed to active metabolites
- Monacetylmorphine
- Morphine
Compared to morphine
• More rapid onset
• Less nausea
• Greater liability for physical dependence
OXYMORPHONE
Addition to ____ group to ____
____times as potent as ____
Increased_____
Potential for ____
Can be given ___
OXYMORPHONE
Addition to hydroxyl group to hydromorphone 10 times as potent as morphine
Increased nausea and vomiting
Potential for physical dependence
Can be given orally
OXYCODONE
Oral agent commonly used for treating ____
____ as potent as morphine, ____ duration of action
Great _____potential…newer preparations prevent ____
OXYCODONE
Oral agent commonly used for treating acute pain
Twice as potent as morphine, similar duration of action
Great abuse potential…newer preparations prevent IV injection
HYDROCODONE
Oral agent for treating____
____ potency and duration of action to morphine
Potential for ___
HYDROCODONE
Oral agent for treating acute pain
Similar potency and duration of action to morphine Potential for abuse
PROPOXYPHENE
Oral agent used to treat pain not relieved by ____
_____ absorbed after ____
____ first-pass hepatic metabolism
• ____ to _____
Common side effects
• _____causes severe damage to veins
Mild _____ symptoms
Off the market in ____
PROPOXYPHENE
Oral agent used to treat pain not relieved by aspirin
Completely absorbed after oral intake
Extensive first-pass hepatic metabolism
• Demethylation to norpropoxyphene
Common side effects
• IV use causes severe damage to veins
Mild withdrawal symptoms
Off the market in 2010
OPIOID AGONIST-ANTAGONIST
These drugs bind to ____ receptors but produce ___ responses or ___ effect
Advantages
• __
• ___
Have a ”___”
• Reserved for patients who _____
OPIOID AGONIST-ANTAGONIST
These drugs bind to mu receptors but produce limited responses or no effect
Advantages
• Produce analgesia
• Limited depression of ventilation
Have a ”ceiling effect”
• Reserved for patients who can’t tolerate a pure agonist
PENTAZOCINE
_____ derivative
• ___ and ____ receptor agonists
Clinical Uses
• Relief of ____
• Treatment of ____
Pharmacokinetics
• ____ first pass hepatic metabolism
• Metabolism by ____ of ____
Effects are enough to precipitate ___
PENTAZOCINE
Benzomorphan derivative
• Delta and kappa receptor agonists
Clinical Uses
• Relief of moderate pain
• Treatment of chronic pain
Pharmacokinetics
• Extensive first pass hepatic metabolism
• Metabolism by oxidation of terminal methyl groups
Effects are enough to precipitate withdraw
PENTAZOCINE
Side effects
• ___, ____ and ____
• ____ miosis
Increasing the dose over _____ cause no more effects
Produces increase in _____
___ the placenta; ___ cause______
____ associated with dysphoria, fear of ____
PENTAZOCINE
Side effects
• Sedation, diaphoresis and dizziness
• NO miosis
Increasing the dose over 30mg cause no more effects Produces increase in circulating catecholamines
Crosses the placenta; may cause fetal depression
High doses associated with dysphoria, fear of impending death
BUTORPHANOL
Limited _____ use
Resembles _____
- Agonist effects are ____times greater
- Antagonist effects are ____ times greater
___ affinity for ___ receptors
• Produces antagonism
__ affinity for ___ receptors
• used for ___ and ____
BUTORPHANOL
Limited intraoperative use
Resembles pentazocine
- Agonist effects are 20 times greater
- Antagonist effects are 10-30 times greater
Low affinity for mu receptors
• Produces antagonism
Moderate affinity for kappa receptors
• Analgesia and anti-shivering
butrophanol PK
____ absorbed after ____ injection
Metabolized in ____ and excreted primarily in the___
• ___ (active or inactive) metabolite - ____
Elimination half-time is___
Rapidly absorbed after IM injection
Metabolized in liver and excreted primarily in the bile
• Inactive metabolite - hydroxybutorphanol
Elimination half-time is 2.5-3 hours
NALBUPHINE
Chemically related to ___ and ____
___ properties of morphine;
___antagonist of nalorphine
Pharmacokinetics
• Metabolized in the ___
• Elimination half-time ____
Antagonist effects occur at ___ receptors
- If given before an opioid, may ___ effects of ____drugs perioperatively
- If given after administration of opioid, it can reverse (___hours) ____effects but maintain ___
NALBUPHINE
Chemically related to oxymorphone and naloxone
Analgesic properties of morphine; 1⁄4 antagonist of nalorphine
Pharmacokinetics
• Metabolized in the liver
• Elimination half-time 3-6 hours
Antagonist effects occur at mu receptors
- If given before an opioid, may diminish effects of morphine-like drugs perioperatively
- If given after administration of opioid, it can reverse (2-3 hours) depression of ventilation effects but maintain analgesia
Nalbuphine
SIDE EFFECTS
____ most common
Less ____ than pentazocine and butorphanol
Depression of ventilation has ___ effect (dose)
______ stimulation effects
• May be____in cardiac patients needing sedation and analgesia
SIDE EFFECTS
Sedation most common
Less dysphoria than pentazocine and butorphanol
Depression of ventilation has ceiling effect (30 mg)
Catecholamine stimulation effects
• May be beneficial in cardiac patients needing sedation and analgesia
BUPRENORPHINE
Derived from _____
• Potent ____ (___ IM = ___ mg Morphine)
Clinical uses
• Postoperative pain related to ___, ___ and ____
BUPRENORPHINE
Derived from thebaine
• Potent analgesic (.3 mg IM = 10 mg Morphine)
Clinical uses
• Postoperative pain related to cancer, renal colic and MI
Buprenorphine
SIDE EFFECTS
___, ___, ____ and ___ of ventilation
- Similar to ___ but may be ___
- Resistant to ___ by ___
Pulmonary ___?
___ Unlikely
Can precipitate ___ in patient taking ___
___ abuse risk
SIDE EFFECTS
Drowsiness, nausea, vomiting and depression of ventilation
- Similar to morphine but may be prolonged
- Resistant to antagonism by naloxone
Pulmonary edema? Dysphoria Unlikely
Can precipitate withdrawal in patient taking morphine
Low abuse risk
DEZOCINE
Opioid ___ similar to morphine
• _____dose
• High ___, moderate ____ receptor affinity
Clinical uses
• _____
Metabolized ____ and eliminated ___ conjugate
Minimal ____ effects
Exhibits a ____ effect for depression of ____
_____ is minimal
DEZOCINE
Opioid A-A similar to morphine
• .15mg/kg
• High mu, moderate delta receptor affinity
Clinical uses
• Postoperative pain
Metabolized liver and eliminated glucuronide conjugate
Minimal catecholamine effects
Exhibits a ceiling effect for depression of ventilation
Dysphoria is minimal
OTHER OPIOID A-A
Nalorphine
• ____ potency to morphine
• Not used clinically due to ____ effects
Bremazocine
• ____ a potent as morphine
- Interacts selectively with ___ receptors
- In animals…no ____, ____
OTHER OPIOID A-A
Nalorphine
• Similar potency to morphine
• Not used clinically due to dysphoric effects
Bremazocine
• Twice a potent as morphine
- Interacts selectively with kappa receptors
- In animals…no depression in ventilation, physical dependence
MEPTAZINOL
____ opioid agonist; selective for ____receptors
- ___ depression of ventilation
- ___ onset; duration ____
- ____oral bioavailability (%)
Pharmacokinetics
• ____ metabolism to inactive glucuronide conjugates
• Excreted by ___
Side Effects
• __ physical dependence,
___miosis, ___constipation
• _____
• ____ be substituted for opioid agonist in physical dependence
MEPTAZINOL
Partial opioid agonist; selective for mu1 receptors
- NO depression of ventilation
- Rapid onset; duration <2 hours
- Low oral bioavailability (<10%)
Pharmacokinetics
• Liver metabolism to inactive glucuronide conjugates
• Excreted by kidneys
Side Effects
• No physical dependence, miosis, constipation
• Nausea and vomiting
• Cannot be substituted for opioid agonist in physical dependence
OPIOID ANTAGONISTS
Opioid agonists with mild _____ changes
• Substitution of an ____ group for a ___ group
Pure ___ antagonists include
- __
- __
- ___
OPIOID ANTAGONISTS
Opioid agonists with mild structural changes
• Substitution of an alky group for a methyl group
Pure mu antagonists include
- Naloxone
- Naltrexone
- Nalmefene
NALOXONE
Used to treat opioid induced ____, depression of ___ in the ___ due to maternal administration, treat ___overdose, detect suspected ____
Dose ____IV
Short half-life ____minutes
_____(dose) can fix depression of ventilation without affecting analgesia
Oral route ____as potent due to first pass hepatic metabolism
Metabolized by __ by ___ with ____acid
• metabolite _____
NALOXONE
Used to treat opioid induced hypoventilation, depression of ventilation in the neonate due to maternal administration, treat deliberate drug overdose, detect suspected physical dependencde
Dose 1-4 ug/kg IV
Short half-life 30-45 minutes
5 ug/kg/hr can fix depression of ventilation without affecting analgesia
Oral route 1/5 as potent due to first pass hepatic metabolism
Metabolized by liver by conjugation with glucuronic acid
• Naloxone-3-glucuronide
Naloxone
SIDE EFFECTS
- Reversal of analgesia
• May be possible to titrate to maintain ___ and reverse ____
- ____
• May occur simultaneously with awakening or just after
Increased ______activity
- Sudden onset of ____
- CV response______
- Cardiac dysrthythmia – ____
Administration to the opioid dependent parturient may result in _____
SIDE EFFECTS
Reversal of analgesia
• May be possible to titrate to maintain analgesia and reverse hypoventilation
Nausea and vomiting
• May occur simultaneously with awakening or just after
Increased sympathetic nervous system activity
- Sudden onset of pain
- Tachycardia, hypertension, pulmonary edema
- Cardiac dysrthythmia – vfib
Administration to the opioid dependent parturient may result in fetal withdrawal
Naloxone ROLE IN TX OF SHOCK
In animals, large doses of naloxone improve ____ and _____.
Dose _____required, suggesting effects are not _____, or mediated by __ and __ receptors
ROLE IN TX OF SHOCK
In animals, large doses of naloxone improve myocardial contractility and outcomes.
Dose >1 mg/kg required, suggesting effects are not opioid receptor mediated, or mediated by delta and kappa receptors
NALTREXONE
Oral _____ with sustained effects > ____hours
Used in treatment of ____
NALTREXONE
Oral antagonist with sustained effects > 24 hours
Used in treatment of alcoholism
NALMEFENE
____ opioid antagonist
• 6-methylene analogue of _____
• _____ IV until effect achieved (MAX dose ____)
_____ potent to naloxone
Prophylactic administration decreases _____and ____ in patient with IV PCA
PRIMARY ADVANTAGE – ____ duration of action
NALMEFENE
Pure opioid antagonist
• 6-methylene analogue of naltrexone
• 15-25 ug IV until effect achieved (MAX dose 1ug/kg)
Equipotent to naloxone
Prophylactic administration decreases N&V and pruritis in patient with IV PCA
PRIMARY ADVANTAGE – longer duration of action
Nalmefen PHARMACOKINETICS
Metabolized in the ___ by ____
Side effects
• _____seen
PHARMACOKINETICS
Metabolized in the liver by hepatic conjugation
Side effects
• Pulmonary edema seen
METHYLNALTREXONE
______ opioid receptor agonist
____ ionized; ____ to penetrate CNS
Attenuates morphine induced_____
Decreases incidence of _____
METHYLNALTREXONE
Quaternary opioid receptor agonist
Highly ionized; difficult to penetrate CNS
Attenuates morphine induced delayed gastric emptying
Decreases incidence of nausea
ALVIMOPAN
Newer ________opioid antagonist
- Oral bioavailability ____%
- Relies on ______ for metabolism
Treat ____ and opioid-induced ____
Increase in ______with long-term use
ALVIMOPAN
Newer mu selective oral peripheral opioid antagonist
- Oral bioavailability 6%
- Relies on gut flora for metabolism
Treat ileus and opioid-induced constipation Increase in cardiac events with long-term use
OPIOID ALLERGY
TRUE opioid allergies are ___
caused by
- ____
- ____
- ______
Fentanyl _____cross-react with morphine _____
• Only____cases of true fentanyl allergy recorded to date
OPIOID ALLERGY
TRUE opioid allergies are rare
- Histamine release
- Orthostatic hypotension
- N&V
Fentanyl does not cross-react with morphine derivatives
• Only 3+ cases of true fentanyl allergy recorded to date
OPIOID IMMUNE MODULATION
Opioid receptors are present on _____ cells
• ____, ____, ____, _____ and _____
Immunosuppression – depression of ____cell
- Following ____ exposure
- ____ withdrawal
_____can impair immune function
OPIOID IMMUNE MODULATION
Opioid receptors are present on immune cells
• T&B lymphocytes, dendritic cells, neutrophils, macrophages and microglia
Immunosuppression – depression of natural killer (NK) cell
- Following prolonged exposure
- Abrupt withdrawal
Pain itself can impair immune function
Opioid
ANESTHETIC EFFECTS
Opioids shown to _____ amount of anesthetic gas required
• Given ____ to surgical incision
ANESTHETIC EFFECTS
Opioids shown to decrease amount of anesthetic gas required
• Given prior to surgical incision
PATIENT CONTROLLED ANALGESIA
Alternative to ______, allows patient to address own analgesic requirements
Advantages include
• Decreased healthcare provider ____, ____ patient satisfaction, ____ opioid consumption, ___ safety
Studies show PCA provides ____ better analgesia, but better pain ____
Remifentanil PCA in the first stage of labor has been shown to provide ____ analgesia while minimizing____ effects.
PATIENT CONTROLLED ANALGESIA
Alternative to intermittent bolus, allows patient to address own analgesic requirements
Advantages include
• Decreased healthcare provider workload, increased patient satisfaction, lower opioid consumption, inherent safety
Studies show PCA provides marginally better analgesia, but better pain satisfaction
Remifentanil PCA in the first stage of labor has been shown to provide good analgesia while minimizing neonate effects.
NEURAXIAL OPIOIDS
Opioids placed _____ target _____ receptors in the ____ in the spinal cord
Unlike local anesthetics, neuraxial placement of opioids does not result in ______, _____ or ______
Epidural placement of opioids results in
• ____ receptors and _____ absorption
• Offers minimal to no over IV administration
• Uptake into ___, _____ absorption and diffusion across ___
NEURAXIAL OPIOIDS
Opioids placed intrathecally target mu receptors in the substantia gelatinosa in the spinal cord
Unlike local anesthetics, neuraxial placement of opioids does not result in sympathectomy, sensory block or weakness
Epidural placement of opioids results in
• Mu receptors and systemic absorption
• Offers minimal to no over IV administration
• Uptake into fat, systemic absorption and diffusion across dura
NEURAXIAL OPIOIDS
Pharmacokinetics
• Uptake into ___, ____ absorption or diffusion across ___
- Passage through dura dependent on ____
- Only ____% of epidural morphine crosses the dura to enter the ____
- Less lipid soluble drugs more likely to stay in ____
- Morphine movement cephalad can result in ____ depression of ventilation
- ___ and ____ can facilitate process
- Lumbar to cisterna magna (__hours) 4 and lateral ventricles ___hours)
Epidural injection results in ____ blood concentrations produced by IM injection
______ can enhance intrathecal effects of morphine
NEURAXIAL OPIOIDS
Pharmacokinetics
- Uptake into fat, systemic absorption or diffusion across dura • Passage through dura dependent on lipophilicity
- Only 3% of epidural morphine crosses the dura to enter the CSF
- Less lipid soluble drugs more likely to stay in CSF
- Morphine movement cephalad can result in delayed depression of ventilation • Coughing and straining can facilitate process
- Lumbar to cisterna magna (1-2 hours) 4 and lateral ventricles 3-6 hours)
Epidural injection results in similar blood concentrations produced by IM injection
Epinephrine can enhance intrathecal effects of morphine
neuraxial opioids
SIDE EFFECTS
Dose dependent
Four classic side effects of neuraxial opioids are
• ____ – most common; seen in OB, ?dose related? most likely
related to _____migration and interaction with _____ nucleus.
- ______
- _______–most common in young males,likely due to
interaction of opioid with____receptors in the ___ and
• ____ – most serious side effect, occurs faster
with ___. CSF migration and interaction with ventral medulla (morphine).
- What monitor device to use?_____
- ____ effective in attenuating side effects
SIDE EFFECTS
Dose dependent
Four classic side effects of neuraxial opioids are
• Pruritis – most common; seen in OB, ?dose related? most likely
related to cephalad migration and interaction with trigeminal nucleus.
- Nausea and vomiting
- Urinaryretention–mostcommoninyoungmales,likelydueto
interaction of opioid with spinal cord receptors in the sacrum and
• Depression of ventilation – most serious side effect, occurs faster
with lipophilic. CSF migration and interaction with ventral medulla (morphine).
- Pulse oximetry, Oxygen
- Naloxone effective in attenuating side effects
Neuraxial opioids
SIDE EFFECTS
_____
_____rare with neuraxial opioids
Reactivation of ____virus (most likely involves ____migration and interaction with _____ nucleus
____, ____ and ____ (reversible with ____), delay in ____, ____
______ damage (possibly related ______)
SIDE EFFECTS
Sedation
Myoclonus rare with neuraxial opioids
Reactivation of herpes virus (most likely involves CSF migration and interaction with trigeminal nucleus
Miosis, nystagmus and vertigo (reversible with naloxone), delay in gastric emptying, priapism
Spinal cord damage (possibly related toxic preservatives)
Neuraxial opioids
NEONATAL MORTALITY
Clinically important _____ has been observed in newborns of mother receiving epidural opioids
Concentration of ___, ____ negligible in breast milk
NEONATAL MORTALITY
Clinically important depression of ventilation has been observed in newborns of mother receiving epidural opioids
Concentration of fentanyl, sufentanil negligible in breast milk
which opioids crosses placenta more easily? meperidine or morphine?
morphine