Opioid Analgesics Flashcards
What tracts send sensory-discriminative pain information to the brain?
spinothalamic and trigeminothalamic afferent tracts (Stoelting). Pain does not necessarily correlate with the degree of tissue damage present.
What are the 4 components of nociception (experience of pain)? neurophysiologic processes
transduction (stim –> electrical impulse), transmission, modulation, perception
Describe how pain occurs in the absence of any of the 4 steps
axonal discharges from compressed or demyelinated nerves (ex: trigeminal neuralgia occurs without transduction from a nociceptor)
unmyelinated C-fibers
- receptive field 100 mm^2
- burning pain (INTENSE heat)
- sustained pressure
myelinated A-fibers
FAST 2m/sec
Type I fibers: respond to heat, chemical and mechanical stimuli
Type II fibers: no response to mechanical, probably 1st signal of heat pain
dorsal horn anatomy
rexed lamina are parts of the DRG: lamina I, II (substantia gelatinosa), sometimes V house pain fibers
VII, VIII are motor neurons
gate control theory of pain (stoelting)
painful info is projected to the brain if the gate is open, and pain is NOT felt if the gate is closed by simultaneous inhibitory impulses.
Ex: rubbing the skin activates myelinated ABeta, which are faster than Agamma or C-fibers
In general, opioid receptors are located
centrally
2 classes of opium
phenanthrenes (morphine, codeine, thebaine)
benzylisoquinolones (papaverine, noscapine) - provide no analgesia
opioid agonists cause & do not cause
cause analgesia
IN THE APPROPRIATE DOSES do not cause loss of touch, loss of proprioception, loss of consciousness
semi-synthesized opioids
modifications of morphine can lead to heroin and codeine, but nowadays it’s easier to just make it totally synthetically
opiate versus opioid
opiate = naturally occurring drug, derived from opium
opioid = all exogenous substances, natural and synthetic, that bind to any opioid receptors
synthetic opioids
- structure
- derivatives
structure: contain a phenanthrene nucleus (synthesized rather than modified)
derivatives: morphine –> levorphanol, methadone, benzomorphan –> pentazocine, phenylpiperdine –> meperidine, fentanyl
transmission of pain signals
first order neurons have cell bodies in the DRG (dorsal root ganglion) rexed lamina
principle effect of opioid receptors
GPCRs (a few minutes to take effect) decrease neurotransmission by presynaptic inhibition. enkephalins, endorphins, dynorphins act on 1st order neurons to inhibit the release nt’s like ACh, DA, NE, substance P pre-synaptically.
post-synaptically (at 2nd order neuron) - they cause increased K+ conductance –> decrease function. This is what exogenous substances will target.
location of opioid receptors
brain, spine, (least likely) periphery
opioids may regulate fns of other ion channels
NMDA (but we’re not usually thinking of this - we’re usually thinking of mu, kappa, delta)
Opioids do not…
… block nerve impulses. The only way to do this is via local anesthetics. They just alter the responsiveness of afferent nerve endings to noxious stimuli
opioid receptors’ location
brain:
- periaqueductal gray (recognizes pain, tells the body it needs to address it endogenously)
- locus ceruleus (alertness - think dexmedetomidine)
- rostral ventral medulla
***spinal cord: primary afferent and interneurons of the dorsal horn (rexed lamina!)
names of 4 opioid receptors
for the original binding ligand, or tissue of origin: mu - morphine delta - vas Deferens (mice) sigma - SK&F 100047 kappa - ketocyclazocine
mu receptors (in general)
principally responsible for supraspinal and spinal analgesia, addiction also possible
mu 1 and mu 2 receptors
Mu1 ASS BUME Analgesia (Spinal and Supraspinal) Bradycardia Urinary retention Miosis (pinpoint pupils) Euphoria (mu 1 gets higher than mu 2)
Mu2 CAPD-spinal
Constipation
Analgesia (spinal) only receptor that doesn’t affect supraspinal
Physical dependence
Depression of ventilation
(mu 2 is the only one that doesn’t get supraspinal)
kappa
MADDss Miosis Analgesia (spinal and supraspinal) Dysphoria (not feeling comfortable), Sedation Diuresis
To a lesser extent, hypoventilation and high-intensity pain.
Agonist-antagonist often act on principally on kappa receptors (low abuse potential)
delta
CRUP-SS Constipation Respiratory depression Urinary retention Physical dependence Analgesia (spinal and supraspinal)
Test: Which receptor least likely to cause urinary retention
kappa
PK of opioids, in general
- lipophilic, but not as lipophilic as barbiturates, but still get effect. most are absorbed PO, some undergo significant 1st-pass effect, small dose effects are terminated by redistribution, multiple doses and gtt’s are terminated by metabolism
- most metabolized in the liver (except remifentanil)
- excreted primarily by kidneys
- “pharmacogenetics”
opioid CV effects
- in healthy pts, bradycardia with sustained BP (worse in combo with induction drugs).
- impairment of SNS response, orthostatic hypotension d/t venous pooling, histamine release
- doesn’t sensitize the heart to catecholamines though
- synergism with BZ’s, NO, causes myocardial effects
- cardiac protectant effect
what is the cardiac protectant effect
enhances myocardial resistance to oxidative and ischemic stress
-sigma and kappa receptors
opioid respiratory effects
“slow deep breaths”
- dose-dependent depression of ventilation (but they try to keep their minute ventilation so just increase VT) via mu and delta rec’s
- Interfere with pontine and medullary ventilatory centers (regulate rate and rhythm of breathing)
- Decreased responsiveness to CO2 (by decreasing ACh release in the medullary center of the brain)
- RIGHT Shift in O2-CO2 response curve (the body wants to release more O2, bc CO2>O2)
- Could have ETCO2 60 and they’re not breathing heavily
- OD sx: pinpoint pupils, slow deep breaths
- Bronchial effects (decrease ciliary action, increase airway resistance via bronchial smooth muscle and histamine release)
- cough suppression
factors that affect depression of ventilation
Extremes in age, Natural sleep, Pain
Also think about tolerance to narcotics!
Extremely old and young pts are more affected by this
cough suppression
Depression of medullary cough centers
Codeine (bulky substitution on number 3 carbon position)
Dextromethorphan – dextrorotary – cough suppression without analgesia or respiratory depression
Falyar – have given opioids and during induction pt was coughing
common CNS effects
“opioids are not anesthetics… sedate but awareness possible!”
“sedate patients are not pain free!”
-decrease cerebral blood flow, and possibly ICP (in the absence of hypoventilation)
-use cautiously in head trauma pts -an increase in CO2 will still cause cerebral vasodilation!)
*alter wakefulness, miosis (so can’t assess that), depression of ventilation, increased sensitivity when BBB is compromised
-DO NOT alter the effects of NMBs
analgesic effects are two-fold
inhibit ascending transmission of nociceptive info
activate descending pathways
could have a set of nerves sending excitatory pain signals and it be the same set of nerves that could modulate them to slow down
SE: miosis
ANS component of Edinger-Westphal nucleus of oculomotor nerve
- can be antagonized by atropine (bc chemically similar) but this is the least of the worrisome SEs
- severe arterial hypoxemia can result in the presence of morphine
SE: 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 DA and GABA receptors
-Evidence supports resistance d/t laryngeal musculature contracture (tx: NMB or naloxone) example of woman with true laryngospasm who got 20 of succ
SE: sedation
opioids will induce some sort of sedative effect, but doesn’t mean they’re not uncomfortable
morphine induces sedation that precedes analgesia in up to 60% of pts
SE: biliary tract
Inappropriate for cholecystectomy: morphine is the most guilty!!
-RUQ pain
-Opioids cause spasm of biliary smooth muscle and the sphincter of Oddi
Tx: Glucagon 2mg, IV will reverse smooth muscle spasm (doesn’t antagonize analgesic effects)
-Morphine can contract pancreatic ducts
-Increase in amylase and lipase levels
-Mimics acute pancreatitis
SE: GI tract
- 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 – only works in the gut
- Narcan works everywhere
Do narcotics treat chronic pain effectively?
No - the chronic pain pathway is not the same as the acute pain pathway. Pain can initiate itself anywhere along that pathway
SE: N/V
- (mostly bc of this) Stimulation of receptors in the chemoreceptor trigger zone in the medulla (Serotonin type 3 receptors (5HTZ) and Dopamine type 2 receptors)
- Increased GI secretions and delayed gastric emptying (more gastric acid in there, not feeling comfortable) –> more N/V
- N/V not common in recumbent patients
- Vestibular effect?
- Opioids, anesthetic gases, reversal agents make you sick
SE: GU
- Opioid-induced augmentation of detrusor muscle tone results in urgency, but…
- Tone of urinary sphincter enhanced, making voiding difficult
SE: cutaneous changes
- Morphine* causes BVs to dilate (–> warm, flushed skin)
- Histamine release, not an allergy –> conjunctival erythema, pruritis, might even cause a rash
- Example of Dr. Funk getting morphine intrathecal crazy itching
Placental Transfer
Readily cross the placenta, results in neonatal depression
- Morphine greater than meperidine
- Chronic use can cause neonatal physical dependence
- Naloxone may precipitate neonatal abstinence syndrome
-(neuromusc blocking and general anesth’s don’t cross) – but any drug with any lipophilicity (opioids) will cross the placenta and take effect
