3. Ch 11 Opioids Flashcards
(29 cards)
opioid epidemic
ODs falling
due to prescription opioids
fentanyl cheaper than heroin
sackler family and prescription drug crisis, settlement lawsuits
narcotic analgesics
reduce pain w/o unconsciousness
euphoria, high dose = coma/death
Opium
poppy extract
active ingredient morphine
opiates are derived from poppy/morphine
opioid - opiates, semi-synthetics (heroin, first marketed as nonaddicting cough suppresant), synthetics (fentanyl), endogenous peptides (endorphins)
heroin
2 acetyl groups added to morphine
more lipid soluble
converted to morphine in brain
more potent than morphine IV, equipotent PO
4 components of opioid intoxication and adverse effects
Route-admin dependent
Rush - wave euphoria, 10 seconds
High - general well-being, lasts for hours
Nod - overlaps high/escape reality
Being straight - no high/rush/nod, but also no withdrawl, withdrawl 8hrs after
adverse effects - vomiting (area postrema), unconsciousness, body temp/BP falls, respitraory failure, GI tract effects
Opioid receptors
4 subtypes, mu/delta/kappa/NOP-R
most abuse-dependent actions on mu
Mu Opioid Receptor
function
high affinity morphine
MOR KO = no self admin, no CPP, no dependence, no analgesia/resp depression/constipation
Gi - inhibits adenyl cyclase = reduce cAMP, does chronic effects in tolerance/withdrawl, K channel opening and Ca channel closing = analgesia, reduce NT release
MOR locations
analgesia - medial thal, PAG, median raphe, LC, spinal cord
positive reinforcement - VTA/NAcc
cardiovascular/resp depression, nausea - brainstem
Opioid inhibition
Postsynaptic - receptors activate G protein and open K channels, reduces firing
Axoaxonic - activate G proteins and close Ca channels, reduces NT
Presynaptic autoreceptors - G proteins and reduce release of co-local NT
2 kinds of pain
pain varies intensity/quality
early pain - sharp, noxious onset, ADelta axons, large diameter/myelinated
late pain - dull throbbing, chronic pain and collaterals to limbic, C fibers thin unmyelinated
3 ways opioids inhibit pain
opioids bind to receptors and mimic endogenous opioid inhibition
1. within spinal cord
2. descending PAG pathways
3. higher brain sites, emotional/hormonal pain aspects
pain regulation and PAG
treat chronic pain with stimulate PAG, tolerance occurs after repeat, cross-tolerance with morphine injections (so morphine-like susbtance released)
GABA in PAG inhibits projections to raphe nuclei (5HT) and LC on spinal cord that inhibits ascending pain signal.
MOR/opioids inhibit the GABA, which removes inhibition on 5HT neurons = allow more inhibition of pain signal
ICSS and opioids
acute treatment lowers threshold, enhances reward system
chronic raises threshold, breaks reward system
Mesolimbic DA path and opioids
opioids in VTA increase DA firing and increase DA release in NAcc
BUT lesion DA doesn’t abolish self-admin (DA-indepent methods of reinforcement)
B-endorphin and opioids increase VTA firing by inhibiting the inhibitory GABA projections onto Mesolimbic cell, allow more release of DA into NAcc
Chronic use of opioids
physical dependence
neuroadaptic state response to chronic use,
during withdrawl = overshoot, rebound hyperactivity = symptoms (pain/diarrhea/hyperthermia)
severity of withdrawl depends on drug and ROI
e.g. heroin IV peak 48-96 hrs, withdrawl done in a week
methadone PO gradual increase over days and decrease over several weeks
Himmelsbach model of tolerance/dependnece
nervous system adapts to presence of drug, devleop tolerance
drug withdrawn = rebound physiological effects (symptoms)
acute morphine = inhibit adneyl cyclase, cells made more cAMP, withdraw morphine = cAMP rose significantly
NE alpha 2 autoreceptor
withdrawl activates noradrenergic system
low energy/irritable/anxiety/cramp/sweats
Alpha2 autoreceptor agonist like clonidine treat symptoms
3 MAT drugs
medication assisted treatment
3 fda drugs
methadone
buprenorphine
naltrexone
methadone/buprenorphine are susbtitution therapies
naltrexone is MOR antagonist, NEED to be DETOX’D first!
Methadone maintenance
MOR agonist
no euphoria PO, relieves cravings, daily supervised Rx
cross-dependence with heroin, prevent severe withdrawl
cross-tolerance, lower euphoria with heroin = less relapse, but also problem for analgesia in ER
Buprenorphine
partial MOR agonist
same method as methadone
but weaker effect/longer duration, lower cost, more freedom for addict
Suboxone
buprenorphine and naloxone (MOR antagonist)
when taken PO, buprenorphine is abosrbed, naloxone is not
if CRUSHED/INJECTED, naloxone blocks buprenorphine’s euphoria, = withdrawl symptoms, abuse deterrent
MOR antagonists
naltrexone - most common, longer duration than naloxone
only effecitve for highly motiavted people, craving is not elimianted
must detox first (clonidine, cold turkey, methadone taper)
remain opiate free for 5-10 days prior to treatment, naltrezone causes severe withdrawl, low rates compliance
vivtrol - extended release naltrezone (still must detox)
how does naloxone work
treats opioid overodse
by outcompeting opioids on the receptor, but then withdrawl symptoms
imodium
diarrhea drug, MOR agonist
acts on GI receptors to decrease activity = constipation
efflux by P-glycoprotein prevents loperamide from crossing BBB, inhibit P-glyco = cross BBB and get high
