Opioid tolerance, dependence, and abuse Flashcards
Tolerance
gradual reduction in efficiency of drug. Narrows TI -> need more drug to achieve same effect.
Dose response curve shifts to right/left with tolerance
right
Two types of tolerance
pharmacokinetic
pharmacodynamic
pharmacokinetic tolerance
increased capacity to metabolize/excrete drug due to repeated exposure. Thought to be due to induction of metabolic enzymes
Less drug reaches site of action -> need more drug
pharmacodynamic tolerance
changes to neurons that requires pt to need more drug
lower response from neurons when drug binds
Need more drug
How to address tolerance?
increase the dose OR remove the drug - applies to both PD and PK
Development of opioid tolerance appears to be primarily due to pharmacodynamic/ kinetic changes?
pharmacodynamic
Possible mechanisms of opioid tolerance (3)
Receptor desensitization
changes in downstream signalling
immunological mechanisms
receptor desensitization
ligand binds and DOES NOT produce an effect/same effect. Could be due to receptor expression, phosphorylation, etc
Changes in downstream signalling
signal transduction pathways are working differently -> pathway may not work so others have to work differently. Many reasons why this could happen
Immunological mechanisms
opioids can activate immune cells (microglia) -> they release proinflammatory factors -> factors reduce how neurons respond to opioids.
Key properties in opioid tolerance
tolerance can be overcome by increasing drug dose
reversible over time upon discontinuation
different physiological responses develop tolerance at different rates
cross-tolerance can occur
Rapid tolerance
happen quickly - analgesia, euphoria, sedation, respiratory depression. If you take the drug for a long time, you won’t show tolerance
Slow tolerance
miosis and constipation. You won’t develop tolerance to these issues
Cross-tolerance
develop tolerance to one drug, give the pt a second drug, pt shows tolerance to that drug even though thye’ve never taken it. Typically happens with drugs in the same class
Opioid rotation
take pt off one drug and put on another to gain efficacy. Useful in tolerance and when pt cannot handle SE of current drug
Opioid rotation used in specific circumstances
complete/full cross tolerance
incomplete/partial cross tolerance
complete/full cross tolerance
develop tolerance to one drug, switch to second drug, pt shows just as much tolerance
incomplete/partial tolerance
develop complete tolerance to one drug, switch to second, get partial effect
When switching to second opioid due to tolerance, should new opioid be more/less potent
more potent
Are NMDA receptors located in the spinal cord
Yes
What happens if you antagonize NMDA receptors
analgesia -> antagonize, block glutamate from binding ->less activation of projection neuron -> inhibit ascending pathway
What is ketamine
NMDA receptor agonist
Ketamine plus opioid combined produces
analgesia
ketamine issues
hard to get therapeutic dose
lots of SE
Opioid physical dependence
Body becomes used to having the drug in order to function normally. When drug isn’t there, you get withdrawal sx. Pt has changes on cellular level
physical withdrawal sx
hyperalgesia hyperthermia hypertension diarrhea pupillary dilation
affective withdrawal sx
agitation
anxiety
depression
dysphoria
Opioid withdrawal
pt feels like they’re going to die
easiest way to relieve sx is to take more drugs
Superactivation hypothesis
cAMP pathway is downregulated with continued opioid use -> other signal transduction pathways activate to compensate -> stop taking meds, cAMP is no longer inhibited and reactivates at much higher level -> compensation systems are still working -> hyper-excitatory state due to increased cation influx
Tx of opioid withdrawal
taper drugs pharmacological options: methadone buprenorphine clonidine
Do most people who use opioids develop dependence
NO
How does methadone work
maintenance tx for people who cannot get off opioids -> give just enough so they don’t experience withdrawal. Racemic mixture -> L is NMDA receptor antagonist, D helps in process. Key is to maintain steady state. It is both a mu receptor agonist and NMDA antagonist
Methadone maintenance tx
long duration of action, moderate doses can prevent withdrawal without producing rewarding effects
Buprenorphine tx
Partial agonist. Able to treat physical sx without high effect -> pt less likely to become dependent on it, but not a sure thing -> some people get stuck on it
key property of partial agonist
display both agonist and antagonist effects. In presence of full agonist, partial will act as antagonist to compete for receptor and reduce the ability of full agonist to produce max effect
Clonidine tx
alpha-2 adrenergic agonist (autoreceptor). Blocks autonomic sx of withdrawal: HTN Tachycardia Nausea Vomiting Sweating
Best long term tx to keep pt opioid free
Buprenorphine > methadone> clonidine
Naltrexone
(revia, vivitrol)
opioid receptor antagonist
Pt MUST be drug free for 7-14 days
Crosses BBB
oral dosing not recommended b/c too easy to skip dose -> IM best
Won’t work if given to pt with drugs in system b/c tx antagonizes opioid receptors -> will get severe withdrawal sx
Can patient become sensitized to long term tx with Naltrexone
YES
What will happen if patient takes opioid agonist after using naltrexone long term
Huge response to the opioid/agonist due to upregulation of opioid receptors
Naloxone
opioid receptor antagonist
short acting -> IV in case of OD
Big problem with opioids?
mental and psychological aspects
what is psychological dependence
when you need to drug to feel good -> people look for a “high”. Very difficult to treat
Pathway in brain responsible for pleasure
mesolimbic. Releases dopamine
Where is DA released
in the ventral striatum
What happens with increased levels of DA
increased -> pleasureable high effect (abuse levels)
too much -> positive sx of schizophrenia
Drug craving
Intense preoccupation with obtaining the drug. Can linger for years.
Do cravings develop independent of tolerance
yes
How do opioids produce rewarding effect (mesolimbic pathways)
- Dopeminergic neuron in VTA -> releases dopamine in ventral striatum
- GABAergic neuron in VTA -> inhibits dopaminergic neuron
- GABAergic neuron has mu opioid receptor
- Enkephalinergic neuron also in VTA -> releases enkephalin to INHIBIT GABAergic neuron
- if GABAergic neuron inhibited, Dopaminergic neuron can release DA into Ventral striatum and activate D2 receptor (which is inhibitory)
What is addiction
purely psychological -> feeling high, drug cravings. Can lead to compulsive search for drugs
