Lec 18 Opioid Analgesics and Antagonists Flashcards
25 y/o male with no past medical history presents to ER w/ 10/10 sharp left leg angle pain after falling off side of building,
was taking ibuprofen 400 ever 3 hrs with no relief, in ED has broken left tibia, planned for surgery/case
also in acute renal failure
which do you give A. oral oxycodone w/ acetaminophen [percocet] B. IV ketoralac [NSAID] C. IV morphine [opioid] D. IV hydromorphone [opioid] E. IV acetaminophen
D. IV hydromorphone [opioid] because safe for renal failure!
What type of receptors do endorphins act on?
mu
What type of receptors do enkephalins act on?
delta
what type of receptors do dynorphins act on?
kappa receptors
What are the types of opioid endogenous peptides?
endorphins/morphine
enkephalins
dynorphins
Where are mu receptors located?
- predominately brainstem, arcuate nucleus, pituitary, immune cells
What is function of the 3 different types of mu receptors?
u1: analgesia
u2: respiratory drive, miosis, euphoria, GI motility
u3: vasodilation
What is general function of opioids on mu receptors?
supraspinal and spinal analgesia, resp depression, sedation, euphoria, decreased GI transit, physical dependence
what is general function of opioids on delta receptors?
supraspinal and spinal analgesia
what is general function of opioids on kappa receptors?
analgesia, psychomimetic effects of some opioids
Where are delta receptors located?
widely in CNS and immune
Where are kappa receptors located?
widely in CPS including spinal cord and hypothalamus
What is function of opioid receptors along the pain path?
- direct action on inflamed/damaged peripheral cells
- inhibition at spinal cord
- inhibition in higher paths of brain
Where do opioids tend to distribute?
to highly perfused tissues –> lungs, brain, liver, kidneys, spleen
How are opioids metabolized?
- converted to polar metabolites by liver
- excreted by kidneys
How are opioids absorbed?
- well absorbed subcutaneously, intramuscularly, or orally
- because of first pass effect –> need higher dose for oral form to get therapeutic effect
At which receptors does morphine act?
selective to mu receptor
What is significance of morhpine’s effect on pupils?
- opioids block activity of inhibitory GABAergic interneurons –> increased PNS
- causes miosis [pupil constrict]
- miosis = important sign of opioid intoxication
Do pupils constrict or dilate with opioid use?
constrict
What are clinical uses for morphine?
- acute pain
- chronic cancer related pain
- anti-dyspneic [shortness of breath]
- weakly antitussive/anti-diarrheal
What are 2 possible adverse affects associated with morphine metabolites
- accumulation of 6-glycuronide associated wtih renal toxicity
- accumulation of 3-glyc associated wtih neurotoxicity/seizures
What are main side effects of morphine?
- sedation [at initiation or dose escalation, get tolerance w/in days/wks]
- nausea [at initiation, tolerance w/in 7 days, give antiemetics]
- constipation [no tolerance]
other: delirium, dry mouth, urinary retention
why do you develop opioid tolerance?
- upregulation of cAMP, failure of receptor recyclig
What is WHO 3 step ladder?
if pain should deliver drugs in this order:
step 1: for mild pain
–> NSAID and acetaminophen
step 2: low potency opioids for moderate
–> codeine, oxycodone, hydrocodone, oral morphine, or tramadol
step 3: stronger opioid for severe
–> morphine IV, hydromorphone, fentanyl, methadone
+ can give non-opioid adjuvant at any time for extra benefit
Which drugs are better choices for neuropathic pain?
- methadone and non-opioids better for chronic neuropathic pain
Which 3 drugs best if pt with renal failure? which can you not use?
- fentanyl
- methadone
- hydromorphone with lower dose/frequency
can’t use: morphine, codeine
Can you use morphine with kidney/liver disease?
not in renal failure or dialysis, can use with caution in stable cirrhosis
Can you use codeine with kidney/liver disease?
NOPE
Can you use oxycodone with kidney/liver disease?
yes but w/ caution, not preferred
can you use hydromorphone with kidney/liver disease?
preferred in kidney disease
caution in liver disease
Which drugs overall best with renal/liver disease?
fentanyl and methadone are preferred
hydromorphone also good for kidney but use with caution in liver disease
Can you use fentanyl in kidney/liver disease?
yes = preferred
can you use methadone in kidney/liver disease?
yes = preferred
What do you have to take into account when switching one opioid to another?
- calculate equianalgesic dose
reduce for incomplete cross talk - reduce equal dose by 50%
What is incomplete cross-tlak?
- someone with tolerance for one opioid may not be as tolerant to another opioid
- due to differences in :molec structure, way opioid interacts with pts receptors
- only applies to rotation from one opioid type to another not from Iv to PO of same opioid
56 yo male with history depression, family history alcoholism, chronic back pain after car accident 5 yrs ago
presents to pain clinica asking for refill on hydromorphone.
Says he is taking for last 2 months
- methadone
- hydromorphone for extra pain
The patient has developed: A. Tolerance B. Dependence C. Opioid Use Disorder (addiction) D. Pseudo-addiction E. All of the above
s
What is dependence?
development of withdrawal syndrome following dose reduction or administration of antagonist
what is tolerance?
change in dose-response relationship induced by exposure to the drug and manifest as a need for higher dose to maintain effect
What is opioid use disorder?
pattern of opioid use leading to clinically significant impairment or distress
What is addiction?
compulsive use despite harm, craving, impaired control of drug use
What is pseudo-addiction?
behaviors that look like addiction but are driven by pain and disappear with more adequate analgesia [ex. clock watching, excessive complaints]
What is the biologic base for addiction?
- mesolimbic pathway
- in general, addictive drugs increase dopamine in mesolimbic system
What structures are involved in mesolimbic system?
- ventral tegmental area [VTa]
- nucleus accumbens
- amygdala/hippocampus
What is the mech of addiction specifically for mu opioids?
- in VTa cause inhibition of GABAnergic –> disinhibition of dopamine neruons
- in PAG, arcuate nucleus, and locus coeruleus cause release of endorphins that directly influence the nucleus accumbens [NA] in manner similar to that of stimulants
What is the function of the mesolimbic dopamine path?
- reward [motivation]
- pleasure/euphoria
- motor function [fine tuning]
what is the function of the mesolimbic serotonin pathway?
- mood
- memory processing
- sleep
What is the likelihood that a patient will develop opioid use disorder when taking opioids? A. <1% B. 5-10% C. 10-25% D. 25-33% E. 50-66%
A. <1%
What is rate of developing OUD [opioid use disorder/]?
- for pts who take opioids for pain –> less than 1%
- in cancer –> 0-7%
increased risk for pts with prior substance abuse
What are risk factors for OUD?
- biological [fam history of drug abuse, male]
- social [poor social support, history of drugs]
- psych [substance abuse, sexual abuse, comorbid psych disease]
Which 3 opioids can you detect in standard urine tox screen?
- coedeine
- morphine
- hydrocodone
What are the 3 general approaches to OUD treatment?
- psycho-social therapy
- opioid agonist therapy [methadone or buprenorphine]
- opioid antagonist therapy [naltrexone]
Which drug do you use for opioid antagonist therapy?
naltrexone
What two drugs can you use for opioid agonist therapy?
methadone
buprenorphine
What is mech of methadone action?
- full mu-opioid agonist
- NMDA glutamate receptor antagonist [anesthetic, analgesia of neuropathic pain]
What are unique side effects of methadone?
- prolonged QTc
- cardiac arrhythmia
What is the clinical pain use for methadone?
- chronic pain more than acute [bc long half life]
- neuropathic pain [bc NMDA antagonist]
Is methadone safe to give in renal/liver disease?
yes
Why does methadone work for opioid use disorder?
- prevents withdrawal symptoms
- normalizes most neuro-endocrine alterations found with chronic opioid use
- oral use –> slow rate of increase in plasma/brain levels thus less euphoria than other opioids
Which 2 opioids do you use preferentially for analgesia?
morphine
hydromorphone
Which opioid do you use preferentially for dyspnea?
morphine
Which opioid do you use preferentially for cough?
codeine
Which opioid do you give preferentially for preanesthesia? why?
fentanyl
because it has a short duration of action (1-2 hrs)
Which 2 opioids do you give preferentially for regional anesthesia?
- morphine
- fentanyl
Which opioid do you use preferentially for cardiovascular surgery? why?
- high dose fentanyl
- it produces minimal cardiac depression
Who is eligible for methadone as treatment for OUD?
- > 18 yo who have been dependent on opioids for > 1 yr
OR can be less than 1 yr IF: pregnant, previously treated, or following prison release
How long are you on methadone for OUD treatment?
months or yrs, depends on starting dose and speed of reduction
What is the induction phase of OUD treatment? stabilization? maintenance?
induction: given when individual abstained from using opioids for 12-24 hrs
stabilization: when pt no longer experiencing cravings for drug of abuse
maintenance: when pt doing well on steady dose
What is mech of action naltrexone?
opioid antagonist
How does naltrexone differ from naloxone?
naltrexone: 2x as potent and longer lasting than naloxone, tolerance does not develop, can give 2-3x wkly
What are side effects unique to naltrexone?
DVT
hepatitis
eosinophlic pneumonia
What are challenges of using naltrexone?
- not effective in absence of structured program
- contraindication: pts receiving opioid analgesics or pts with dependence or withdrawal
Which type of OUD treatment has lower rate of birth issues?
buprenorphine
which is least expensive OUD treatment?
methadone
How do you manage pain while on OUD therapy [methadone vs buprenorphine vs naltrexone]?
methadone: slightly increase dose of opioids if tolerance
buprenorphine
- if severe: consider changing to methadone or short acting opioid
- if mild: use buprenorphine alone
naltrexone
- discontinue and switch to buprenorphine or methadone
What are early symptoms of opioid withdrawal?
- anorexia
- anxiety/restlessness/depression/insomnia
- craving + intense drug hunger
- headache
- tachycardia
- lacrimation
- goosebumps [piloerection]
What are symptoms of late opioid withdrawal?
- muscle/bone pain
- ab pain
- low fever, high BP
- mydriasis
- N/V
- hot/cold flashes
- muscle spasm
Which opioids have shortest time to start withdrawal?
- fentanyl
- then hydromorphone
- then oxycodone = heroin = morphine = hydrocodone
Which drugs have longest time to start withdrawal?
- methadone
- then hydrocodone = morphine = heroin = oxycodone
- then hydromorphone
What is treatment for opioid withdrawal?
- opioid agonist therapy [methadone is best choice]
- non-opioid therapy
- supportive [fluid resuscitation]
Is mortality likely with opioid withdrawl?
No– mortality is very low!!
What is best form of non-opioid therapy for opioid withdrawal?
clonidine [alpha-2 adrenergic]
