6A. Analgesics Flashcards
• Morphs over to pain after endo procedures
Ppl come from spontaneous pain from pulpitis
• Best way to get rid of this pain = pulpotomy
• Drugs are just the bridge
• Most studies deal with impacted ____ model
Pain pts experience after removal of impacted 3rd molar
Why are most of the dental studies in literature using this model?
• ONE REASON ‐‐ fda considers it a pivotal model to get ____ info
• To get an analgesic FDA approved once you make it through preclinical
trials and phase 1 / 2 trials
• Look up these! The stages of drug development from preclinical,
phase 1, phase 2, phase 3
• Post marketing surveillance phase 4
• Safety report
• Commercial
• You get to phase 3 ‐‐ need at least 2 big efficacy studies in 2 pain models
• Often 3rd molar surgery is one of them
third molar
pain
How do clinicians go about RXing pain relievers • Evidence based literature
• Vicoprofen
200mg ____ + 7.5 mg ____
POST SURGICAL DENTAL PAIN IS MAINLY DRIVEN BY ____
• That’s why ____ work so well
• Prostaglandins play a good role
• Not just as good as opioids but if rx right, they’re ____
Vicoprofen was combining a somewhat low dose of ibuprofen and reasonable dose of hydrocodone
• Cheetah’s worth of pain in patient
• What will we do for this person
ibuprofen hydrocodone inflammation NSAIDs better
This lady takes vicoprofen and cheetahs worth of pain gets calmed or tamed
• Not to say this drug doesn’t work
Good concept at the time
Way before opioid crisis
• ____ consistently works better than acetaminophen
So he’d rather go down this route for combo
• Hydrocodone –> 5-10% of ppl may be at risk for misuse
Amount of ibuprofen in this combination, at least in post surgical dental impaction pain, is ____
• There’s a dose response of ibuprofen up to at least ____ mg
Higher dose = more cloudy
Also depends on formulation
• Rapid release formulation may work better than tablet ones
• There might be something of getting to pain relieve quicker that gives them
better dose response This is a DEA ____ drug
• Anything with hydrocodone is
• Oxycodone + acetaminophen
____
Can call it in, can have ____
But don’t want to give refills on something like this because might have dry socket
But didn’t have to jump through many loops
• Dea sched 2 = no ____ ins Prescribing a lot is bad
• If use this prep I would tell ppl to take it with an advil or a motrin IB 400 of ibuprofen
Or take it with 500 acetominophen
Or take it with 200 ibuprofen + 500 acetominophe
ibuprofen
suboptimal
400
sched 2
DEA sched 3
refills
call
This drug never got any traction
It could never make it onto hospital formularies
Left = young lady ‐‐> post surgical pain after 3rd molars
Whole world is spinning around
Combunox formulation • Combined ox • \_\_\_\_ 5mg combined with 400 mg \_\_\_\_ • Dea \_\_\_\_ She takes the combunox and in an hr she is now eating pasta with her lovely mom
Oxy is kind of like the jack daniels of oral opioids
• Hydrocodone is red wine
• Codeine is the miller lite
But can get to the same place with 12 oz of miller lite as 1 oz of jack daniels except jack daniels is 12 x more powerful
• Oxycodone ____x more powerful than codeine
• ____ as hydrocodone
Again, good marketing
oxycodone
ibuprofen
sched 2
12
twice
• Spoke about this in pain mechanisms
• To get these impacted 3rd out, lots of soft tissue trauma
• ____ is standard of care
Studying the pain relievers ____ surgery
• He limits the fentanyl dose to 50 ug
Not that worried that it’s a confounder b/c it comes on pretty quick and wears off ____
But if push it to 100ug, about 5‐10 % of ppl get nauseated
• And then give them study drug and 30 min later you throw up
• That research subject is lost
• Will not start looking through vomit to see how much of pill is there or
not there
local anesthetic
after
quickly
This is like having a size 28 mouth and 32 teeth
• How many of these procedures/yr in US?
5 million
• There are ppl coming out with papers saying we shouldn’t be doing many of these
But later on = tooth becomes symptomatic, bone gets denser
• Can cause ____ fracture
• You gotta section this tooth Remove alveolar bone
Manipulation of bone == good predictor that theyll have significant ____ after anesthetic wears off
jaw
pain
• Once that local wears off 95% or more of these pts have pain of ____ intensity
• Not only good at distinguishing active drugs to inactive drugs
First thing you wanna show is that it beats pain reliever
But pain is severe enough that you can show that ____ 400mg is superior to acetaminophen 600mg
• Can distinguish very active drugs from moderately active drugs in this model
• On these studies always have a ____ med
Some ppl getting active, some get placebo
But anytime after that first hour, someone’s not getting pain relieve or got it and wore off, and it’s within 4 hr inpatient window, they will rescue them
First rescue = ____
• Wont work that great in a lot of ppl
• But after that everyone gets transitioned into ibuprofen + acetaminophen
• If prescribed around clock, will do good
• Most ppl
• Wont need opioids
moderate to severe
ibuprofen
reversal
pure opioid
With this type of dental surgery or ankle sprain, killing 1000s of cells at that local surgical site
• Membrane lipids become available to ubiquitous ____ to make
ARACHIDONIC ACID
• What class of drugs blocks phospholipase A2
____
Glucocorticoids
Don’t want to put ppl on long term glucocorticoids
The interesting thing about glucocorticoids is that theyre good at reducing ____
• Difficulty in opening the mouth
Also good for preventing post‐op ____
Not good by themselves as acting as ____
Btw why do we keep ppl on these drugs SHORT TERM?
• Issues with drugs include
• Can cross ____ and can make some ppl angry, loopy
• Suppression of ____ axis
• On these drugs for more than a couple of weeks, shuts down, and have some other surgical procedure done, don’t release natural cortisol and now rapidly become hypoglycemic and unconscious
• ____ crisis
• Immunosuppression
• Can accelerate ____
• All with long term use‐‐ more for systemic, less for topical
phospholipase A2 steroids trismus swelling pain relievers BBB HPA acute adrenal osteoporosis
Arachidonic acid acted on by ____
• We know there are at least 2 isoforms
• COX 1
• COX 2
• We think most of good action is from blocking ____ but it’s not that clean
• ____ is a key mediator that sensitizes free nerve endings to other mediators
of pain
• At physiologic doses, don’t typically cause pain by themselves but they
lower the thresholds of these free nerve endings
• Respond more vigorously to other chemicals
• ____
• ____ activated from inactive precursor kininogen
• Not totally a bad guy where else did they show up?
• What class of drugs therapeutically increases bradykinin
• ____ block the conversion of angiotensin 1 to angiotensin 2
• But also block the breakdown of ____
• One of the natural vasodilators in the body
• ____ BP and also good for ____
• Ace inhibitors = all drugs that end in ‐pri
cyclooxygenase cox2 PGE2 histamine bradykinin ace inhibitors bradykinin lower CHF
- When we get back into mechanism of NSAIDs
- Most good
- Analgesic + anti inflammatory effects
- Hard to show that NSAIDs reduce post op swelling in surgery
- Can show in arthritis patients
- Probably more on rheumatoid than osteoarthritis
- Hard to demonstrate in ____ pain
- Why? These drugs also have some ____ activity
- While may decrease rxn of inflammatory mediators, can get more bleeding into interstitial sites
- But can cause GI ulcers + kidney failure
- ____
- ____ inhibition consequence b/c actually good guys here
- Increase ____ in the stomach
- Misoprostol ‐‐ stimulate prostaglandins
- But can also be ____
- But it is an ____ DRUG
- Block prostaglandin synthesis in stomach? Can increase risk of ____ and bleeds
- More of an issue with ____ term use
- IN KIDNEY
- Prostaglandins increase ____ + water/sodium retention
- Poor ____ fxn ‐‐> may think twice before giving NSAID
- Might have to go to ____ or Percocet
- 1‐2 advil may send them into acute renal failure
- These drugs cant be used on everyone
post surgical dental
antiplatelet
toxicity prostaglandin cytoprotection abotifacient anti ulcer
GI ulcers
long
blood flow
renal
vicodin
Peripheral Targets for Analgesia
• This is more of the full story of what’s going on
• Free nerve ending
Lots of potential targets to hit to treat post op pain
5‐HT and NE
• Intriguing that in the ____, they seem to enhance pain or stimulate pain receptors
• In CNS they tend to be ____ with NE being more powerful than 5‐HT
• Fred spoke about TCA sometimes used in chronic pain patients
• Not b/c all depressed
• Sometimes depression is big part of chronic pain
• But even works in some ppl that aren’t clinically depressed
periphery
analgesic
Peripheral Targets for Analgesia
TNF
• Enbrel, Remicade‐‐> TNF inhibitors and also low dose methotrexate
• One is monoclonal that hooks on; other blocks receptor
• Big on ____ diseases, rheumatoid arthritis
• Why is osteoarthritis better than rheumatoid
• Osteo ‐‐ gradually wearing out of cartilage in a couple of joints
• Rheumatoid is full blown autoimmune dz
• Everything gets chewed up
• Erosions
• Affects other organs
• ____, while good at reducing pain, do nothing as far as dz
progression
• But what’s the issue of blocking TNF?
• Side effect
• ____!
• TNF might not be great target unless very controlled delivery (right at site, not
systemic)
AI
NSAIDs
immunosuppression
Peripheral Targets for Analgesia
NO
• Nitric oxide
• Natural vasodilator
• Nitric oxide, cyclic ____ pathways get low = erectile dysfunction
• Chemical in body that opposes things like E PI and NNE
• Want balance of vasodilators + vasoconstrictors
• If block NO, not selective may cause ____ and ED
• ____ DESENTIZES FREE NERVE ENDINGS
Other things work better
CNS perceives pain
• ATP : when cells get damaged release ____
There are several drug companies comping up with ____
• More on chronic pain side
• Important, upregulated in central
• ATP/ADP important chemicals in our body
• Price to pay
GMP hypertension prostaglandins ATP purinergic receptor antagonist
How much do ppl hurt following post surgical dental pain
• The higher this number ‐‐> worse pain
• BOTTOM LINE ‐‐ the pain after removal of impacted third molars, if ____ partial bony impactions (bone denser will hurt) ‐‐‐> if ____ (doesn’t hurt as much)
____ bone impactions of mandible actually produce pain intensities that are higher
• Greater than some nasty chronic pain syndromes
BOTTOM LINE
• These type of ppl need effective pain relievers
• How do you keep them and still keep in ambulatory
• Post surgical dental plain DRIVEN BY ____
What he’s telling us doesn’t transition into pancreatic end stage cancer pain
• Not just inflammation ‐‐ tissue expansion, neoplastic cells invading other
tissues, etc
• NSAIDs may be part of mixed but will need opioids
• Don’t worry about becoming tolerant or physically dependent
• Wont usually become psychologically addicted
lower
upper
full
inflammation
Basic Principles of Clinical Studies
- ____-blind
- ____ allocation of treatment to subjects
- inclusion of ____
- inclusion of ____ treatments
- identical ____ of study medication
This is the gold standard of how to do clinical studies
• Double blind
• Random allocation of treatment
double random placebo standard appearance
• Study to prove utility of post surgical dental pain model
• Can separate drug from sugar pills
• Pain relief scores
4 would be complete; nothing gets to total pain relief
• Clearly can see utility
• PLACEBO is not at ____
Reds are together, blue together same studies
• There were some placebo responders
Approaching slight ____
• Acetaminophen lacks ____properties
Now think its hitting ____ variant
• Or more in CNS
Has to do with drug actually when hits areas of low pH, doesn’t survive well
But mg per mg in this model ‐‐> not in osteoarthritis, aspirin and acetaminophen are equally ____
Can push this dose response up a little bit more if you give them 1000 of acetaminophen
zero pain relief anti-inflammatory COX2 analgesic
LIVER TOXICITY IS THE WORRY
• McNeil is maker of all Tylenol products including tylenol with numbers
BETTER KNOW how much codeine in those numbers With these drugs recognize common trade name
• “I didn’t know acetaminophen was in the Percocet”
• Robitussin flu
There can be in that teaspoon full, in addition to antihistamine & cough suppressant, can be 325 mg of acetaminophen
• They don’t know it have headache, take 2 extra strength Tylenol
• THERPEUTIC OVERDOSE
• Bottom thing where acetaminophen on the opioid combinations, max dose is reduced tot
____ mg
That’s the FDA
told all drug companies you’ve got one year to make your Vicodin from 500 mg to ____ or ____ acetaminophen
Some of this dealt with not just OD of the opioid component but also acetaminophen
Btw you don’t get tolerant to ____
• Liver toxicity DOES NOT GO AWAY WITH ____ DOSING
• Respiratory depression of opioids ‐‐ can get tolerant
325 300 325 acetaminophen extended
Doesn’t work as well anymore • Most of efficacy comes from \_\_\_\_/acetaminophen • And side effects from hydrocodone • Reduced acetaminophen mgs • THIS IS DEA \_\_\_\_ NOW!!
Acetaminophen dose down to ____
• Use to be 500, 600, 650
They were all DEA ____ drugs but found out that among 19‐44 yr olds the number one misused RX immediate release opioid was ____ AND VICODIN GENERICS
•
ibuprofen schedule 2 300 shcedule 3 vicodin
We talked about this in intro to pharm
• Occassionally when drug is processed in the body one of its pathways can lead to
production of ____ metabolite
• Acetominophen therapueutic dose ‐‐> 95% of it after it does its thing binds to ____ and that inactivates it
5% of acetominophen we swallown goes down ____ pathway
• Family, subfamily, individual gene is the number
• To form highly reactive, hepatoxic metabolite ____!!
• Typically the little bit of NAPQI that is formed is rapidly scavenged by natural antioxidant known as ____ within liver and organs
• However when someone unintentionally takes 10 g of acetominophen all at once (20 extra strength tylenol) this pathway gets ____
• More % goes down CYP route, less glucoroination route
• Get much more NAPQI formed, too much for glutathione to handle
• End of with irreversible ____ damage
Most pts when they OD on acetominophen products, look good for 24‐48 hrs but then turn ____
• By that time you cant reverse the damage done
• ____ (MUCAMIST) in Emergency room
• Essentially increases glutathionne in body
• But for it to protect liver, must be given first ____ hrs
• Clearly for ACETOMINOPHEN OVERDOSE!!
toxic glucose + acid group (glucoronic acid) CYP2E1 NAPQI glutathione saturated liver jaundice anacetylcysteine 16
Old study that hasn’t been done on post surgical dental pain
Minor knee surgery pain Placebo controlled
Pain relief on Y axis
Little 0 to a lot 3. NOTHING GETS TO COMPLETE
Each curve are an average of 20 ppl
Good placebo response in this study
But can also see that the acetominophen ‐‐ two over the counter tylenol ‐‐ performed just as well as ____ 60 mg
• Amount of codeiine in two T3s
• Amount of hydrocodone in 2 vicodins (10 mg hydrocodone)
• And = to amount of oxycotoin in percocet
____ increased peripherally and centrally. Central is where ____ has most of action
• ,____, diclofenac, etc work better than optimal doses than acetaminophen RELISTEN
codeine
prostaglandins
acetaminophen
ibuprofen
