8. Pain Mechanisms Flashcards
1
Q
Psychological Factors Affecting Pain Response
- Cultural differences
- Observational learning (modeling)
- Fear and anxiety
- Perceived control of events
- Cognitive appraisal (the meaning of pain) • Coping style
- Attention/distraction techniques
- Big psychogenic component to pain
- ____ descent - complain of their pain; ____ less likely to complain
- Fear and anxiety ____ pain thresholds
- Wiggle the cheek, listen to music
A
italian/jewish
asian/irish
lowers
2
Q
ACUTE PAIN
• Provoked by an ____ cause, i.e., tissue damage with an expected course to resolution.
• Usually disappears in days or ____
•Behavioral responses: ____, restlessness,
increased sympathetic drive •Responds to routine ____/interventions
• Serves a protective biological function
A
identifiable
weeks
anxiety
analgesics
3
Q
A big puss ball.
• Lidocaine is a weak \_\_\_\_, in acidic pH, won't penetrate well here because it's now \_\_\_\_; lacking \_\_\_\_ solubility
A
base
charged
lipid
4
Q
CHRONIC PAIN
• Pain which:
Persists a ____ beyond the usual course of an acute disease or associated with a chronic
pathological process
• Behavioral Response : Quiet, ____, lack of emotion
• Routine ____/therapy do not relieve the pain
• Serves no ____ function
* Neuropathic pain syndromes fall into this * Behavioral response is not as acute * Addicting \_\_\_\_ don't work on chronic pain (inc. advil, motrin, etc.)
A
month depression pain relievers biological opioids
5
Q
• In effort to treat chronic pain go from HP to HP to find some pain relief
• ____ - more and more drug to get the same effect - downreg in receptors
• ____ - stop taking drug or give an antagonist, you will go into abstinence/withdrawal system - withdrawal is always opposite of what the drug does (CNS excitation vs. suppression)
○ Opioid withdrawal - muscle and joint achiness, diarrhea (opposite of constipation)
• ____ - psychological dependence, risky behaviors to yourself/others to get drug even though you know it’s risky
A
tolerance
physical dependence
addiction
6
Q
Factors involved in the presentation of chronic pain
\_\_\_\_ Marital problems Problematic family relationship Grief, personal loss \_\_\_\_ Personality disorder \_\_\_\_ rewards for complaining of pain Controlling others with pain behavior
AND
____ of injury
or disease
RESULTS IN
Presentation of ____ pain
* 10-15% of third molar patients are at risk of addiction, like the feeling of pain relievers * If you don't address \_\_\_\_, they don't improve (TMD patients, for example)
A
drug abuse
depression
financial
history
chronic
depression
7
Q
Total Pain Relief Index
* Developed at \_\_\_\_ * The higher the number, the more \_\_\_\_ the pain
Dental impactions (both full and partial) are very high on the index (____ > ____)
A
mcgill
intense
full
partial
8
Q
Proposed Peripheral Mechanism of Non-narcotic analgesics action
* Membrane lipids become available to phospholipase A2 (ubiquitous enzyme) to generate AA > acted upon by COX > \_\_\_\_ * PG - at physiologic doses do not cause pain, but sensitize \_\_\_\_ in soft tissue, periosteum to histamine (from mast cells) and bradykinin (inactive precursor) ; maintain \_\_\_\_ BF, increase mucus layer in stomach * Now with an influx of Na > AP generated > spinal cord medulla brain > perceive pain * Advils etc. > analgesic effects by inhibiting \_\_\_\_; can cause GI ulcers which can lead to bleed, increase renal toxicity and increase \_\_\_\_ blood flow; all of these stem from blocking prostaglandin synthesis (COX inhibitors)
A
PGE2 free nerve endings renal COX renal
9
Q
Peripheral Targets for Analgesia
* 5HT - serotonin - at site of injury it’s a \_\_\_\_ provoker, but in CNS it's important in \_\_\_\_ and \_\_\_\_ - depends on where it's released * TNF - embrol, remicade - inhibit, \_\_\_\_ patients are taking these - immunosuppressives * NO coming out of BV (NT) - natural \_\_\_\_ in body - knock it out, half the people will have \_\_\_\_ rising - NO-cGMP pathway affected resulting in \_\_\_\_ dysfunction * ATP - cells dump when \_\_\_\_ - \_\_\_\_ receptor antagonist - may work better for \_\_\_\_ pain and not acute
A
pain mood analgesic RA vasodilator BP male erectile damaged purinergic chronic
10
Q
• Drugs that block before COX - glucocorticoidss - ____, ____, to reduce post-op ____ from dental impaction surgery
○ Limits ____
• They are also ____
• Raise blood sugar; taken chronically cause ____
• Suppress hypothalamic-pituitary-adrenal axis - when into emotional stressful situation - going into cold, release of cortisol, makes symp work better, but on drugs you don’t get naturally cortisol release, and you get ____ and unconscious - ____
A
pregnazone cortizone swelling trismus immunosuppressant cataracts hypoglycemic acute adrenal crisis
11
Q
Biosynthesis of Endoperoxides, PGG2 and PGH2
• Acted on upon by \_\_\_\_ - the intermediate PG don't have \_\_\_\_ importance (PGG, PGH)
A
COX
physiological
12
Q
Arachidonic Acid Metabolism
• Alt pathway - lipoxygenase > \_\_\_\_: pro-inflam, big players in \_\_\_\_ including asthma; \_\_\_\_ (singulair) - pill, prevent asthmatic attacks, and apporved for seasonal allergies ○ Drugs that block lipoxygenase - liver toxicity • PGI2 (prostacyclin) - found in endothelium of BV - released, \_\_\_\_ and inhibits platelet \_\_\_\_ • Thrombaxin A2 - \_\_\_\_, stiulates platelet \_\_\_\_ ○ Balnce bt these two • Baby aspirin is selective at KO \_\_\_\_ and sparing \_\_\_\_ ○ Platelets have no nucleus, aspirin irreversibly binds \_\_\_\_, the platelet is non-functional - always forming new platelets ○ Endo cells have a \_\_\_\_ - can make new COX easily ○ Relatively selective effects
A
leukotrienes AID montoleukist vasodilator aggregation vasoconstrictor aggregation
thrombaxin 2
PGI2
COX
nucleus
13
Q
Salicylates
• Aspirin irreversibly inhibits COX; other NSAIDs eventually let go ○ Dosed every 4 hr; drugs are dosed base on half-life (1-2 hr), and first mebtaolite SA (half-life of 3 hours); dosed based on \_\_\_\_ half-life of parent and metabolite • SA manipulated into SS - comes on a little \_\_\_\_ • SA - no longer has \_\_\_\_ activity, still have pain relief; cannot used for \_\_\_\_ protection • \_\_\_\_ - aspirin derivative - new generation NSAID - more powerful and better in post-surg pain than maximum doses of aspirin; trade name is Dolabid (taken twice per day)
A
combined quicker anti-platelet cardio diflunisol
14
Q
Phenylpropionic Acid Derivatives
* Better tissue \_\_\_\_ and \_\_\_\_ penetration for left two * Some component of pain-relieiving is central - penetrate CNS better than aspirin * Side effect profile is better (full analgesic doses of aspirin)
A
penetration
CNS
15
Q
- Rx prescription to Over the counter
- Has to work at ____ dose, ____ and ____ onset and decent duration
- Safe because people are ____
A
lower
safe
quick
self-medicating
16
Q
Role of Prostaglandins
* PG > \_\_\_\_ (painful menstrual cramps); ibuprofein penetrates uterus better than \_\_\_\_, works better * Acetominophen is not a weak \_\_\_\_ * High levels of PG in brain > contribute to fever (\_\_\_\_ effects); after dental surgery, is having anti-pyretic a good thing? No > fever is early sign of post-op infection * Constitutively made in certain regions; stomach: \_\_\_\_, break on HCl secretion and increase mucus; kidney: good guys, increase renal \_\_\_\_ (PGI2), increase \_\_\_\_ of water and sodium (retention if drug blocking this)
A
dismenuria acetominophen acid anti-pyretic cyto-protectants BF excretion
17
Q
Mechanism of Action of NSAIDs: Old Theory
* Reported how aspirin did its thing, blocking COX * \_\_\_\_ isoforms of COX
A
two
18
Q
• All these drugs end in coxib, all selective
• Problem giving someone that’s old w/ cardiovascualr disease and giving a pure COX-2 inhibitor > unopposed ____ and platelet ____
○ This ultimately hit increased ____ and strokes
• [NOTES]
A
vasoconstriction
aggregation
19
Q
- Only one that is still on market is celebrex (which one???)
- Valdecoxib = bextra
- [NOTES]
A
???
20
Q
PGs and Pain
* PG are senstizing \_\_\_\_ > hyper-algesic, more sensitive to pain provoking things * \_\_\_\_ - sunburn, doesn't hurt until you press on it * \_\_\_\_ involved in eventual painr esponse
A
free nerve endings
hyperalgesia
Ach
21
Q
Peripheral Nerve Fibers
* Doesn't have to be chemical; \_\_\_\_ (TRPV1/2 receptors that respond to \_\_\_\_), \_\_\_\_ receptors (H+), \_\_\_\_-sensitive receptors (extracting a tooth) * Polarization of NF > AP make way centrally (\_\_\_\_); EFFERENT is going outside the CNS
A
heat capsacian acid-sensitive pressure afferent
22
Q
Types of NF Associated with Nociceptive (Pain) Impulses
• Adelta - lighlty \_\_\_\_ > conduct pretty quickly ○ Pain - \_\_\_\_, not just quick, can figure out where it hurts • C - \_\_\_\_, slowly conducting ○ Pain - not as well defined, the \_\_\_\_ from finger to hand
A
myelinated
localized
unmyelinated
spreading
23
Q
Type A Delta Fiber Characteristics
- Small, ____
- Faster than ____
- Much slower than ____ myelinated
- ____ pain
A
myelinated
C fibers
large
sharp
24
Q
Type C Fiber Characteristics
- ____ diameters
- ____
- ____ conduction velocities
A
small
unmyelinated
slow
25
Amides I
* Local anesthetic - ends in caine - blocks ____ channels
* Look similar
* ____ in the middle - metabolized in the ____
* Local anesthesia wares off - drug moving away from the site; if you want to keep it there you use ____
* Amino terminus end - ____ solubility; carpules are full of water
* Aromatic group - gives drug ____ solubility (penetrate nerve sheets and nerve membranes)
* Low ____ at adminster site - makes it hard to get in
```
Na+
amides
liver
epinephrine
water
lipid
pH
```
26
The effects of lidocaine on the compound AP
* Same experiment with ____, used in intractable chronic pain syndromes, AP never comes back > toxic; prolonged ____
* If slow down recovery, add ____; wears off bc vasculature picks it up and moves it away and processes it in the bdoy
alcohol
neurotoxicity
Epi
27
Blockade of all sodium channels in 3 consecutive nodes of ranvier
• Critical length hypothesis
• To kkncok out myelinated nerve > you need to deliver enough aneasthtic that's as long as ____ consectuive nodes of ranvier
• Bc sensory nerves like ____; the nodes are closer together than big nerves like motor fibers; they knock out quicker but recover quicker
○ In real world, depends on where nerve fibers are in nerve trunk; ____ on outside, they'll be exposed first and KO first
3
aDelta
aDelta
28
Local anesthetic mechanisms
Sodium channel blockade
Membrane expansion
* Either directly plugging up the ____, or entering the lipid phase and ____ it and squeezing the channel closed
* Charged vs uncahrged form????
* In order to get in, it must be ____; in the actoplasm, the pH is down so it ____ up and binds within the membrane and closes the channel
channel
expand
uncharged
charges
29
Esters
• Ester, chewed up in BS by ____ (different from succinhyl choline)
• Doesn't have ____ end - to get it in solution - it's dissolved in ____ - do not want to shoot into a nerve, good for ____ pain
• Gives off ____ after metabolized, where people have allergic reactions to these
○ Not observed with ____
• ____ - goes up the nose (in covanaise)
• ____ - add carbons to locals - make powerful and icnrease duration of action; this doesn't work for other drugs; opioids, the most powerful have shortest duration of action
```
cholinesterases
amino
polyethylene glycol
topical
PABA (para-amino-benzoic acid)
amides
tetracaine
procaine
```
30
Clinical Presentation of Toothache Patient
Definitive therapy is RCT (endo) or extraction and not ____
analgesics
31
Placebo vs. Benzocaine
• Placebo = ____ (must compare to the vehicle); the placebo is not totally ____, can potentially block AP if given enough
- Benzo is more effective, DUH
polyethylene glycol
| inactive
32
The Lidocaine Transmucosal Patch (Dentipatch)
• Good for topical ____ anesthesia, not for teeth procedures
soft tissue
33
* [NOTES]
| * Vasoconstrictor - oxymetazolene
YEAH CMON
34
Target area for nasal mist anesthesia
```
• 2nd ____ to 2nd ____
• ____ and ____ alveolar nerves
• 1s molar
○ Mesial buccal root - ____ alveolar nerve
○ 2 roots - ____ alveolar nerve
○ Doesn't catches those well
```
```
bicuspid
bicuspid
anterior
middle superior
mesial superior
posterior superior
```
35
* Success - ability to complete filling without giving the injection
* 1st bicuspid forward - ____%
* 2nd bicuspid dropoff - in 25-35% of individuals they don't have middle superior alveolar nerve, the 2nd bi is innervated by the ____ alveolar nerve, which is when the nasal can't get to it
95-100
| posterior superior
36
Tetrodotoxin
• Toxin in the ___ and ____ of fish
• Local molecule - absorbed ___ and knocks out ___ channels all over the body
○ Muscles affected - ___ muscle - not beating
```
gonads
ovaries
readily
Na+
cardiac
```
37
Primary afferent (1st order) neuron synapsing on 2nd order neuron in spinal dorsal horn
* AP generated, travel up ____, and reach a synapse (____ neuron) with a ____ neuron; crosses to other ____ of the spinal cord/medulla
* To stimulate 2nd order neuron, something is released at 1st order
adelta
1st order
2nd order
side
38
• NT in packets of vesicles
○ ____, ____ (calcitonin gene realted peptide), and ____ (excitatory AA)
○ When released, receptors on ____ order neuron to become activated, channels open and depolarization
• ____, 5 AA containing peptides, body's natural opioids - break on the release of NT
• Drugs with ____ have the least organ toxicity
○ Opioids don’t cause ____ - bc we have natural opiods in our body
```
Substance P
CGRP
glutamate
2nd
enkephalin
natural receptor
organ toxicity
```
39
Transmission of Nociceptive Impulses Dorsal Horn Synapse of the Afferent Pathway
• Enkephalins can exist ____- and ____-synaptically
○ When bind to their receptor on nerve terminal of first neuron, they prevent the release of SP, CGRP, or glutamate
○ When they bind to receptors on 2nd order neurons - cause ____ - ____ channels open and leave the neuron
• First order nerve terminals within dorsal horn of spinal cord or medulla (substantia gelatinous) - have ____ receptors - if stim : with clonidine, block release of NE, and can block release of itself; NE/clonidine can block release of some of the pain-provoking NT; other use of clonidine, useful for some ____ syndrome (worn on patches), can inhibit release of these pain NT
• Post-synpatically, 2nd order neurons have ____ receptors - GABA is inhibitory causes hyperpolarization by increasing ____ inward; drugs that affect this > ____ (valium) don't bind directly to GABA receptor, bind their own receptor which increases ____ of GABA for its receptor; drugs have sedative and ____ effects, but no ____ effects
```
pre
post
hyperpolarization
K
alpha 2 arenergic
pain
```
```
GABA
Cl-
benzo's
affinity
anti-anxiety
pain/analgesic
```
40
Neuropeptides
READ THE SLIDE
* Substance P - 10 AA, ____ protein, but bigger than ____ or NE
* Small NT, primary place of synthesis is ____; big molecules that are NT are in ____ and travel via ____ direction
* Thought that SP was only in CNS, but it's also found in the ____, some is traveling in wrong direction (____ direction)
* Can be a ____ - to Ach it can tamp up its effects, it can also tamp down depending on the NT
* In periphery, contirbutor to peripheral ____ and inflammation; and in ____
```
small
Ach
nerve terminal
nerve cell bodies/ganglia
enterograde
periphery
retrograde
neuromodulator
pain
osteoarthritis
```
41
Substance P: Distal nerve effects
* Substance P is also located in free nerve endings in ____, along with the ____ order neurons in ganglia
* When spilled out, accelerates release of pain-proviking chemicals like ____, serotonin, enhanced released of ____ - plays a role in pain generation out in periphery
* Drug that you can buy OTC that depletes SP - topical oitnments containing ____
```
periphery
first
histamine
PG
capsaicin
```
42
Capsaicin
* ____ (brand name)
* Rub on initially, a lot of burning - due to SP release - but if you keep applying it - deplete the free nerve endings of SP - ____ and ____ effects (reduced joint swelling in ____)
* Allows you to ____ the treatment, little blood levels - but if high blood levels > destroys ____ selectively - localization is safer
```
zostrix
analgesic
anti-inflam
osteoarthritis
localize
C fibers
```
43
• Crosses over to other of cord; pain on right side is crossing to the ____ side
• ____ containing enkephalins
• At the synapse, the 2nd order synapses with 3rd order in the ____
• Pathways that go in opposite direction - descending analgesic pathways - ____ pain signals - some start in ____ > drop down to neurons containing enkephalins and turn them on; some NT from the descending neuron is ____ and ____ (where ____ activity is also occurring) - a break on the system
○ Not usually turned on enough to turn off pain
○ Not feeling any pain in ____ individuals, may be bc these pathways turned on
○ ____ also stimulate descending pathways
```
left
interneurons
thalamus
dampen
medulla/midbrain
NE
ST
alpha2
```
PTSD
opioids
44
Trigeminal Nociceptive Pathways
• Input from mouth and from face - comes in via ____ - the ganglia (gasieron); neurons come in from ____, from first synapse and drop into the ____, and synapse ____ horn, releases synapse P or glutamate or CGRP, stimulate second order neuron, crosses over to other ____ of medulla, synapses in ____, and then synapses with 3rd order but the NT are unknown
```
trigeminal nerve
pons
medulla
dorsal
side
thalamus
```
45
Poppy Plant: contains opiates (narcotics)
§ Morphine
§ Codeine
§ Thebaine > oxycodone
```
Synthetic opioids
§ Meperidine
§ Hydrocodone
§ Oxycodone
§ Methadone
§ Heroin
```
• Opiate - a natural product of poppy plant
○ Morphine > can form ____, in the body it metabolites into morphine
○ Codeine - ____ contains codeine
○ Thebaine converted into ____
• Opiod - partially or totally synthesized in lab
○ Hydrocodone - major in ____
○ Oxycodone - in ____ and perc's
○ Methadone - comes on ____, but prevents the craving and stimulates same receptors; can be abused; not a cure, used in ____ to stop the shooting behavior and craving, and have to then wean them off - drug has a very long ____
○ Heroin
```
heroin
tylenol
oxycodon
vicodin
oxycotin
```
slower
rehab
half-life
46
Opioid Receptors also Located in Periphery!!!
• Thought only a CNS thing
• Major side effect - ____, not a central effect
• ____ opiod receptors in stomach and GI > stimulate > decreases peristalsis (more powerful then anticholinergic)
• Chronic cancer, chronic pain - require opioids, being constipated all the time is not a good thing
○ Develop a slick molecule - ____, opioid receptor antagonist, major use in opoiod rehab, pure antagonist (v diff from methadone), wean off opiod and introduce naltrexone, blocks opioid receptors for ____ hours, if give it to them quickly the'll go into withdrawal
○ Cant take drug with on naltrexone; perc will block it
○ Deal with constipation - add a ____ - cannot cross BBB, doesn't go into the brain, so only treats the constipation
• Atropine gets in, but glycopyrolate doesn't
```
constipation
mu
trexone
48
charge
```
47
* Diff types of opioid receptors
* [NOTES]
* ____ are smaller than enkephalin (4 AA, endogenous)
* ____ - partial agonist - similar to chantix - issue: need a weaning off period, and like methadone it's abused > major fomrulation is ____ (subutrex), some people absorb and mix with valium it’s a nother way to get high; made ____ (pinch of naloxone in there) > sends them right into opioid withdrawal, when used sublingual, very little naloxone gets to receptors
* Ways to treat opioid withdrawal - ____, partial ____ and ____
* ____ - after market for five years, claimed not to be addicting but ended up being addicting; at one opioid receptor it simtulates and the other it blocks
```
endomorphin
buprenorphine
sublingual
saboxone
agonist
agonist
antagonist
pentazocine
```
48
• Beta-endorphin - released in ____ (like epi from adrenal medulla) and released into ____
• Within the structure is ____; a bigger molecule pro-opioid ____ gets cleaved into beta-endorphin
They all arise from ____
```
posterior pituitary
BS
metenkephalin
melanocortin
precursors
```
49
* Oxy to heroin? Why?
* ____ + ____ > stop responding to CO2, don't want to breath
* Naloxone - ____ , taken opioid and stretch it out, now has higher ____ for receptor but doesn't activate it
heroin
fentanxyl
antagonist
affinity
50
Opioid Agonist
____ (Duramorph®), heroin, ____ (Sublimaze®), methadone, oxycodone (in Percocet®), and ____ (in Vicodin®)
are opioid receptor agonists.
• Opioid receptors are ____
morphine
fentanyl
hydrocodone
GPCR
51
Drug Antagonist
____ (Narcan®) and naltrexone are opioid receptor antagonists.
* Higher ____ for receptor than the drug, and covers the ____ site and not activating
* ____ gets into brain; ____ does not get into the brain
```
naloxone
affinity
activity
naltrexone
methylnaltrexone
```
52
Intranasal Naloxone
* Different from intranasal local; here, spray, get into BS and reverse ____
* Most have ____mg naloxone - deliver as plume; injectible dose is 0.4, but sytemic absorption ____ is not as good as ____
opioid overdose
4
intranasally
injection
53
Peripheral Pain Pathway
• Primary ____ nerve is stimluated, pressure, incisonal pain, fracture > AP > NT release > SP, CGRP, glutamate > upstrairs crosses ____ of spinal cord
afferent
| side
54
Convergence of Multiple Inputs
• Can have multiple ____ fibers synapsing on same second order neuron > convergence may explain ____ pain; toothache but complaining about pain in ____ region > all stimulating second order neuron
presynaptic
referred
ear
55
Mechanism for Gate Control of Pain Transmission
• Breaks postsynaptically - ____, opening up ____ channels, but there are breaks ____ also
hyperpolarization
K
pre-synaptically
56
* 1st order n neuro with Sub P that can s timulate 2nd order neuron
* Nerve fiber from descedning coming from brain into spinal cord - some of these chemicals released are ____ and ____ (in periphery, pain producing, in CNS may be part of analgesic pathways), stimulate ____ neuron to release enks and blocks rleease of SP on 1st order neuron
* Large myelinated nerve fibers that carry ____ (not pain) from periphery that synapse on enk neuron that can be break - stimulated by ____, or by ____
```
ST
NE
enkephalin
propioception
acupuncture
rubbing
```
57
* Beta-endorphin released from ____ is similar to EP released from adrenal medulla (backup system)
* From here, it's a neurohormone, the drug can move around systemically like a ____; has ____ solubility; stimulates ____ receptors systemically
posterior pituitary
catecholamine
lipid
opioid
58
* Some free nerve ending, instead of synasping with 2nd order, it can directly or indirectly synapse with ____ NS out of cord, specifically the ____ NS; in ____ pain, this is why the symp NS gets turned on
* Some free nerve endings, it can also synapse via efferent fibers of ____ NS; people with ____, and the free nerve endings are getting stimulated, you can have muscle ____ in area which makes the pain syndrome even worse
```
efferent
sympathetic
acute
somatic
TMD
contraction
```
59
* Stimulate symp in acute pain > ____, inc HR/contraction, ____, some constrict and dilate (depending on ____ receptors); ____ is turned off
* Sympathetic - shorter, and ____ exit
* Para - ____ and ____ exit
```
mydriasis
BV
A1/B2
GI
thoracic-lumbar
cranial
sacral
```
