8. Pain Mechanisms Flashcards
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
italian/jewish
asian/irish
lowers
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
identifiable
weeks
anxiety
analgesics
A big puss ball.
• Lidocaine is a weak \_\_\_\_, in acidic pH, won't penetrate well here because it's now \_\_\_\_; lacking \_\_\_\_ solubility
base
charged
lipid
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.)
month depression pain relievers biological opioids
• 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
tolerance
physical dependence
addiction
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)
drug abuse
depression
financial
history
chronic
depression
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 (____ > ____)
mcgill
intense
full
partial
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)
PGE2 free nerve endings renal COX renal
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
pain mood analgesic RA vasodilator BP male erectile damaged purinergic chronic
• 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 - ____
pregnazone cortizone swelling trismus immunosuppressant cataracts hypoglycemic acute adrenal crisis
Biosynthesis of Endoperoxides, PGG2 and PGH2
• Acted on upon by \_\_\_\_ - the intermediate PG don't have \_\_\_\_ importance (PGG, PGH)
COX
physiological
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
leukotrienes AID montoleukist vasodilator aggregation vasoconstrictor aggregation
thrombaxin 2
PGI2
COX
nucleus
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)
combined quicker anti-platelet cardio diflunisol
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)
penetration
CNS
- Rx prescription to Over the counter
- Has to work at ____ dose, ____ and ____ onset and decent duration
- Safe because people are ____
lower
safe
quick
self-medicating
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)
dismenuria acetominophen acid anti-pyretic cyto-protectants BF excretion
Mechanism of Action of NSAIDs: Old Theory
* Reported how aspirin did its thing, blocking COX * \_\_\_\_ isoforms of COX
two
• 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]
vasoconstriction
aggregation
- Only one that is still on market is celebrex (which one???)
- Valdecoxib = bextra
- [NOTES]
???
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
free nerve endings
hyperalgesia
Ach
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
heat capsacian acid-sensitive pressure afferent
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
myelinated
localized
unmyelinated
spreading
Type A Delta Fiber Characteristics
- Small, ____
- Faster than ____
- Much slower than ____ myelinated
- ____ pain
myelinated
C fibers
large
sharp
Type C Fiber Characteristics
- ____ diameters
- ____
- ____ conduction velocities
small
unmyelinated
slow
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
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
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
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
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
Clinical Presentation of Toothache Patient
Definitive therapy is RCT (endo) or extraction and not ____
analgesics
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
The Lidocaine Transmucosal Patch (Dentipatch)
• Good for topical \_\_\_\_ anesthesia, not for teeth procedures
soft tissue
- [NOTES]
* Vasoconstrictor - oxymetazolene
YEAH CMON
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
- 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
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
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
• 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
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
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
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
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
• 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
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
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
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
- 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
• 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
- 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
Opioid Agonist
____ (Duramorph®), heroin, ____ (Sublimaze®), methadone, oxycodone (in Percocet®), and ____ (in Vicodin®)
are opioid receptor agonists.
• Opioid receptors are \_\_\_\_
morphine
fentanyl
hydrocodone
GPCR
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
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
Peripheral Pain Pathway
• Primary \_\_\_\_ nerve is stimluated, pressure, incisonal pain, fracture > AP > NT release > SP, CGRP, glutamate > upstrairs crosses \_\_\_\_ of spinal cord
afferent
side
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
Mechanism for Gate Control of Pain Transmission
• Breaks postsynaptically - ____, opening up ____ channels, but there are breaks ____ also
hyperpolarization
K
pre-synaptically
- 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
- 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
- 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
- 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
