Midterm 2 Flashcards
Pain Threshold and Tolerance
Threshold: when you feel pain
Tolerance: when you can’t take it anymore
Measuring this is still subjective because actually measuring motivation (doesn’t tell us about their actual pain)
Rating scales
- VRS Verbal Intensity scale
- VAS Visual analogue scale
- NRS Numeric pain intensity scale
- Faces scale
VAS better than NRS because in NRS you remember the previous number you used
FACES scales are problematic because they start happy instead of neutral
Problems with these scales: hard to say when we are measuring, context matters (could be in pissy mood), “pegs” people don’t understand the worse and use 10 too much (to send a message) (people have different ideas of what worse pain looks like), is is useful for WITHIN but not BETWEEN patients.
We always imagine pain as worse than it really is
Clinical pain score
Combines:
- ongoing pain
- allodynia
- hyperalgesia
- functionning
The score you give actually is a lot of things that have nothing to do with what we assign the score to (not just nociceptors)
FACS
By Paul Ekman
Facial Action Coding System
Encodes for facial muscle movements associated with pain expression
Melzack
Came up with:
- Pain descriptors by intensity
- Peak intensity diagram (sprained ankle to causalgia)
- MPQ McGill pain questionnaire (20 categories, pick 1 of each. Splitting attempt between inflammatory/neuropathic). Made a shorter version with descriptors + PPI + visual analog
DN4
Short pain questionnaire
10 questions, 1 point per question, need 6+ to be neuropathic pain
Owestry Disability Index
Test if your pills are working
Come up with a disability score
10 sections
Pain Catastrophizing
Catastrophizing = rumination + magnification + helplessness
High catastrophizing = more likely to get chronic pain, and to not get better
WOMAC questionnaire (3 sections)
Western and MacMaster
3 sections: pain, stiffness, disability
QST Quantitive Sensory Testing
Detect threshold and tolerance
Use mechanical/thermal stimuli and have method to measure it
Psychophysics: go up and down around threshold until 50% chance to find exact
German way: do series of QST, express patient values in z-scores, how many SD away you are from average. Try and split patients into categories based on symptoms ( need an average and everyone trained the exact same)
Biomarkers of pain
Don’t actually have any but:
tissue damage, cardiovascular (heart rate, BP), stress (cortisol), neural (EEG, imaging (best biomarker)), chemical (don’t work), molecular (DNA variant, mRNA levels) (don’t work because DNA doesn’t change with pain, and mRNA would need spinal tissue but can’t)
fMRI as biomarker?
YES:
- only one accepted
- differences in brain activity (brain agrees with the ratings so don’t need ratings)
NO:
- Found big overlap with imagined/pretend pain suggesting brain can be tricked, and so people could fake it
Why we use animals
Pain uses rats
Science in general uses mice
- Causation experiments (can’t in humans)
- can lesion any tissue
- can record or extract any tissue
- can give unapproved drugs
- can alter gene expression
- can be precise at turning neurons on/off
- can control environmental pre-exposures
- cheaper, faster, less regulated
- they don’t have fake motivations (ie macho)
Challenges to using animals
- wrong species
- they don’t talk
- they’re prey (could hide pain)
- lot tougher than we are (stoic compared to us)
- ethical issues (no consent)
Different animal ethics
Deontological: rule is the only to decide if something is right or wrong (and animal research is against the consent rules)
Consequentialist (utilitarianism): end justify the means
Thermal Assays
- Hot plate test: wait for reaction (lick paw, jump off,…) and stop times to compare thresholds. 50 degrees, no pain at first cause takes time for skin temperature to adjust. This measures conscious decision
- Tail-Flick test: measure threshold with time to flick out of water, this measures spinal reflex
- Hargreaves test: radiant heat paw withdrawal, toe-toaster. Apply heat on either side
Mechanical Assays
- Von Frey Filaments: apply to different body parts. Not sure if measure pain or annoyance
- Randall-selitto test: pinch paw, measure how much pressure it takes for them to pull away
- Weight bearing, grip force, gait changes,…
Chemical assays
- Writhing test: give chemical and measure how many belly contractions
- Formalin test: can measure up to one hour (early acute phase / interphase quiescent period / late tonic phase)
Inflammatory Assays
Inject inflammogens and then do mechanical or thermal stimulus. Can cause allodynia and hyperalgesia
Neuropathic assays
Surgery, cut a nerve in the foot and then measure thermal or mechanical
Axotomy (complete denervation) vs Partial denervation. Measure Autotomy (bite off own foot) when feels like phantom limb and count how many phallenges left in the morning
3 big criticisms for Status Quo (animal modelling)
- Reflexive vs Conditioned measures: need to condition the animal to pain to avoid reflexes. Behavior could be caused by personality or thirst rather than just pain. Use motivational conflict (inflame cheek and have to press cheek to get reward solution). Use Conditioned place preference
- Pain-affected measures: ignore comorbidities (sleep, anxiety, attention) that develop after some time.
- Symptom epidemiology vs dependent measure use: we are not measuring the main problem in humans (least humans complain about is thermal but what we measure most in animals)
Individual differences in pain perception
Real question isn’t what causes pain but why pain in some people but not others?
Only 7% of surgical patients get chronic post-surgical pain (which is a lot of people still)
Morphine does for sufficient analegesia is 2-80mg/kg which is a 40 fold (huge difference)
Reasons:
- Organismic: nature, about you, genetic background, sex, age, psychological traits,…
- Environmental: nurture, what happens to you, past experiences, gender, psychological states, diet,…
Biopsychosocial model
Disease better explained by interplay of 3:
biologival, sociocultural, psychological
Heritability of pain
- Twin studies: There is a big range. Mostly environment but still 35-40% heritable
- Inbred mice: clones as results of decades of inbred, still about 45%
OPPERA
Prospective study of risk factors for temporomandibular disorder (TMD)
Longitudinal study
300/3200 people developed TMD naturally
2x more likely to develop if ILL and SCL 90r (how bothered by unexplained bodily sensations)
Sex differences
- Majority of pain patients are women
- Could be because more sensitive, or gender differences in going to the doctor (less male patients)
- Did study to see excess prevalence (not just patients) and found that women are 5-10% more likely to have symptoms
- Women are always more sensitive no matter what or how in lab
- Pain mechanisms must be different because Minocycline does nothing on females
Why sex differences
- Ultimate (why a diff?) vs Proximate (how a diff?)
- Nature of difference could be: organizational (developmental effect of gonadal hormones), activational (post-pubertal acute effect of gonadal hormones), genetic effects (X vs Y chormosome)
- Level of difference could be: experiential, sociocultural, psychological, cellular, neurochemical
ie. Hunter-Gatherer (hunter need skin pain, gatherer visceral pain), systems seem to match hypothesis
Reflex in neonates
Takes babies a while to get their reflexes in order
Mice get it somewhere in early adolescence (much smaller reaction to same stimulus), eventually goes away
Exaggerated and uncoordinated in neonates
Pain and aging
Big sex differences start in middle age
Women are more likely to be sick but stay alive longer, men are more likely to die
Decrease of male pain patients at older age because only the stronger are left, the weaker ones have died already
Racial disparities in health care
12% of black kids offered opioids for appendicitis vs 40% white kids.
Higher pain ratings for black people (opposite of stereotype, could be because mistreated)
Circadian rythms of pain
Some pain peak in AM and PM (some make sense because walking all day ie) but others could be for internal reasons
Lifestyle factors effect on pain risk
Most significants are: paid employment, body mass index, and marital status
Smoking and activity level are not significant
People who attended college less likely to feel pain
Pain and spousal support
Punishment (stop complaining) is not significant
Solicitousness (let me help) makes pain worse
Distraction makes pain better
Same results for children
Empathy for pain
Lots of overlap of cortisol activation when in pain and when think boyfriend is in pain
Also rate pain as higher if she liked the guy (no effect if didn’t like). So empathy makes pain worse
In mice, feel more pain when cagemate injured than stranger
Pain and diet
The more soy the less hypersensitivity in mice
Did not work in humans if taken after injury, so it is useless
Placebo effect
Discovered by Henry Beecher in WWII
About one third of people respond to it
Only significant for pain (not anxiety, obesity,…)
For subjective things it is very real
It activates brain circuits and actually make things work (not regression to the mean of after seeing the docotr)
Hidden vs Open drug administration
Compared routine medical practice / treatment stimulation w placebo / hidden dose of active treatment (no expectations because don’t know when you’re getting it)
Remifentanil study:
drug that relieves pain but can make it worse when infusion stops. Found that placebo worked better than drug
Factors affecting placebo
- Subjectivity vs Objectivity of measure
- nature of verbal suggestions (placebo language)
- previous experience
- belief, expectations, desires of both patient and doctor
- therapeutic context (interaction, white coat, deep voice lead to bigger placebo)
- physical properties of placebo (expensive pill vs cheap pill)
- Personality variables (optimism more liekly)
Placebo neurochemistry
Field owned by Benedetti
Found that there is some opioid receptors at work, and that there are more than 1 type of placebo analgesia
Nocebo effect
Evil twin
Expect bad will lead to bad
If i tell you the drug i’m giving you will increase your pain it actually will
Placebo response in Clinical pain trials
Response ( how the group did in trial, could be because of effect but also other factors)
Good trial when the drug beat placebo.
Newer studies have placebos that work better than before, the placebo effect is getting bigger with time, and worse in US ( because direct drug ads, that act as conditionning)
How we discover Analgesics vs how we would want to
- How we do: find plants and try them for stuff -> folk knowledge -> drug refinement (medicinal chemistry) -> drug repurposing
- How we want: neurochemistry -> pharmacology -> drug development (medicinal chemistry)
Neurotrophins
Rita Levi-Montalcini
If you take cells in a dish and add nerve growth factor (NGF) it makes the cell grow dendrites
Neurotrophins bind to receptors
Blocking NGL kills pain
Biology of inflammation
Swell because bringing more immune cells in area (watch graph(
Steroids
Used to block inflammation
Major side effects if take too much (acne, weight gain, purple striae, buffalo hump,…)
Aspirin
Willow bark (salicylic acid)
Added a little twist to take away side effects (acetylsalicylic acid)
Used in 18% of cases
NSAIDS non-steroidal anti-inflammatory drugs
Not Acetaminophen
They all block COX1 and COX2
PGE2 is the only one for pain
They work well, but many side effects
COX1 is made all the time, COX2 is made when needed, so we really want to block COX2 because it’s in pain area
(Acetamipnophen, naproxen, ibuprofen are COX1 specific )
Coxib controversy
Risks of cardiovascular event, started noticing heart attacks
0.3% additional annual risk of CV over placebo
They knew before it came out and tried to hide it, lawsuits led to lost of 7B$
TRPV1
David Julius (1st pain nobel prize)
Pain transducer
The chemical (capsaicin) evolved as painful so that animals won’t eat it (except birds so they can spread seeds)
Tried TRPV1 antagonists to kill pain: successful but not more than naproxen, and gave fever so too dangerous
Can use an Agonist where the first few minutes hurt but then ion channels are desensitized (shut off and can’t open again)
Sensory transduction of thermal sensation
Under 10 is pain (cinnamon, garlic) TRPA1, and over 40 is pain (peppers) TRPV1
There is a TRP channel for temperature range, all in sensory neurons
Transduction of mechanical pain
Ardem Patapoutian (nobel)
TACAN
Piezo
TMC
Why Lidocaine works
Lidocaine is an anaestethic, acts as nerve block which works for everyone but not for long. Sodium channel blocker
Use protein Nav1.7+8+9 (SCN9A) cause only ones specific to peripheral nervous system and don’t touch central.
Anticonvulsants for pain
Never approved for pain and yet being used
Gabapentin first, lost patent (goes generic), then what we use today Pregabalin (went generic also)
Opiate pharmacology
Agonist: drug similar enough to key to open lock
Antagonists: drug similar to fit in lock but stays stuck and prevent other keys to open it
Regular analgesics are full-agonists
Potency matters for overdoses, becayse very little doage difference can be lethal
Descending modulation of pain
Reynolds found that could do rat surgery with just electrode as analgesic (found later that it depended on where in brain)
3 spots where opioid give analgesia: PAG (same found for electrode), RVM, and spinal cord
System is already there and opioid activate it
SIA stress induced analgesia
Evolutionnary purpose (dear that strains ankle while being chased)
Found proof in rats, mice , and athletes that analgesia was higher when stressed
Opioid-Induced Hyperalgesia
Descending modulatory system can enhance pain too:
after injury, after prolonged exposure to opioids:
Hyperalgesic for 7 days after fentanyl injection
Morphine caused longer chronic pain episode
Opioid Receptors
Mu
Delta
Kappa
the more these are activated the less post-synaptic fires
All analgesic but
Mu has the usual side effects (constipation, euphoria,…)
Kappa causes dysphoria (feel shitty, so not used)
Delta causes analgesia but not enough
These are in small intestine (gut), what causes constipation
