Midterm 2 Flashcards
what is ectopic firing?
fires all by itself to no apparent stimulus (whats happening to diabetic rat)
what is the role of glial cells?
Not electrically excitable like neurons, but they can be activated and they have receptors and transfer NT
what is microgliosis?
when they get activated and get angry
- Caused by injury in periphery
what are microglia?
function is immune surveillance
what is the function of astrocytes?
blood-brain barrier, neural support
what is an advantage of subjective/objective measures?
subjective: less constraint
objective: more reliable, tighter data
what is a cold pressor test?
The immersion of hand or elbow in cold water (~4C)
- Eventually the limb gets ischemic (low blood supply), which hurts
what is pressure algometry?
press down on a body part and machine keeps track of how much force is exerted
- Keep pressing until person says stop
explain the pain threshold and tolerance study (how many seconds)
pain threshold achieved at 25 sec and pain tolerance was achieved at 80 sec
- Tolerance: raise heat until person says to stop
- Threshold: say “now” when warm becomes painfully hot (threshold is temperature)
what is time a proxy (substitute) for?
It’s an easy way to measure the temperature that researchers think is painful
what is the human heat pain threshold?
43-46 degrees C
- Maybe hypertensives have a slightly lower threshold than control
why do we need to measure something other than threshold and tolerance?
Threshold and tolerance don’t tell you about clinical pain (it’s something we can measure, but not what we want to study)
- Could also be measuring people’s willpower
- Problem with threshold: its very subtle
what is the visual analog scale and why is it better than NRS?
no numbers, but on a spectrum
- Some people say a low number bc they want to make their healthcare provider feel like their treatment worked – they’ll memorize the number and choose a lower one later
what is the faces scale?
used for kids snce they have a hard time understanding descriptors
- Problem: the zero face is smiling (no pain doesn’t mean you’re smiling)
- Should start at neutral
- Another problem: when?
describe the use of the double VAS
Top: intensity
Bottom: unpleasantness
what is the most common pain rating on a scale?
11
- They don’t understand what researchers are asking – it’s far too common
what is causalgia?
type of neuropathic pain after traumatic injury
explain how much things hurt, from most to least (Melzack)
MOST:
- causalgia
- digital amputation
- childbirth
LEAST:
- sprained ankle
explain the FLACC scale for babies
Face
Legs
Activity
Cry
Consolability
who came up with a facial action coding system for pain?
Paul Ekman
what are pain descriptors?
Idea that you can define pain by the words that people use to describe it
explain Ron melzack’s pain descriptors by intensity
Came up with collected adjectives that people use to describe pain (divided into categories)
- Sensory: Temporal, spatial, punctate, incisive (cutting), constrictive (squeezing), traction, thermal, brightness
- Top: ones that were thought to be least intense of the category / bottom: most intense in category
explain the McGill pain questionnaire
- 20 qualitative questions
- PPI: present pain index
- 6 point verbal rating scale
- You pick the one that most describes your pain
- Idea: different types of pain would feature different types of descriptors
- Doesn’t work that well, except with one exception: inflammatory pain is more dull aching, whereas neuropathic pain is more sharp shooting axis
explain the MPQ short form questionnaire
- Instead of picking descriptors, you’re given descriptors
- Takes less time to fill out
- Advantage: shorter appointment times
explain the DN4 neuropathic pain questionnaire
- Allows clinicians to see if patients have neuropathic pain or not
- 4 questions, 10 points
- Yes to every question: 10 / no: 0
- 0-3: not neuropathic
- 4-7: probably
- 8-10 definitely have neuropathic
what is Hypoesthesia?
less feeling of
what is the Oswestry Disability Index?
- Asks how well your painkillers are working
- Mostly about how disabled are you
what is pain catastrophizing?
psychological concept that is an amalgamation of rumination, magnification, and helplessness
- Rumination + Magnification + Helplessness
- predicts who will get chronic pain and what their prognosis will be
what is the WOMAC questionnaire?
- Developed specifically for arthritis pain and arthritis in general
- Measures different contexts
- Section c: measure of disability
- Developed by western and mcmaster
what is quantitative sensory testing (QST)?
- Two ways – bedside examination + quantitative sensory testing
- Less controlled but can be done at the bedside in a clinical context (pinprick, metallic rollers)
- Very precise equipment, very precise instructions
- Use of psychophysics: series of methods of giving a bunch of different intensities of a stimulus to see where the threshold is
what is skin temperature?
32 degrees
what were the Different baseline heat thresholds in QST and heat hyperalgesia study?
42.1-44.5
explain the QST and mechanical allodynia study
- Data from 1 patient
- QST with: cotton whisp, Q tip, and brush
- Dynamic mechanical allodynia
- Left: forces that 3 items exuded
- Right hand: non noxious
- Left hand (painful hand): much more noxious
- You would think that the noxious stimuli would be more noxious compared to others ones, but they’re about the same
explain the QST the german way (PHN I and II)
-Determined that there are 2 types of PHN, gain of function and loss of function and they respond to QST procedures in diff
ways
PHN I:
- heat hyperalgesia
- pinprick hyperalgesia
- dynamic mechanical allodynia
- static hyperalgesia to blunt pressure
PHN II:
- cold/warm hypoesthesia
- tactile hypoesthesia
- pinprick hypoalgesia
- static hypoalgesia to blunt pressure
explain electrical, chemical, and mechanical pain testing in muscles
- Chemical: infuse chemicals into patients
- Electrical: stimulate muscles directly to get pain ratings
- Mechanically: pressing really hard with a probe (stimulate muscle and skin)
- A lot more invasive than regular QST
what are biomarkers?
measure with a machine
what is the original biomarker?
tissue damage
- Thought that the amount of pain should follow the size of the wound, but that does not work
what are neural biomarkers of pain?
EEG, microneurography (direct measurement of c fibers), imaging (controversial – some ppl think its good and others don’t)
what are chemical biomarkers of pain?
substance p, beta endorphin, nerve growth factor (all others don’t work but this one is still on the fence)
what are molecular biomarkers?
DNA, mRNA
- Why are these problematic?
- DNA variants: DNA doesn’t change no matter what happens
- mRNA: can have more or less expression of that gene – mRNA expressions differ in every tissue, which we don’t have access to unless mRNA levels in the blood turn out to be useful
what are cardiovascular biomarkers?
- heart rate
- blood pressure
- heart rate variability
what are stress-related biomarkers?
- cortisol (etc.)
- galvanic skin response
Can fMRI be Used as a Biomarker of Pain?
True in small sample, false in large sample
explain Hypnotic vs physically induced vs imagined pain
There’s a lot of overlap, even when there wasn’t pain
- If your brain is active in pain matrix, that might not mean pain
why use animals?
- can conduct causation experiments
- can stimulate/lesion any tissue
- can assay, record from, or extract any tissue
- can give unapproved drugs
- can alter gene expression (temporarily or permanently)
- can turn particular types of neurons in
particular locations on and off at will - can control pre-exposures
- cheaper, faster, less highly regulated
- no malingering, no stoicism/machismo,
- no demand characteristics
explain the consequentialist approach to animal experiment ethics
add up costs and benefits and come to a conclusion
explain the deontological approach to animal experiment ethics
there are things that we just shouldn’t do
explain the trends of Algesiometry in Rodents
- test with chemical, electrical, heat, cold, mechanical, spontaenous pain
- Mechanical testing has increased over time, and everything else is on a lower level
- Why? Mechanical hypersensitivity (allodynia and hyperalgesia) is a bigger problem than heat hypersensitivity
- heat testing has gone down
- electrical is never done at all bc animals dont get exposed to electric shock
what are challenges to the use of animals?
- they’re the “wrong” species
- they don’t talk
- they’re prey
- they’re a lot tougher than we are
- ethical issues
explain the hot plate test
Made out of ceramic and heated to a particular temperature
- Measure amount of time it takes for the animal to shake/lick paw (they don’t jump off right away)
- Measuring acute heat pain (the pain will only be there for a sec or two until the rat decides to do something)
- Why they choose to lick specific paw is unclear
difference between tail flick test and hot plate test
- Tail flick test is a reflex
- Hot plate test is a CONSCIOUS decision to do something
explain Hargreaves’ test
- Radiant heat paw withdrawal test: how long it takes for mouse to hop away from heat lamp (Hargreaves response)
- Put heat on each paw separately
- Measuring thermal acute pain
explain the von frey filament test
Made to test mechanical sensation
- Set of fibers range from thick to thin
- Each fiber can only exert x amount of force
- Measuring animal’s threshold of annoyance instead of pain (maybe)
The vast majority of pain research is about:
hind paw skin pain
explain the Randall-Selitto Test
- Only works in rats; mice will not stand for being held this way
- Putting the rat’s foot between two pieces of plastic and increase the force
- At some point to rat squeaks or does something
- IITC: more modern and automated version
How do you infer pain in weight bearing tests?
unequal input on both sides (weight on one side more)
How do you infer pain in grip force tests?
if mouse is unable to hold on with the same amount of force as before
How do you infer pain in gait changes?
if they are favouring or guarding one side they will show a different gate pattern (indirect measure)
explain the writhing test (what do you inject)
Inject nasty chemicals that cause inflammation or activate nociceptors into body parts
- Most common: acetic acid - irritates muscle wall in viserca
- Mice will squash their belly on the ground (measure how many times and for how long)
- Measuring behavioural response over time
- More behaviours –> more pain
explain the formalin test
Injection of formalin (dilute formaldehyde) that starts fixing tissue and cause inflammation
- Early: lots of licking
- Quiescent: looks like it’s much better
- Late: start licking again for 60-90 mins
what are the Most common inflammatory substances?
- carrageenan
- complete Freund’s adjuvant
- zymosan
- mustard oil
explain tonic/chronic inflammatory assays
Effects will last days to weeks
- They don’t do anything (lick, shake, nothing)
What they do do:
- Inflammatory thermal hyperalgesia on hargreaver test
- Inflammatory mechanical allodynia on von frey test
- Inflammatory cold allodynia: put acetone on paw (it evaporates) causing a cooling sensation (painfully cold), leading animal to lick paw
explain surgical Chronic Neuropathic Assays
Interfering through primary afferent through the foot (because the foot is easiest to test to see of there are changes)
- Making an injury that causes partial damage to nerve supply in the foot
- Remember: neuropathic pain is most often caused by partial pain
- Only things to measure: Cold and mechanical allodynia, thermal hyperalgesia
explain complete denervation (which nerves are cut and why there can’t be pain)
cut sciatic nerve and saphenous nerve to accomplish this (produces axotonomy: they start biting off their toes)
- Score it by counting how many toes are left
- There can’t be any pain, because there’s no afferent input from foot to spinal cord
if complete denervation isn’t painful, why are mice biting off their foot?
Leading explanation: they don’t think it’s part of them anymore (animal model of phantom limb)
what is complete axtonomy?
amputation
how can you cause neuropathy?
- viruses
- drugs
- Cause dysfunction of nerves, or cutting/inflaming them
name nociplastic and neuropathic types of pain
- Nociplastic: fibromyalgia
- Neuropathic: diabetic neuropathy, post-herpetic neuralgia
what is vulvodynia?
nociplastic disorder whose main feature is allodynia of the vulva
- lots of yeast infections
explain vulvodynia studies in mice
Gave mice yeast infections and treated them with antifungal over and over
- Noticed that after 3 rounds, they were getting allodynia that stayed instead of resolving
- Produced a state of permanent allodynia in mice
- Took 3-5 months
- Better way to study vulvodynia, but it takes too long
name The Big Three Criticisms of the Status Quo
(1) The methods that we use are reflexes, but the problem has nothing to do with reflexes
(2) Pain is associated with a bunch of comorbidities – why aren’t we measuring them?
(3) Disconnect between epidemiology of clinical symptoms and what we measure in animals
what is the opposite of reflexes?
conditioning
explain the motivational conflict between pain and drinking (operant conditioning study)
- Inject carrageenan in cheek, gets inflamed
- Wants to drink sweet water for reward, but only way to get it is press cheek against a heated plate
- Carrageenan produces mechanical and heat allodynia
- Not a reflex, the animal is making a choice
Why is this complicated? Maybe the experiment changed something other than pain
explain the conditioned place preference to analgesia
Used clonidine or conotoxin (analgesics)
- Partition in middle
- Other floor: saline
- Animals will spend more time on analgesic side when they have the choice, since they weren’t in pain
- SNL produced pain
- Complicated, requires a bunch of training
name the differences in percentages of pain in reality vs research
96% have spontaneous pain
64% have mechanical hypersensitivity
38% have thermal hypersensitivity
- Percentage of paper research:
48%, 42%, 10%
why are we understudying spontaneous pain?
Not as convenient to study and we couldn’t come to a conclusion on how to measure it
what is the mouse grimace scale?
index of how much pain the mouse is in
which species have criteria for pain perception?
- Birds have all of them
- Amphibians and reptiles have some of them
- insects may feel pain
what are organismic/experiential factors?
organismic: factors inside your body that can affect pain
experiential: things that happen to you
why do Ratings go from 5-95 for exact same stimulus?
- People might be using scale differently
- Perceptual variation
__% of people that go in for a surgery get chronic post-surgical pain
7%
How many surgeries are preformed every year in Canada?
1 million
explain pain ratings from patients Immediately upon waking up from anesthesia
60+: Most common score
Average: 70
Nurses gave a small dose of morphine and came back every hour - what were the averages?
- Massive variability – some required 1-10
- Average: 4 doses
- Range: 2-83 micrograms per kilo of body weight
difference between trait and state
Traits: stable / states: malleable
explain the biopsychosocial model
Biological: genetics, gonadal hormones, endogenous pain inhibition
Psychological: anxiety, depression, cognitive factors, behavioural factors
Social: age, ethnicity, family history, sex roles
_________ leads to autotomy, others leads to ________________
Sciatic nerve, mechanical allodynia
what is the heritability of pain?
30-40% heritability on average
- Experimental pain lowest heritability
- about the same in mice
how many genes are there?
22,000
what are monogenic pain disorders?
too little or too much pain caused by malfunction of a single gene
- Each disorder affects 300 people in the world (incredibly rare)
HSANs (Hereditary Sensory and Autonomic Neuropathy) all involve:
pain insensitivity
_______ of the total genes are pain genes
6000
what is omnigenic?
all genes contribute to all traits
what is omnigenic?
all genes contribute to all traits
what is Temporomandibular Disorder (TMD)?
when your jaw hurts for no reason
based on the odds ratio, which types of psychological questionnaires predicted TMD?
- PILL
- SCL: subscore of somatization
- Both measure somatization: perseverating about bodily sensations (similar to catastrophizing)
- Tendency to somaticize have a higher chance of developing TMD
explain difference in development of osteoarthritis regarding gender
develop late: female / early: male
- Flaw: these are diagnoses women go to the doctor more, and therefore get diagnosed (you can be on here if you’re not diagnosed)
- The fact that men don’t want to go to the doctor is a gender difference
explain Sex Differences in Chronic Pain Prevalence study (which % more)
- In every single study (except one), women were more likely to say yes to having chronic pain
- Median: 5-10% more women
- Flaw in conclusion: maybe women are more susceptible to developing diseases that feature pain (not necessarily more sensitive, just more likely to have conditions with pain a symptom)
explain Experimenter Sex-Subject Sex Interactions study
- Women have higher ratings when they were tested by men
- Men gave lower when they were tested by women
- Manipulation of attractiveness: took same experimenter and change what they wore
- Attractive : men gave lower ratings attractiveness and women gave higher ratings
- Confirms stereotypes
- Has not been replicated since
what does minocycline do?
blocks microglia
explain Sex Differences in Pain Mechanisms study (with doses of minocycline)
- Give subjects injury –> become allodynic (no sex difference)
- Give various doses of minocycline
- Male: reverse mechanical allodynia
- Female: no dose does the same thing (microglia do not play a role in females, something else has to be causing it)
- The biology between males and females is way more than we thought
what is the nature of the sex difference in pain sensitivity?
- Gonadal hormones (organizational)
- Puberty (activational)
- Genetic effects
what are the levels of the sex difference in pain sensitivity?
experiential
sociocultural
psychological
systems-level
neurochemical
explain Exaggerated and Uncoordinated Flexion Reflexes In Neonates study
- Very young animals have higher reflex excitability
- Settles down to adult levels by 21
Bottom: human data
- With age, amount of force needed to feel pain goes up
- Hip flexion reflex – very young babies will splay out their legs on both sides
- Older age: ipsilateral side of stimulus
- Eventually, they won’t do it at all
explain pain and aging studies in humans
- Chronic pain appears to peak n middle age (true for both groups)
- Old people have less pain (higher thresholds)
explain pain difference in races
- African americans are more sensitive to pain, more pain disability, undertreated for pain
- We don’t know why this is, and we don’t know what we’re looking at
why does OA peak at night?
you walk all day
which Lifestyle Factors mattered/didn’t matter for Chronic Widespread Pain Risk?
- Alcohol consumption, physical activity, diet: not significant
- Mattered: job, physical exertion at work (50%) increased risk, BMA, married, lower social classes (not that significant)
Punishment, solicitment, or distraction - which is better for pain?
- Punishment didn’t matter
- Solicitousness: increases pain levels (avoid method)
- Distraction: lowers pain levels (use this method)
explain the Singer et al empathy for pain study
- Couples came in and put girlfriend in MRI and was told bf would get electric shock
- Gf herself was shocked at a different time
- A lot of overlap – same brain areas lit up when gf saw bf in pain and when she was in pain
- Women have higher empathy than men, which is why they used the gf
what is the biggest genetic difference between males and females?
how far you can throw a ball at age 16 lol
explain the Loggia et al empathy for pain study
- Tested people for pain while watching a neutral video
- Shown a person on video from someone who was already in the experiment (confederate)
- Sad story vs angering story (you like him vs you don’t like him)
- If you liked the confederate and he was in pain: your pain was higher
- The guy you didn’t like: didn’t affect your pain
- Empathizing with someone you like increases your pain levels
explain Pain and Diet (Soy in Rats) study
- Had most allodynia and hyper if given the MBAR diet (lowest amount of soy)
- High soy is good for pain
- High soy diet before injury ONLY
explain Empathy for Pain in Mice study
- Looking at abdominal constriction (writhing)
- Two mice in cylinder and they know each other: more pain (doesn’t happen if they don’t know each other)
who discovered placebo?
Henry Beecher
is the placebo effect real for pain?
yes
how can classical conditioning explain placebo working?
Conditioned to believe that pill will make you feel better, as pills have been used for pain relief your whole life
how can natural history explain placebo working?
- Natural history (regression to the mean) important for clinical trials
- Odds of going higher vs lower after treatment: will regress back down (might mean treatment worked or that at the time you went for treatment it was abnormally high)
- Can’t tell difference between this
- Not the placebo effect, just an alt explanation
Canada & USA consumes _____ of the world’s opioids
~ 80%
what are the Most common routes of administration for patients with chronic pain?
Oral
(eg: tablets, capsules)
Transdermal
(eg: skin patches)
what are the Most common type of opioids prescribed for patients with pain?
Codéine
Hydromorphone
Oxycodone
Morphine
Fentanyl
how are opioids used for acute pain?
- important analgesic function
- prescribed after surgical procedures
- after dental procedures
how much have opioids for chronic pain risen?
Substantial rise │ Past 2-3 decades
- Long-term opioid therapy (≥ 90 days)
what is the ethical argument for using opioids for cancer/palliative care?
Palliative care community argued that dying in pain is ethically unacceptable
- Ethical argument extended to chronic noncancer pain (CNCP)
- CNCP: may produce pain, suffering & disability of comparable intensity
- Leave patients in unbearable pain or suffering = unethical medical practice
what is the role of scientific publications in opioids?
Two studies that contributed to opioid crisis:
* Porter: letter to the editor, not even a paper
- Claimed opioid addiction is rare
- Based on weak methodology
- No ceiling on amount of opioids prescribed
*Portenoy & Foley
- Reviewed 38 medical charts
- Conclusion: opioid therapy is “safe”
American pain society and American academy of pain medicine released statements about opioids regarding:
Opioids should have a role in the treatment of chronic non-cancer pain
(1996)
explain opioid marketing in the late 1990s
- Late 1990s, opioid marketing by pharma industry was aggressive
- Specific types of opioids were marketed as less addictive than other medications
- Opioid sales have quadrupled between 1990 & 2010
what happened with Purdue Pharma in 2007?
In 2007, Purdue Pharma paid a $ 630 million fine
- Misleading the public & prescribing physicians
- Claimed that Oxycontin was less addictive than other opioids
explain the Effectiveness of opioids for chronic pain study (Busse)
- Reviewed 96 randomized controlled trials (RCTs)
- Opioids superior to placebo for pain
- Modest improvements in function
- Average pain reduction provided by opioids across all types of studies together: 2 out of 10
- Problem: most RTCs were less than 3 months
- The conclusion says that opioids work better than placebo in a short period of time, we don’t know about long
what are potential problems associated with opioids?
- physical dependence
- opioid misuse
- opioid addiction
how many opioid-related deaths were there in 2022?
3500 opioid-related deaths
explain detailed stats behind opioid deaths
- 75 % occurred among males
- 90 % among young & middle aged adults
- ~ 45 % involved another substance (e.g., alcohol, cocaine or benzodiazepines)
what does pharmaceutical mean?
manufactured and approved by a pharmaceutical company for medical purposes
why is fentanyl a main contributor to opioid deaths in Canada ?
access, potency (easier to smuggle –> you can get more in a smaller package)
what is opioid abuse?
Opioids not prescribed to the user by a physician
* obtained from friends
* from family members
* on the street
- Opioids used by individuals:
- for nonmedical reasons
- for recreational purposes
(i.e., to get «high»)
what is opioid misuse?
Opioids prescribed to the user by a physician
* prescribed for a medical reason
(e.g., pain)
- Opioids used by patients differently from how
they were prescribed
Past-year nonmedical use of prescription opioids among adults:
~3-5%
Past-year nonmedical use of prescription opioids among adolescents :
~5-10%
why do adolescents engage in opioid abuse?
Adolescents view prescription drugs (e.g., opioids)
as “safer” than illegal drugs
- Among adolescents, the main sources of prescription opioids are :
- peers
- leftover medications
what are the 2 types of Prescription opioid misuse (in chronic pain patients)?
Unsanctioned dose escalations (opioid overuse)
-to improve sleep | mood
-to experience the euphoric effects
Concurrent use of unsanctioned substances
- alcohol | illicit drugs
- prescription drugs
Prevalence of opioid misuse in primary & tertiary care settings:
~20-30%
Discovered through: self-reports, clinical interviews, medical records, urine tox screeens
what is opioid dependence?
Characterized by somatic (i.e., physical) withdrawal symptoms following cessation of opioids or decreases in opioid blood levels
- Normal/expected response resulting from prolonged opioid use
- Individuals (e.g., pain patients) who have developed opioid dependence sx do not necessarily have an opioid addiction problem
what is opioid use disorder?
proper diagnostic term for opioid addiction
- Diagnosed through semi-structured interviews
- Can’t diagnose based on self-report questionnaires
Prevalence of OUD in patients with chronic pain:
~10%
DSM-5 criteria of opioid use disorder (OUD)
- Social problems
- Occupational problems
- Failure to fulfill life role obligations
- Risky use
- Taken in larger amounts than intended
- Psychological problems due to use
- Compulsive use
- Unsuccessful efforts to cut down
- Craving
Under medical supervision: tolerance and withdrawal not included
how many symptoms of OUD do you need for different severities?
2-3: Mild
4-5: Moderate
6+: Severe
what are Other types of substance use disorders (SUDs) in DSM-5 ?
- Alcohol use disorder
- Cannabis use disorder
- Sedative, Hypnotic, or Anxiolytic use disorder
- Stimulant use disorder
- Inhalant use disorder
- Hallucinogen use disorder
- Tobacco use disorder
(all involve same diagnostic criteria)
what are Risk factors for opioid misuse & addiction (among patients with chronic pain)?
- Younger males
- Family history of substance use disorder (SUD)
- Personal history of SUD
- Greater levels of pain = more chance of misuse
- Patients with psych disorders
explain the Correlation between self-reports and opioid misuse
Correlation between self-reports and opioid misuse is modest (people lie about how much they use)
what is craving?
- Refers to the subjective desire to consume substances
- Long history in the broader substance use/addiction literature
- Extensive basic & clinical research on craving
- Those who catastrophize are more likely to report craving
what is wrong with Abrupt discontinuation of opioid therapy?
- Problematic │Unethical
- Reduce access to pain care │Under-treatment of pain
- Risky opioid-seeking behaviours
what are the Key recommendation domains for opioid prescribing?
- Avoid initiating opioids among those with specific risk factors
- Prescription of < 90 mg OME daily
- For those on ≥ 90 mg; Tapering opioids to the lowest effective dose
contrast traditional vs new role of psychologists involved in the management of patients with pain using opioids
Traditional: coping skills, adjustment to pain, high functioning and QOL
New: Prevent/reduce risks of opioid use problems
explain Risk screening to prevent opioid misuse & addiction
Before initiating opioids: identifying patients «at risk» for misuse and addiction
- interviews, self-report
- history of SUD, mental health
- risk stratification, opioid tx plan
explain Interventions to prevent/reduce opioid problems
- Monitoring: misuse behaviours, pain outcomes, questionnaires, interviews
- Psychological interventions: CBT, acceptance and mindfulness-based interventions
explain CBT
- Providing patients with education and ensuring motivation to comply with prescriptions
- Cognitive restructuring (changing thoughts and perceptions)
- Help patients cope with cravings and urges to misuse opioids
explain Acceptance & commitment therapy (ACT)
- Focus is not on changing negative cognitions or emotions
- Patients encouraged to “accept” unpleasant states (eg: pain, cravings)
- Redefine personally meaningful values
explain the first MRI images
first subject (Damadian) was too fat, so they used a more fit subject (Minkoff) and it worked
what did the first MRI images include?
tissues, cavities in torso
what is BOLD?
measures oxygen levels in the brain (specific brain regions)
explain the First brain imaging study of pain
Done by John Talbot
- used PET to find out that:
-Pain is represented in the brain
-It is not localized in a single spot
what is a Neurosynth pain map?
it will generate a brain map based on previous neuroimaging studies
explain Don Price’s model of pain
idea is that nociceptive input from spinal cord leads to nociceptive sensation, autonomic response, arousal (threat response), higher order processes (perceived intrusion, threat —> insular cortices), immediate pain unpleasantness, second order appraisal (contextualizing the pain —> prefrontal cortex), secondary pain affect
explain the difference between Brain models for modulation of pain by attention and emotions
- attentional: more impact on intensity
- emotional: more impact on unpleasantness
explain brain signatures
- give voxels a specific weight to learn the pattern of them
- look at brain response and predict stimulus
- good diagnostic value for pain related things like heat, but not pain anticipation or recall
does fibromyalgia amplify pain processing?
yes
explain the Theoretical model of the neurobiology of placebo (function of ventromedial and dorsolateral in pain)
- ventromedial PFC: gives meaning to pain
- dorsolateral PFC: expectancy of pain
IDEA: interplay of pain regions inhibited by other brain regions that put the break to their expression
does placebo have a real effect on neurological signature?
no
what are T1 weighted images?
measure integrity of cortical thickness, grey matter volume, etc (anatomy of the brain)
what are diffusion weighted images?
look at white matter tracts
what are resting state images?
measure BOLD, take different regions and look at associations between them
- significant correlated signal between functionally related brain regions in the absence of any stimulus or task
- Used for translational neuroimaging - very popular but not a lot of delivery so far
why do reproducible brain-wide association studies require thousands of individuals?
The correlation is small with small sample sizes because they increase biases
- error shrinks as number of subjects increases
when is the peak in brain matter volume?
18 years old
- subcortical expands later in life
- growth rate diminishes except for ventrical
which disorders have strikingly different grey and white matter volume in females?
schizophrenia, MCI, alzheimer’s
(also ventrical expansion for males and females)
explain hidden vs open drug administration
- routine medical practice: active treatment and knowledge of treatment
- placebo: knowledge only
- hidden dose: active treatment only
what is Remifentanil
a drug that relieves pain, but can worsen pain when the infusion stops
explain the Remifentanil study
4 phases of study:
- Baseline: give pain ratings (VAS 60)
- No expectancy phase: started to get drug but they didn’t know (went down from 65-55)
- Positive expectancy: getting drug and being told about it (55-40) expectation was bigger than effect of drug
- Negative expectancy: told drug stopped, but it didn’t (expectancy was hyperalgesia) (back up to baseline – 60, eventhough they were getting drug)
- Expectancy is as big as the drug itself
is a placebo a state or a trait?
state
what psychological traits are significant for placebo?
- State anxiety
- Optimism
- Extraversion
For things that are more subjective (pain, depression), placebo effects tend to be:
bigger
what are factors affecting the placebo effect?
- Greater expectation, greater placebo effect
- Previous experience affects placebo because of conditioning
- Belief/expectation/desires of the patient AND clinician: why RTCs are double-blinded
- Patient-clinician interaction: therapeutic context (#1 predictor if any psychological therapy will be effective)
- Physical properties of placebo itself effects effect
how does patient-clinician interaction (the “therapeutic context”)?
- Bedside manner: mix of enthusiasm and dedication to patient getting better
- More patient feels the doctor wants them to get better, higher placebo
- White coats enhance placebo
- Deep voices produces bigger effects
how do the phsyical properties of the pill itself affect placebo?
- Bigger pills are better, IVs are better
- More effort patient sees, more placebo
- More expensive, bigger effect
explain the Opioid-Mediated Placebo study
Hidden open design
- Started with pain intensity of 7
- At time 0, given pill they are told is a placebo (they also have an IV)
- Black circled started getting infused with opioid receptor blocker (placebo effect was blocked, so the placebo effect is being produced by the activation of opioid receptors, which is done by endorphins)
- Open circle group continued to receive saline
explain the Non-Opioid-Mediated Placebo study (what do morphine and ketolorac produce)
CONCLUSION: morphine and ketolorac produce analgesia – ketolorac placebo analgesia is CB1 dependent, ketolorac analgesic isn’t
- Theres more than one way to produce the placebo effect neurochemically
what is rimonabant?
blocks CB1 receptors
what is the nocebo effect?
if you have the expectation that your pain will increase, then your pain will increase
- You can have placebo and nocebo at the same time
- Only difference is what the desired effect is
who is THE guy for placebo research?
Benedetti
explain the neurochemistry of the nocebo effect study
- Gave someone placebo and replaced in ½ the subjects proglamide (drug that blocks CCK receptors)
- Those that got the drug – placebo got bigger
- If blocking CCK made placebo effect bigger, then CCK would be responsible for placebo/nocebo getting smaller (nocebo effect)
- If you hope/expect pain to be released, that inhibits pain
- If you hope/expect pain to be increased, increases pain by CCK receptors
explain The Placebo Response in Clinical Pain Trials (gabapentin and pregabalin)
- Both drugs beat placebo by a point or so
- Because of the trials both drugs were approved
(Gabapentin & Pregabalin) - difference in trials: placebo response of pregablin trial is bigger
When we analyze where placebo trials were done, those done in US really showed the effects, whereas elsewhere they weren’t significant – why?
The US and New Zealand are the only countries that allow direct-to-consumer drug advertising
explain ACTTION and FDA placebo trials and why it might be called “cheating”
- Placebo response was bigger in trials of ppl who had DPN vs PHN
- More likely to have a Positive trial with PHN patients
Placebo effect is as small as it could be in a clinical trial because :
(1) you don’t know whether you’re getting the drug, (2) the drug may not work
In the real world, the placebo effect is way bigger – why?
- Trusting doctor is giving you an approved drug
- Why clinical trials are so critical – we need to know whether they really work or not
explain the order of How We Would Like to Discover Analgesics
neurochemistry –> pharmacology –> drug development
what is transduction?
how environmental signals get turned into neural code
who is Rita Levi-Montalchini?
won nobel prize for discovering that if you take cells and add growth factors, those neurons set up processes (how they connect to each other and form a synapse on target)
what is BDNF?
brain derived neurotrophic factor (nerve growth factor)
nerve growth factor causes:
peripheral and central sensitization
NGF only binds to:
track A
BDNF and N-4/5 bind to:
track B
neuro-3 binds to:
mostly to track C and a bit to A
what are the 5 pillars of inflammation?
- rubor: redness
- calor: heat
- tumor: swelling
- dolor: pain
- loss of function as end resutl (but goes away eventually)
inflammation is thought to be the root of all evil, including:
- cancer
- cardiovascular
- alzheimers
- pulmonary disease
- arthritis
- autoimmune disease
- neurological diseases
- diabetes
what is the #1 cause of death?
sepsis (infection)
explain the biology of inflammation
inflammation is body’s response to wound
• Wounds cause bacteria to enter body
• Inflammation is how our immune system recognizes where to act
what are the most powerful inflammatories known?
steroids
how are steroids used for back pain?
epidural injection
what is dexamethasone?
works, but side effects get worse as you use it more
why can no one be on chronic steroids?
the side effects are unacceptable
what are the side effects of steroids?
blurred vision, weight gain, depression, bloody stool, pancreatitis, low potassium, high blood pressure, etc
what happens when opioid receptors are blocked?
placebo effect is blocked
- the placebo effect is being produced by the activation of opioid receptors, which is done by endorphins
what does blocking CCK do?
makes placebo effect bigger
- CCK responsible for placebo/nocebo
difference between ketolorac placebo analgesia and normal ketolorac analgesia
ketolorac placebo analgesia is CB1 dependent, ketolorac analgesic isn’t
