Lecture 4: Pain Measurement in Humans and Animals Flashcards
What would be a subjective definition of physical tiredness?
-feeling of tiredness with a physical appearance (eg. heavy and tense feeling in the body, mild pain)
What would be an objective definition of physical tiredness?
-any practice induced reduction in the ability to exert muscle power of force. (impairment of muscle fibers, decline in motoneuron input
What would be a subjective definition of mental tiredness?
-feeling of tiredness with a mental flavour (mild sadness, cannot think straight, relaxed in a pleasant way, tensed and irritable, heavy feeling in the head)
What would be an objective definition of mental tiredness?
-any practice induced reduction in the ability to perform mental work. (inability to concentrate, slowness in thinking, learning and memory difficulties, lack of creative force in thinking)
What is a thermode?
- machine that can heat up or cool down
- the temperature can hold for a few seconds
- apply it usually on the volar forearm.
- they measure ether pain threshold or pain tolerance
What is a pain threshold?
-at what point does the stimulus become painful (it’s starting off at belong painful)
What is pain tolerance?
How much pain you’re willing to accept.
What were the findings of the study where they compared pain threshold and pain tolerance for people with normal blood pressure and people with hypotension?
- they are given the thermode
- hypotensive showed shorter latency for pain threshold and tolerance
Why do they measure time (latency) in pain studies? What is time a proxy for?
- you’re interested in the temperature at which the person reacts
- time is a good proxy for temperature as long as you assume people’s skin all warm up at the same temperature
What is the verbal pain intensity scale?
-gives verbal descriptors (ex: severe, very severe) from no pain, to worst possible pain
What is the issue with VPS ? (Verbal Pain intensity scale)
- Can be hard to know exactly what each term means
- Hard to translate in order languages without altering the meaning of it
What is the NRS? (Numeric Rating Scale)
-Scale with numbers form 0 to 10, with sometimes some descriptors called pegs, for 0, 5, and 10.
What is a Visual Analogue Scale? (VAS)
-Line with pegs on left and right, and you put a stroke in the line corresponding to where your pain is at
Why is the VAS better than the NRS?
-VAS, much less likely to be biased by a number you gave before. (ex: chiropractor story)
What is the faces scale?
- faces showing different expression from good to bad.
- especially helpful with kids
What is the problem with the faces scale?
-no hurt: smiling. but this is not necessarily the case because not being in physical pain is not associated with being particularly happy.
What are things that are hard to capture in a rating?
- when? right now, last week, average last week, worst pain last week…
- in what context? at rest, at the end of the day, i the morning…
- pegs
What other ways are there to use rating scales?
-dual VAS using specific terms for the pain (eg, unpleasant, intense)
What did they find in a McGill study where they measured 2 pains, heat pain and ball blown in the oesophagus ?
- They wire the 2 pains so that are both a 4.
- They found that unpleasantness scores of oesophageal distension were alot higher than for heat pain.
About the two scales found on the internet that go from 0 to 10 with precise descriptions of each stage. Why are they not used in pain research?
-descriptions are asserted but no proof that they are true
How is the patient’s rating accuracy is confounded ?
-When patient is asked to rate their pain , they will often give a high number, because they want the doctor to take it seriously, and not make them feel like they came for no reason.
What is the problem with the interpretation of pegs?
- The individual interpretation of pegs depends on each people experience.
- A woman who has experienced childbirth pain has a larger scale than a man who hasn’t experienced kidney stone or gunshot wound.
What were the findings in the study where they compared the imagined pain of a certain pain state to the actual pain experienced by someone?
- General trend: people imagine that things are gonna hurt more than they actually do.
- But the sample size is to small to actually count on these results
What is the lumping and splitting problem with pain scales?
- attempt to list the things that contribute to the pain (ongoing pain, allodynia, hyperalgesia, functioning)
- the pain has alot of symptoms and alot of meanings but we’re boiling it down to a number. But how much of each symptom are responsible for the pain? we don’t really know. Maybe that’s way we stay on a single number.
How do you rate pain when the patient isn’t able to do it themselves? (eg. babies)
-FLACC Scale for babies: 5 categories are observed (face, legs, activity, cry, consolability). Rated from 0 to 2
How does the FACS (Facial Action Coding System) work?
Who created it?
- Paul Ekman
- coded the facial muscle action to infer emotions.
How was the McGill pain questionnaire developed ?
- Ron Melzack asked participants to come up with all adjectives they can think of that can describe pain.
- He made a questionnaire from these words. In each category you choose what word goes best with your pain.
- There is also a PPI: 6 points NRS.
- The idea is that it would be useful in diagnosis
- Problem: it’s long.
What is the DN4 questionnaire?
- 4 categories of questions
- 2 are patient interview
- 2 are patient examination
What is the oswestry disability index?
-Measures disability: how are people living with the pain
What are the three components of catastrophizing in the pain catastrophizing scale?
- Rumination: focus on negative content, generally past and present, and results in emotional distress.
- Magnification: exaggeration
- Helplessness
What is the controversy with the pain catastrophizing scale?
-Some people feel it decredibilizes their pain, makes them feel unvalidated, and like they don’t have the right to express their pain and be treated.
What is the WOMAC questionnaire?
- special questionnaire for arthritis.
- Not ideal as a pain questionnaire, but good to assess how bad the patient’s arthritis is.
What are the three main sections in the WOMAC questionnaire?
- Section A: context (walking, at rest, standing up…)
- Section B: Stiffness
- Section C: disability
What are the two types of testing and the stimulus done in the QST? (Quantitative Sensory Testing)
- Bedside examination
- Quantitative sensory testing: -Mechanical and thermal stimuli
What are the methods used in QST?
-Bedside examination, mechanical stimuli: paintbrush, cotton swab, gentle pressure with fingertip, pinprick
-Bedside examination, thermal stimuli: metallic roller kept at 20c or 40c, acetone/menthol.
-QST, mechanical: Von Frey Hair, Pressure alogometry
.QST, thermal: thermotest.
In an experiment with QST what are the temperature threshold relative to skin temperature?
- cool threshold: 31.1 C
- warm threshold: 37.7 C
- cold pain threshold: 13.8 C
- heat pain threshold: 43.5 C
According to a study with QST and heat hyperalgesia, how big is the change in pain heat threshold when the skin is injured?
-injuries cause anything from 4.8 to 5.6 degrees of hyperalgesia (meaning the pain threshold is 4.8 to 5.6 lower than on normal skin)
What was found in the study with QST and mechanical allodynia?
- applied dynamic mechanical stimuli on hurt side and unaffected side: no activation of nociceptive afferents on normal side, moderate pain on hurt side.
- three types of stimuli applied: cotton wisp, cotton-tipped, brush.
- Found: you would expect the brush to be more painful than qt because higher force exerted but it’s actually less painful.
What are the two types of PHN according t the german study with QST?
- PHN I: Peripheral and central sensitization, there is sensitization
- PHN II: deafferentation of small and large fibers, loss of function because they lost so many fibers.
In the german study according what does the QST parameter allow to make decisions on ?
The treatment used for the pain patients
What are the different ways in which you can cause pain directly onto a muscle?
- inject chemicals
- apply mechanical pressure
- apply intramuscular or intraneural electrical stimuli.
- apply miscellaneous stimuli with heated isotonic saline or focused ultrasound.
What is the dermatological biomarker of pain?
-tissue damage
What are the cardiovascular biomarkers of pain?
- heart rate
- blood pressure
- heart rate variability
What are the stress-related biomarkers of pain?
- cortisol level and other hormones
- galvanic skin response
What are the neural biomarkers of pain?
- EEG
- microneurography
- IMAGING (functional. structural, chemical)
What are the chemical biomarkers of pain?
- substance P
- beta-endorphin
- cystatin C
- NERVE GROWTH FACTOR
What are the molecular biomarkers of pain?
- DNA variants
- mRNA levels
Why are people so interested in finding biomarkers of pain?
- Because the QST is still a subjective measure considering you ask people about their symptoms.
- some researchers believe it is more accurate to use biomarker instead of self-report.
What is the problem with having DNA variants as a molecular biomarker for pain?
- Your DNA is the same from birth to death
- Biomarker is helpful to see whether you are in pain RIGHT NOW, so in this case, yo can’t really know if DNA variant is a biomarker or not.
What pain biomarker are people most excited about?
FMRI
What happens on the FMRI when a patient that is presently in pain is analysed?
- more parts of their brain we’re lit up, so there was more activity in the brain
- However this was not replicated.
What leads to believe that FMRI is not actually a very accurate biomarker for pain?
- People who were in pain, were hypnotized into thinking they were in pain, or were imagining being in pain, all three had brain activity happening more or less in the same places.
- This shows that even when there is no stimuli at all, the FMRI shows some supposed pain. So is it really trustable as a biomarker for pain?
What did the use of the mouse in pain research take off in 1990?
-the finding of transgenesis
What are the advantages of working with rats instead of mice?
- alt easier to train
- they are not only preys but also predators
- makes them more relaxed and flexible
What are demand characteristics?
-People want to help experimenters so they act differently when they are experimented on.
What are things you can do with animals that you can’t do with humans?
- causation experiments
- stimulate/lesion any tissue
- assay, record form or extract any tissue
- give unapproved drugs
- alter gene expression
- turn particular types of neurons in particular locations on and off
- control pre-exposures
- cheaper, faster, less highly regulated
- no malingering, no stoicism/machism, no demand characteristics.
What are the main challenges with using animals for research?
- “wrong” species
- don’t talk
- prey
- tougher than we are
- ethical issues: the research is for our benefit and not for theirs, and they didn’t consent.
What does the school of deontological ethics believe?
-the normative ethical position that judges the morality of an action based on the action’s adherence to a rule or rules: an act that is not good morally can lead to something good.
What does the school of consequentialist ethics?
The normative ethical position holding that the consequences of one’s conduct are the ultimate basis for any judgement about the rightness of that conduct.
How do you measure spontaneous pain in a mouse or rat? observable characteristics
- ear position changes
- orbital tightening
- cheek bulging
- nose bulging
- whisker changes
Why are researchers more interested in measuring mechanical pain than heat pain now ?
-because it’s less avoidable, the rat cannot take their paw of the surface and lick it.
How does the hot-plate test work?
- Place the animal on a heated plate past their threshold. (50c)
- Eventually, they react: they lick their paw or pick it up and shake it. As soon as you see this behavior you take em of the hot plate.
- Ethically okay because they are only in pain for a second or two.
How does the tail-flick test work?
-Put animal’s tail in hot water and wait until they flick their tail out.
What is the core difference between the reaction of the animal on a hot surface and in hot water?
- hot water: core reflex
- hot plate: need to think of an action.
How long does it take for a mouse to remove it’s tail form 49c water?
Generally takes about 5 to 10 seconds, depending on the strains of mouse.
What is also called the Hargreaves’ test ?
- radiant heat paw-withdrawal test
- toe-toaster test
How does that Hargreaves’ test work?
Put animal on glass surface, and point a heat point into their paw, they will hop away.
You can use the other part of the body as a control.
How does the von Frey filaments test work?
- Use of calibrated fibers such that regardless of how much force you use, they can only apply a max amount of force when they bend.
- In animals we apply them to the hindpaws.
Why is stimuli so often applied to hindpaws in studies with rats?
They are standing on them so they are easy to aim
How does the Randall-Selitto Test work?
- Get the rats paw in between pressure device with little points.
- You wait for the rat to squeak or struggle
What are three types of mechanical assays?
- weight bearing
- grip force: we can observe what side they privilege when they limp
- gait changes
How does the Writhing test work?
- inject acetic acid, magnesium sulfate, hyper/hypotonic saline, bradykinin.
- You see how much pain they’re in by seeing how much they move their abdomen.
How does the formalin test work?
-Inject formalin into hind-paw: first 10 minutes: alot of licking and biting of hind-paw, then it goes away
How do tonic/chronic inflammatory assays work?
They inject inflammatory product, and a diff time points after that injection, they use different types of tests mentioned earlier to measure thermal hyperalgesia, allodynia….
How is inflammatory thermal hyperalgesia measured?
- inject inflammatory substance
- Do Hargreaves’ test.
How is inflammatory mechanical allodynia measured?
- inject inflammatory substance
- do von Frey filaments test
How is inflammatory cold allodynia measured?
- inject inflammatory substance
- inject acetone
- observe animals behavior
How is neuropathic studied with surgical intervention?
- To study neuropathic pain, you induce a PARTIAL injury surgically, and measure thermal hyperalgesia, mechanical allodynia, cold allodynia.
- Found: if you completely sever a nerve that will cause phantom limb pain.
What is autotomy?
autotomy: it turns out that if you cut out both sciatic and saphenous nerve, you will see very high degrees of autotomy, which is the animal start to bite off their toes.
What are the two theories on why animals do autotomy behavior after axotomy even though their not supposed to feel pain cause the nerves are cut and there is no pain information?
- there is phantom limb pain
- other reason: if there is no afferent, it probably doesn’t feel like it’s your foot, so the animal will be confused on what it is and just eat it.
What is another way than nerve severing to imitate neuropathic pain?
You can inflame the nerve and give it a number of drugs, ex: you can give the animal diabetes with streptozocin.
What is the issue with cancer treatment and neuropathy?
- Tumor drug widely used today has side effect which is neuropathy.
- If you could solve that side effect you could give higher doses to cure cancer.
What technique is used to imitate back pain, headache, and osteoarthritis?
-inflammation
What technique is used to imitate diabetic neuropathy, post-herpetic neuralgia, and fibromyalgia?
-nerve severing
Why are imitation procedure not good enough?
- Not just inflammation in osteoarthritis
- No nerves cut in actual neuropathy.
How was vulvadynia studied?
- In the studies they had noticed that these women had yeast infection.
- They took female rats, gave them yeast infection, and see if they developed vulvadynia, and they did.
What was the issue with the vulvadynia study?
- Never done again, never replicated, because experiment takes months.
- So it is a better model than imitation theoretically, but no one is ever gonna do it again.
What is the idea of the criticism about reflexive vs. conditioned measures?
- What we’re ultimately using in pain studies are reflexes. We’re using assays that produce these changes like hopping away.
- Problem is: the real problem of chronic pain patients is their actual pain, not their reflexive response to the pain.
In response to the reflexive vs conditioned measures problem, what to types of conditioning were put in place ?
- operant conditioning
- classical (pavlovian) conditioning.
What is operant conditioning?
- learned escape from pain (electric shock or heat/cold noxious stimuli)
- learned analgesic self-administration
- motivational conflict between pain vs food/water
What is classical (pavlovian) conditioning?
- conditioned place avoidance (formalin-paired chamber, chamber where allodynia is experienced)
- conditioned place preference (analgesic-paired chamber
Describe a study with motivational conflict between pain and drinking.(operant conditioning)
- substance called carrageenan is injected into rats cheek
- the only way to get their reward (sweetened water) is to endure heat on hypersensitive area
- depending on their behavior you can see if they are experiencing hyperalgesia or allodynia.
What is carrageenan?
-inflammatory substance that will produce thermal or mechanical hypersensitivity.
What is the downside of the study with motivational conflict?
-it is much more complicated and long than the most common studies.
Describe the conditioned place preference procedure.
- There is a box with 2 different sides.
- Everytime the rat goes to side a it gets an analgesic and in side b it doesn’t.
- After conditioning them you open the door between side a and b.
- You observe on which side they decide to go: if they go on analgesic side that means they were in pain.
What is the problem with pain affected measures?
When subjects are in pain they complain of other side effects, like sleep problems, anxiety, attention issues etc…
What are examples of non-rewarding analgesics?
clonidine and conotoxin
What were the findings of the conditioned place preference?
- When they had SNL (Spinal nerve ligation) they preferred the chamber that was paired with the analgesic.
- CONCLUSION: SNL hurts.
What is the ranking of chronic pain symptoms in humans? (by recurrence and how bothering they are)
1) spontaneous pain
2) mechanical hypersensitivity
3) thermal hypersensitivity
What is the prevalence of spontaneous pain in humans?
96%
What is the prevalence of mechanical hypersensitivity in humans?
64%
What is the prevalence of thermal hypersensitivity in humans?
38%
What is the prevalence of thermal hypersensitity measures in animal models?
48%
What is the prevalence of mechanical hypersensitivity measures in animal models?
42%
What is the prevalence of spontaneous pain measures in animal models?
10% (So they say)
What is the problem occurring between symptom epidemiology and dependent measure use?
The things that are measured are not at all in accordance with the symptoms that are the more recurring and bothering in humans.
What are the different factors of the mouse grimace scale?
On a scale of 0 to 2:
- orbital tightening
- nose bulge
- cheek bulge
- ear position
- whisker change
What do we use the mouse grimace scale for?
the measure of spontaneous pain in mice.
What do we believe about non mammals and pain?
We believe that non-mammals do feel pain.
