Midterms Flashcards

Question

Describe the burden of pain as depicted by Turk et al. (2011)

Answer 1

- Chronic pain affects every aspect of a patient's life, contributing to a loss of both physical and emotional function, affecting a patient's levels of activity (ability to work at home and job and engage in social and recreational pursuits) - There are also often serious economic consequences as a result of health-care bills and potential loss or decrease in financial income - Functional activities: sleep disturbance, work (might lose your job), household chores, leisure activities, energy - Social consequences: marital and family relations, intimacy, social isolation, dramatic personality change - Socioeconomic consequences: health-care costs, pay for an manage disability, lost productivity, can't contribute to the economy - Emotional functioning: irritable, angry, anxious, depressed - Sometimes people don't realize how much of a burden it is and in how many life domains it's a burden - Not only does pain hurt, but it also stops you from doing things that you would like to do and that people expect you to do

Answer 2

- Difficulty with basic actions (difficulties in 1 or more of: movement, emotional, seeing, hearing, or cognition): 1. Low back pain (51.6%) 2. Knee pain (37%) 3. Severe headache or migraine (31%) 4. Neck pain (30%) 5. Shoulder pain (17.7%) 6. Hip pain (15%) 7. Finger pain (14%) - Complex activity limitation (having limitations in 1 or more of: self-care (ex: showering, brushing teeth), social, or work): 1. Low back pain (55%) 2. Knee pain (38.6%) 3. Neck pain (34%) 4. Severe headache or migraine (33.5%) 5. Shoulder pain (21%) 6. Hip pain (18%) 7. Finger pain (16%) - These numbers are very high - Lower back appears to be the worst (if your back hurts, it's probably harder to walk around) - Knee pain and migraine/headache are also pretty high (hard to get up)

Answer 3

- WHO arranged it - Compiled from interviewing people with 1, 2 or 3 disorders - The bigger the box (more area covered by the box) the more disability it causes - Pain ones: 1) back pain, 2) headaches, 3) Other MSK, 4) Neck pain, 5) Osteoarthritis - Other MSK (muscular skeletal pain) -> not back or neck pain - Non-communicable diseases (where all the pain ones are) comprise those that cause the most disability, then communicable, maternal, neonatal, and nutritional disease, then injuries

Answer 4

- Distribution of family problems in a community sample of migraine sufferers (Smith 1998) - n = 350, f = 269, n = 81 - Asked whether pain affects the following social functions 1. Postponed housecleaning and yard-work (81%) 2. Postponed household duties (79%) 3. Postponed laundry and shopping (79%) 4. Postponed cooking (76%) 5. Postponed activities with spouse (69%) 6. Postponed activities with children (62%) 7. Negative impact on family (61%) 8. Given up parental care on children under 12 (61%) 9. Negative impact on partner relationship (25%) 10. Decline in sexual relations (24%) 11. Stayed in bed (18%) - You can see what this would do to your relationship with your spouse and your kids

Answer 5

- Findings: with the onset of severe pain, men lose their friends whereas women tend not to - Represents the solidity of female friendships in middle age that can survive things that male friendships can't

Answer 6

- % reporting moderate to very severe - N = 126 1. Difficulty sleeping (~65%) 2. Lack of energy (60%) 3. Drowsiness (40%) 4. Concentration difficulties (36%) 5. Depression (35%) 6. Anxiety (~25%) 7. Poor appetite (~18%) - Drowsiness and lack of energy could be associated with the difficulty sleeping - Comorbidities are important in pain research because if you go up to patients and ask them if they'd rather have their pain taken away or be able to sleep at night, most patients say they'd rather sleep at night - Not clear what the direction of causation is (is the problem that your pain is making it difficult to sleep? or is your lack of sleep worsening your pain? - Answer: it goes in both directions (there's almost always evidence for causation in both directions)

Answer 7

- Socio-demographic and clinical characteristics of people with and without chronic pain - Socio-demographics with chronic pain (n = 3585): - Female: 56.6% - Over 60yrs old: 32.7% - Married/de-facto: 60% - Completed school: 37.7% - Employed: 56.5% - Suicidality with chronic pain: - Thoughts: lifetime = 19.5% and past 12 months = 3% - Plan: lifetime = 6% and past 12 months = 1% - Attempt: lifetime = 5% and past 12 months = 0.7% - Seems like suicidality increases with chronic pain

Answer 8

- Suicidal thoughts/ideation - Suicidal plan (forming a plan) - Suicide attempt

Answer 9

- Includes individuals with no pain, regional pain (ex: knee pain), and widespread pain - Looks at the survival/death rates of these individuals over a 14yr period - It starts at a certain time-point with everyone being alive and every time someone dies, it goes down a notch - Over a 14yr period - 10% of individuals with no pain had died over the 14yr period - ~12.5% of individuals with regional pain had died over the 14yr period - ~18% (almost 20%) of individuals with widespread pain had died over the 14yr period - These individuals had died of cardiovascular disease or cancer

Answer 10

1) Cardiovascular disease 2) Cancer 3) Pulmonary disease - All together these encompass ~95% of all deaths in developed economies

Answer 11

- Back pain: 200 billion (this is about the same as the gross domestic product of Portugal) - Arthritis: 189 billion - Headache: 14 billion - Back pain and arthritis are incredibly expensive

Answer 12

- Pain: 625 billion - Heart disease: 300 billion - Cancer: ~250 billion - Diabetes: 190 billion - Pain cost the economy more than diabetes and heart disease combined - This represents the loss of the economy

Answer 13

- Shows the services utilized and the estimated total cost of these - Total employment-related cost of back pain = 10 668 million euros (people that would've been at work if they didn't have pain) - Total direct cost of back pain = 1632 million euros - Total NHS and community care cost = 1067 million euros - Total cost of private services = 565 million euros - Some of the money is direct cost (ex: NHS government cost) - Shows that there are big direct costs and even bigger indirect costs

Answer 14

- Someone paying out of their pocket - Either the government or the people themselves

Answer 15

1) Pain as punishment for sin - In the old testament, pain was a direct punishment for sin - Ex: the apple punishment for Eve -> from Eve eating the forbidden apple, god said women would be in pain during childbirth 2) Pain as redemption - Ex: pain as redemption for sins - Jesus on the cross 3) Pain as (personal) atonement - Ex: "No fatigue, nor disease, nor anxiety, nor sadness, nor pain, nor distress befalls a Muslim, even if it were the prick he receives from a thorn, but that Allah expiates some of his sins for that.” - Prophet Mohammed - Pain has been an important topic in the Abrahamic religions

Answer 16

The Greek Spirit of Punishment

Answer 17

- It originates from Greek god - Greek: “poine” (penalty, payment) -> Latin: “poena” (pain, punishment, penalty) -> Anglo-French: “peine” - Proto-Indo-European: “delh-" -> Latin: “doleo” (I grieve for, lament, deplore) -> Old French: “dolor”

Answer 18

Subpoena: order to appear in court (on pain of punishment if you don't show up)

Answer 19

- People have been talking about pain and pain is a topic that has been worthy of attention by the major philosophers at the time for a long time 1. Aristotle (384-322 BCE): pain is an emotion and lives in the heart - He wasn't right that pain is in the heart but was right that it's an emotion 2. Galen (130-201): pain is a sensation, in the brain - Galen was regarded as the first doctor - He was right about it being a sensation and in the brain - He wasn't completely right because he contradicted Aristotle that pain isn't an emotion but it is 3. Avicenna (980-1037): pain is an independent sensation from touch/temperature - Very influential Muslim philosopher and medical doctor - Said this in year 1000 - It was thought before him (and still thought after him by some) that pain is just a lot of touch or a lot of hot or a lot of cold and that all these 3 things could exist in non-pain forms but if you up the intensity, then they become pain - That ultimately, mechanical pain is just a lot of mechanical touch, and heat pain is just a lot of hot - This turns out not to be true and Avicenna was right - Pain is fundamentally qualitatively different from touch, hot and cold 4. Descartes (1596-1650): there exists a “pain pathway" from the body to the brain - In the year 1600 - The first to talk about there being a pain pathway that goes from the body to the brain (this is true) - Partially right and partially wrong

Answer 20

- The “vindication of God” - The answer to the question of why a good God permits the manifestation of evil - How could a benevolent god allow babies to be in pain, as they surely haven't sinned yet - God lets pain happen to people who don't deserve it - Religious scholars have been debating this for a long time

Answer 21

- Utilitarianism is one of the major branches of philosophy and its philosophical position is that the right thing to do is the thing that brings the most cost-benefit calculation - AKA the thing that produces the most good is the thing you should do - Cost-benefit: pain vs pleasure - Every action should maximize pleasure and minimize pain - Principle of Utility (Jeremy Bentham - 1748-1832) 1. Recognizes the fundamental role of pain and pleasure in human life 2. Approves or disapproves of an action on the basis of the amount of pain or pleasure brought about ("consequences") 3. Equates the good with the pleasurable and evil with pain 4. Asserts that pleasure and pain are capable of "quantification" - and hence of measure

Answer 22

- Mind-body problem: how is it possible that the body can produce the mind? Are they the same or are they different? - Descartes was a dualist and felt very strongly that there was the body and then there was the mind (the soul) and the soul lived in the body as long as you were alive and then when you died, it left the body - The opposite of a dualist is a monist - Monist position is that the mind is a secretion of the brain (the mind is what the brain does) - The fact that we feel that it's a different thing is just an epiphenomenon and that's an illusion and the mind is just the workings of our brain, which means the mind is the brain - This has been a problem in philosophy for a long time - “Phantom sensation the best possible proof of the existence of the eternal soul. If an arm can survive physical destruction, why not the whole person?” - Admiral Lord Nelson (died Battle of Trafalgar, 1805) - He is talking about phantom limb pain - What he's saying is if you can take away the arm and still feel the arm, then you can take away the person and still feel the soul

Answer 23

You can have your arm chopped off and will still feel like you have an arm in space and it will hurt and when someone asks you where it hurts, you point to the empty space

Answer 24

- Situation where you have 2 problems at the same time - 2 disease states/conditions co-occur more than would be statistically predicted

Answer 25

* Biggest philosophical problem * I know that I have a mind, but I can't be sure others have a mind * No way to prove to others that we exist * When philosophers talk about this problem, they bring up pain * Our most common use of pain measure is to ask people what amount of pain they're feeling

Answer 26

- "The fundamental interest that entitles a being to equal consideration is the capacity for suffering and/or enjoyment or happiness." * Peter Singer is an important philosopher * He's a utilitarian and he thinks the use of animals is ok as long as the benefits outweigh the costs * Suffering is pain * He believes animals should have rights, proportional to their ability to feel pleasure or pain * Knowing if they feel pain or pleasure is thus important

Answer 27

- Declaration that Access to Pain Management Is a Fundamental Human Right - We, as delegates to the International Pain Summit (IPS) of the International Association for the Study of Pain (IASP) [...] have given in-depth attention to the unrelieved pain in the world… - And, recognizing the intrinsic dignity of all persons and that withholding of pain treatment is profoundly wrong, leading to unnecessary suffering which is harmful; we declare that the following human rights must be recognized throughout the world: - Article 1: The right of all people to have access to pain management without discrimination - Article 2: The right of people in pain to acknowledgment of their pain and to be informed about how it can be assessed and managed - Article 3: The right of all people with pain to have access to appropriate assessment and treatment of the pain by adequately trained health care professionals - This declaration has no force -> it's just a statement of the way the world should be - In some parts of the world, they have none of these - In some ways this was to encourage other governments to take this seriously

Answer 28

- Lau et al. (2022) - Opioid analgesic consumption per 1000 inhabitants per day - Top 3: 1. Canada 2. Switzerland 3. Germany - Bottom 3: - Egypt - Venezuela - West Africa - For countries that don't have any opioid consumption, if you fracture your leg or go in labour, you're unlikely to get morphine or an epidural - The WHO doesn't consider it a human right

Answer 29

- Pain is all over art - Ex: Frida Kahlo - When she was young, she got seriously injured by a bus and was in chronic pain - She did a number of paintings to illustrate how she felt - Ex: "The Broken Column" - She writes about this as well

Answer 30

- Pain has important legal repercussions - Ex: whiplash - Real and painful injury but there's no way of proving the pain - If you're in pain and you sue the driver of the car that you hit, and they fine for you, you're eligible for damages for pain and suffering - So important to figure out if that person's in pain and if so how much pain because at some point a judge or a jury has to turn that into a dollar amount - Judges dealing with civil court law are very interested in whether we can measure pain - Ex: injuring yourself on the job - Eligible for worker's compensation - Get paid to stay home - Some people would rather get paid for staying home - So it's important to figure out if they're still in pain - At some point, some judge or panel is going to have to determine it - This person will either get ordered back to work or they're going to continue to get money for staying home - Ex: Oxycontin pills - Doctors can get in trouble with the law if they prescribe too much oxycontin - Major issues about pain measurement for legal issues

Answer 31

- An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage - IASP Subcommittee on Taxonomy at the National Pain Meeting in 1979

Answer 32

* Masochists find pain pleasant * Current most accepted hypothesis about masochism: masochists find pain unpleasant but for whatever reason, having pain inflicted on them is the only way they can achieve sexual satisfaction and they're willing to make the trade * If this is true, then pain isn't pleasant to masochists * Studies show that masochists find pain pleasant if it's in a BDSM context but they don't find it pleasant if it's in a neutral context * Prof is doing a study on masochism and gave 800 people a masochism questionnaire and asked them "if you could have the same amount of sexual satisfaction without the pain, is that a trade you would like to make?" * 65% of masochists say no, they like the pain for it's own sake * Maybe the definition is wrong in some proportion of people * For most (who aren't masochists) pain is unpleasant

Answer 33

1) DOMS: delayed-onset-muscle-soreness - Pain you feel the day after exercise - When you feel pain, then you feel like you're getting gains 2) Spicy food 3) Tattoos and piercings - Pain now but pleasure later 4) NSSI behaviours - Ex: cutting - People who feel that they don't have a lot of control in their life - They can control when it starts or stops

Answer 34

- Yes, potential tissue damage is painful - The pain starts before a knife goes through the skin when staring at a knife slowly getting close to cutting you - This comes from evolutionary adaption

Answer 35

* Adequate stimuli: things out in the world that are processed by the nervous system and end up causing some perception * Some things in the world we respond to and some we don't (ex: UV is not an adequate stimulus for vision in humans) * Adequate stimulus for pain: 1) Pungent natural compounds: capsaicin, garlic 2) Noxious cold temperature 3) Noxious hot temperature 4) Environmental irritants (things in smoke if they get in your eye can cause your eye to hurt) 5) Noxious mechanical stimuli (ex: hammer) 6) Inflammatory peptides (something in your body (maybe due to an injury) is causing inflammation and the inflammation is releasing stuff and those chemicals released with inflammation can cause pain) 7) Knife breaking skin means cells have been ruptured (what a wound is) - When cells are ruptured, they release their insides and there's a whole bunch of chemicals there that could be responsible for pain 8) Waking up from surgery - Surgeon has cut through your skin and your muscle wall to get access to your insides which means your cells have been ruptured - Pain from inflammation of wound due to tissue damage - Stitches are further tissue damage - Tissue damage + inflammation

Answer 36

* Sometimes people don't have actual or potential tissue damage * Often they did and there was an injury but it has now healed so there's no current tissue damage or potential tissue damage but they still feel pain * They describe their pain as if there was actual tissue damage * Needed to be a phrase to account for the common situation of someone complaining of pain but there not being tissue damage * Problem: the verb to describe implies verbal description * If you take this definition literally, it would suggest that if you can't describe it, you can't have pain * Excludes animals, babies and people that are mute from the ability to feel pain

Answer 37

- In 2018/2019, a new pain committee was made - Mogil's definition won (this is his) - Raja et al. (2020) - An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage - The problem with the previous definition was the word describe so they just changed this word - This takes the emphasis off the person to describe their pain

Answer 38

1) Pain is not somatosensation (AKA touch) - Anesthesia vs analgesia - Pain is a sensation of its own and isn't touch - Because pain isn't touch, anesthesia isn't analgesia - Anesthesia makes you not feel touch, temperature (hot and cold) 2) Physical pain is not the same as emotional pain - There has been evidence for correlation between the 2 but these studies may not be true due to lack of replication 3) Pain does not mean suffering - Ex: Pain asymbolia 4) Pain does not mean disability - Pain can cause disability but it doesn't always cause disability 5) Pain vs pain behaviour - Pain sometimes leads to pain behaviour - Sometimes people when they're in pain, they moan and guard the limb and they wince and complain - And sometimes they don't 6) Pain is not nociception - Nociception is the operation of the circuitry that ends up resulting in the perception of pain - Everything going on behind the scenes in the brain and the nervous system - Pain is the conscious perception of what nociception eventually produces

Answer 39

- The inability to feel pain - The absence of pain - Analgesic: drug that causes a lessening of pain

Answer 40

- 3 studies that used a trick to produce social rejection (cyberball) - Cyberball is a computer game of 3 people throwing a ball and you’re told that you're throwing the ball with 2 other people but it's actually a computer - They eventually stop passing the ball to you and this causes people to feel social rejection - One of these studies found that this social rejection can cause inflammation - Another one of these studies found that social suffering activates the brain’s “pain matrix” (has been replicated) - Another study found that if you give someone acetaminophen, it can work both on physical pain and emotional pain from playing cyberball as it was shown to reduce social pain

Answer 41

- Some people after having a stroke have lost the ability to feel the affective component of pain - They feel pain but tell you about it with a smile on their face

Answer 42

- Cells: no, maybe they have nociception? Maybe individual cells aren't enough to even have that although they might participate in nociception - Spinal cord: there's nociception going on in the spinal cord, the spinal cord is the absolute nexus of it all, probably doesn't have anything to do with pain - Primary sensory cortex: maybe - Any part of the cortex: maybe, most people that study conscious perceptions believe that perceptions arise as part of a loop of activity between cortical areas and if that's true, then any individual cortical area can have the perception of pain, the perception is in the looping around of the information - Mice: yes - Worms: maybe - Babies: until the 80s, people didn't think babies have pain, they do

Answer 43

* You set up a series of interlaced bars * They can have water going through them * Every odd numbered bar has cool water going through * Every even numbered bar has warm water going through * The water isn't cold or hot just cool or warm (if you put your finger through the bars, you feel cool or warm water) * If you put your whole hand on the grill, people feel a burning cold sensation and can't keep their hand on the grill because it's extremely painful * There's pain but there's no nociception going on here * There's no noxious stimulus there * Nothing's in the painfully hot or cold range * The brain is constructing the pain stimulus/perception even thought there's no actual noxious stimulus * The usual processing of nociception (coming up from the body to the brain) doesn't occur because there's no noxious stimulus to process * Pain vs nociception

Answer 44

- 1979 - AKA Fordyce rainbow - He was one of the early and most influential pain psychologists - Nociception is in the middle which produces the perception of pain (bigger than nociception) - Pain can lead to concept of suffering (bigger than pain) - Universe of behaviours that humans/animals may or may not engage in to show that they're suffering (bigger than suffering)

Answer 45

- Pain that lasts seconds-to-minutes - Body's way of telling you that you're experiencing actual or potential tissue damage and making it stop - Making it stop by jerking hand away - Either avoiding tissue injury or minimizing tissue injury - To teach you to not do this action again: - Pain is the way we learn our physical limitations - We learn what our body can do - Generally is a one-trial learning - Learning what not to do in the future

Answer 46

- Pain that lasts hours-to-weeks - Pain is there to punish movement - If you broke a limb before the days of casting and pins and surgeons, the only way that the injury will stay in place, heal and not get infected, is to not move for a while - Pain is there to punish you for moving before your injury is healed - This is why animals can survive fractures

Answer 47

- Pain that lasts weeks-to-years - It has no evolutionary advantage - It's a pathology - This is what makes something a pathology -> it's not supposed to be there - Analogy: like having a fire alarm stuck on the on position and keeps on going despite there not being any fire anymore

Answer 48

- Carnival performer who had Congenital insensitivity to Pain (CIP) with anhidrosis (inability to sweat) - AKA hereditary sensory neuropathy Type IV - Could put numerous pins on his face without feeling pain

Answer 49

- Sustain numerous injuries without awareness of them - Biggest problem for these people is shifting your weight when sitting for too long - When sitting, you're exerting weight on your spine, which can lead to fracturing your hip and can cause infection if not treated - People with CIP rarely live past their 50s

Answer 50

* There's always some evidence suggesting that different things are the same thing * If you have evidence like that, you would want to lump them together and study this one thing instead of studying multiple things * However, there's always evidence that things are different from each other, so they should be split into different categories * If they really are different things and you lump them together, you'll never figure out anything because you put things together that don't belong together * However, the problem with splitting is that you now have multiple things to explain rather than one thing to explain * There's always a desire to lump as much as you can but evidence forces you to split * Lumpers look for commonalities between things * Splitters look for differences between things

Answer 51

- There are any number of ways for which you can split pain - You can split pain by duration (acute vs tonic vs chronic pain) - You can split pain by etiology (types of pain) - You can split pain by location - You can split pain by symptoms

Answer 52

- Definition of what chronic pain is is completely arbitrary - Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset - The 2 most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and researchers have placed the transition from acute to chronic pain at 12 months - Others apply acute to pain that lasts less than 30 days, chronic to pain of more than 6 months duration, and subacute to pain that lasts from 1-6 months - A popular alternative definition of chronic pain, involving no arbitrarily fixed durations is "pain that extends beyond the expected period of healing" - “acute-to-chronic pain transitioning”

Answer 53

The idea that first you have acute pain and then something happens to turn it into chronic pain

Answer 54

- Splitting pain into either acute pain or chronic pain - Acute pain = injury, post-operative flare - Chronic pain further split into nociceptive, neuropathic, visceral, and mixed pain - Nociceptive pain = Osteoarthritis (16mil) and Rheumatoid arthritis (2.5mil) - Neuropathic pain is further split into central and peripheral pain - Central pain = post-stroke, multiple sclerosis, spinal cord injury, migraine (31mil), and HIV related neuropathic pain (0.3mil) - Peripheral pain = Post-herpetic neuralgia (0.11mil) and diabetic neuropathy (3.2mil) - Visceral pain = internal organ, pancreatitis, IBS - Mixed pain = lower back (55mil), cancer (1.5mil), and fibromyalgia (6mil) - Evidence for and against these splits - US prevalence numbers (shows which are more prevalent than others) - Most to least = lower back, migraine, osteoarthritis, fibromyalgia, diabetic neuropathy, rheumatoid arthritis, cancer, HIV related neuropathic pain, post-herpetic neuralgia

Answer 55

- Costigan et al. (2009) - Pain is split into 4 categories: nociceptive pain, inflammatory pain, dysfunctional pain, and neuropathic pain 1) Nociceptive pain: - No nervous system lesion or inflammation - Stimulus-dependent pain (evoked by high-intensity (only noxious) stimuli) 2) Inflammatory pain - Active inflammation - Spontaneous and stimulus-dependent pain (sensory amplification - evoked by low and high-intensity stimuli) 3) Dysfunctional pain - AKA idiopathic (meaning we don't know), functional, nociplastic, primary pain - No known structural nervous system lesion or disease or active peripheral inflammation that we can find but people are still in pain - Spontaneous and stimulus-dependent pain (sensory amplification - evoked by low and high-intensity stimuli - present with lack of stimulus) 4) Neuropathic pain - Nervous system lesion or disease - Marked neuroimmune response - Spontaneous and stimulus-dependent pain (sensory amplification - evoked by low and high-intensity stimuli) - Costigan believes neuropathic pain has the longest lasting pain

Answer 56

1) Superficial pain (skin pain) - If someone asks where your pain is, you can point right to it 2) Deep pain (muscle, joint, bone) 3) Visceral pain (poorly localized and “referred”) - Viscera = organs on the inside (generally organs under the diaphragm) - Poorly localized: if you have a stomach ache, you can't point to the pain so you just show general area 4) Neuropathic pain - Feels like it's in your skin but has nothing to do with your skin - The pain is in your nerves or maybe in your brain 5) Phantom limb pain - Patients will say that the location of the pain is in empty space where their missing limb used to be - Especially for visceral pain vs skin pain and deep pain vs skin pain, there are a lot of data suggesting that these are different

Answer 57

1) Spontaneous pain - Continuous, paroxysmal (episodes of pain - not always there) - What most of us mean when we talk about pain 2) Evoked pain (AKA pain hypersensitivity) - Allodynia (heat, cold, mechanical, vibration) - Hyperalgesia (heat, cold, mechanical, vibration) - Static (ex: poke) vs dynamic (ex: brush) -> these can be distinguished from each other (there's probably different biologies producing static mechanical allodynia vs dynamic mechanical allodynia) - Activity-evoked (if you have knee OA, at the beginning of the day you may not feel pain in your knee but at the end of the day you have pain due to walking a lot) 3) Paresthesia/dysesthesia - Paresthesia: - Strange sensation - Funny tingly sensation - Isn't pain - Not supposed to be there - Ex: licking a battery or stomach going up to your head on a roller coaster or chills - Dysesthesia: - When you don't like the sensation - Ex: hitting your funny bone 4) Numbness - Lacking sensation - Don't feel anything - Very common in clinical pain - Doesn't receive lots of attention - Often people who have chronic pain will have chronic pain in the same area of their body that's numb -> numbness and pain can happen in the same place at the same time 5) Paradoxical thermal sensations - When something that's supposed to be warm is perceived as cold or something that's supposed to be cold is perceived as warm - This happens a fair amount to chronic pain patients 6) Aftersensations - Sensations that last too long - Ex: bumping your leg on a table and the pain isn't going away after a few seconds and instead lasting about an hour

Answer 58

Allodynia and hyperalgesia

Answer 59

Situation where a previously non-noxious stimulus is now noxious

Answer 60

- Ex: someone gets a bad sunburn - Typically sunburns don't show a lot of spontaneous pain - Unless you poke them on their sunburn - This poke is normally a non-noxious stimulus, but in this context it is now noxious - They probably have mechanical allodynia and thermal/heat allodynia (because if they take a shower at their usual warm temperature, they will experience pain due to sunburn) - Hyperalgesia: if someone slaps them on their sunburn - A slap is noxious but becomes even more painful on a sunburn

Answer 61

* Sign: something that's observed by the clinician through a test * Symptom: something reported by the patient

Answer 62

- 50 low back pain patients - Highest frequency in Interview: 1) Deep pain 2) Ongoing pain 3) Activity-evoked pain & evoked pain (general) 4) Aftersensations & cold-evoked pain 5) Pressure-evoked pain - Highest frequency for quality of dysesthesia: 1) Numb skin areas 2) Tingling 3) Itching - Highest frequency during physical examination: increased pressure sensitivity of deep tissues - There are a lot of symptoms and they have greatly different frequencies - Pre-clinical researchers spend a lot of time researching very rare symptoms and don't spend enough of their time studying the common symptoms

Answer 63

* There are few studies in pain research done on anything other than mice or rats * Squid are predated by bass (bass eat squid) * They had a tank of squid and let in one bass and would wait 30 mins * After 30 mins they checked how many more squid were left * Squid don't have any protection * 4 conditions: * Control condition -> U: uninjured * Normal intact squid * 80% survived in this condition * When waited 30 mins, 4 squid were dead * Control condition: UA: uninjured + anesthetic (put anesthetic in the water) * It didn't make a difference * 75-80% survived * Then took all the squid and cut off one of their legs (injured squid who is presumably in pain (chronic pain because the injury occurred many days before the test)) -> I: injured * Injured squid are less likely to escape and more likely to be eaten while they're injured * Impairs the ability of the squid to swim and get away and probably attracts the bass * Over 50% of them are dead after 30 mins * If you put anesthetic in the water which means they're still injured but they presumably are not in pain -> IA: injured + anesthetic * Now even more of them get eaten * Benefit of nociceptive sensitization/chronic pain * Chronic pain is a benefit to the survival of the squid * The potential evolutionary advantage of chronic pain and the hypersensitivity that's produced by chronic pain is that it reminds you that you're injured and makes you hypervigilant to predation * This is also true in mice (mammals) * Chronic pain leads to hypervigilance to predation * Maybe that's why it's there * You know you're injured and know that you should maybe opt for safety rather than do something you would do if you weren't injured * Humans can be hypervigilant, especially with social stimuli * This has been shown with chronic pain patients * Chronic pain patients are hyper vigilant which leads to anxiety and depression which is greatly comorbid with pain * Does chronic pain have an evolutionary function? * Maybe (only 2 studies on this)

Answer 64

Sensation: * There are things that mitigate against pain being a sensation: * Ex: Stimulus-response mismatch (the intensity of the stimulus doesn't predict the pain levels in any reasonable way -> ex: osteoarthritis or back hernia) * If it was a sensation, then that correlation would be much higher * For most sensations, the correlation between the actual physical stimulus and the perceptual response is really good (ex: in vision, there's a very strong correlation with the amount of photons coming in your eye and how bright you think that is) * For pain, the correlation is very bad * Other ex: habituation (phenomenon whereby repeated or continuous exposure to a stimulus, decreases the subjective strength of the perception) * Ex: the more you listen to a sound, the softer that sound appears to be, even though it's actually not getting softer * Your brain has decided that there's no new info there so there's no point in paying attention to that sound anymore * All sensations habituate except for pain * Pain does the opposite: the longer you experience pain or the more repetitions that you experience of pain, the higher the subjective perception gets (the more pain you will feel) -> sensitization to pain * This is the only sensation that does this Emotion: * A lot of evidence suggesting that pain is processed in the parts of the brain that are concerned with processing the other emotions * There's a lot of evidence that pain is indeed every bit an emotion as it is a sensation Drive state: * Pat Wall came up with concept that pain is a drive state (something that demands an action to try to restore homeostasis) * Ex: thirst, hunger, sleep, bladder fullness, sex drive? * The longer you haven't eaten, the more your body will make you want to eat so it can restore your homeostasis of energy supply * The strength of homeostatic emotion depends on your physiology and your metabolism * Pain is all of these things

Answer 65

Situation where a previously noxious stimulus is now more noxious

Answer 66

* Although allodynia and hyperalgesia sound different, they're actually the same thing * What's responsible for both is simply a stimulus intensity curve shifting over to the left * Normal situation: heat stimulus going from warm to hot * In every case, at low stimulus intensities there will be no pain * At some point, you will reach the person's pain threshold and they will start to report pain and as you increase the stimulus they'll report more and more pain until you get to the maximum amount possible (ex: 10) * This is a sigmoid curve (like most of these psychophysical functions are) * After injury (inflammation or nerve damage), the curve simply shifts to the left * Now at much lower stimulus intensities, what used to get a rating of 0 doesn't get a rating of 0 (allodynia) * Now, what used to get a rating of 4 is now getting a rating of 8 (hyperalgesia) * Different words depending on what the stimulus would've done, but ultimately the same thing

Answer 67

* Descartes was the first person to come up with the concept of pain pathways * He made an illustration of a man whose foot is touching fire and his pain pathways * Depicted the fire, the nerve terminal in the foot, the nerve and the brain - “If for example fire comes near the foot, minute particles of this fire, which you know move at great velocity, have the power to set in motion the spot of skin on the foot which they touch, and by this means pulling on the delicate thread which is attached to the spot of the skin, they open up at the same instant the pore against which the delicate thread ends, just as by pulling on one end of a rope makes to strike at the same instant a bell which hangs at the end." - Rene Descartes (1644) * This is not the way it works * No threads being pulled by the fire * But he was correct that there's a pathway going from the foot to the brain

Answer 68

1) Skin/muscle/joint/viscera (“periphery”) - Pain starts in the periphery (things outside of the nervous system) - Info is sent from the periphery to the spinal cord 2) Dorsal root ganglion (DRG) - The cell bodies of the first neurons are located in the DRG 3) Dorsal horn of the spinal cord 4) Brain

Answer 69

1) Thalamus 2) Somatosensory cortex (where sensory info ends up) 3) Limbic cortex (name for a bunch of cortical regions involved in emotional processing) 4) Prefrontal cortex (involved in planning) - Evidence is accumulating that especially for chronic pain, the PFC is involved

Answer 70

1) Hypothalamus 2) Midbrain 3) Brainstem 4) Spinal cord

Answer 71

The spinal cord

Answer 72

- Skin - Joint - Viscera - Muscle

Answer 73

- Means towards the back - Dorsal part of nervous system deals with sensory info and ventral part of nervous system deals with motor functions

Answer 74

- The info going down is modulating info going up - Stress-induced analgesia: sometimes the brain doesn't want to know about it

Answer 75

- Pain actually doesn't go up, information goes up and also goes back down - The place where it comes up from and goes back down to is the spinal chord - Things ascend and descend - This is a sensory experience

Answer 76

1) Trauma 2) Activation of the peripheral nervous system 3) Transmission 3) Activation of CNS at spinal cord 4) Input 5) Transmission of the pain signal to the brain 6) Pain

Answer 77

1) Pain 2) Transmission of the pain signal to the brain 3) Modulation 4) Activation of CNS at spinal cord

Answer 78

1) Glabrous skin: palm of your hands and soles of your feet - Comprised of Meissner's corpuscle (touch), Pacinian corpuscle (vibration), Krause's end bulb, Merkel's disc, free nerve endings 2) Hairy skin: everywhere else (regardless of how much hair you have, you have hair follicles) - Comprised of Ruffini terminals (stretch), Pacinian corpuscle (vibration), Merkel's disc (touch), free nerve endings

Answer 79

- Found in glabrous and hairy skin - The simple free nerve ending is the most important for pain - Free nerve endings are the ones responsive to pain/noxious stimulus

Answer 80

Nociceptors are unipolar neurons

Answer 81

* Neurons that are responsive to noxious/painful stimuli * Free nerve endings are one end of nociceptors * Unipolar neurons

Answer 82

- Multipolar neurons - Bipolar neurons - Unipolar neurons

Answer 83

- Multipolar neurons have many dendrites and one axon - They're found as motor and interneurons - The cell body and its dendrites are on one side and then the axon is attached and goes toward the other side - 99% of neurons in the body are multipolar neurons

Answer 84

- Bipolar neurons have one dendrite on one end and one axon on the other end and both attached to the cell body which is in the middle - These are rare and found only in ears and eyes

Answer 85

- Unipolar neurons have one process from the cell body, an axon - It branches to connect to receptors and the spinal cord or brain - They are most of the body's sensory neurons - The dendrites are found at the receptor and the axon leads to the spinal cord and brain - The cell body isn't in the middle, it's off to one side, then has axon going one way and axon going another way - The dendrites are the free nerve endings and the axon terminals are in the spinal chord - The cell body is in the DRG

Answer 86

- Neurons are very long - Longest cells in your body - Cell from tip of toe to your spinal chord can be very long - The entire cell is controlled by the cell body and that makes them incredibly fragile - Very easy to damage them - A lot of pain comes from when these neurons are damaged

Answer 87

1) A-alpha afferent fibers - Diameter: 13-20 micrometers - Speed: 80-120 m/s (much faster than others, when putting water through a pipe, the bigger the pipe, the faster the water goes through) - Function: proprioception (muscle control - how you know where your limbs are in space) 2) A-beta afferent fibers - Diameter: 6-12 micrometers - Speed: 35-75 m/s - Functions: touch and vibration 3) A-delta afferent fibers - Diameter: 1-5 micrometers - Speed: 5-35 m/s - Functions: thermal (temperature) and pain 4) C afferent fibers - Diameter: 0.2-1.5 micrometers - Speed: 0.5-2 m/s (much more slow) - Don't have myelin (insulation) - Functions: pain and sweating

Answer 88

* Means going up towards the brain * Sensory fibers also known as afferent fibers

Answer 89

* Efferent means moving away from the brain * Going from the brain to muscles * Deal with motor controls

Answer 90

A fibers are myelinated and C fibers aren't

Answer 91

- Ex: when you stub your toe - Pain comes in 2 waves - 1st wave: immediate pain that's sharp (more intense) - A-delta is responsible for this pain - 2nd wave: later pain that comes in 1-2 secs after and is more dull (less intense) - C fiber is responsible for this pain (slow to get info up to spinal cord -> explains the delay) - Although A-deltas and Cs both produce pain, A-deltas produce sharp pain and Cs produce dull pain

Answer 92

- A bundle of neurons going into the same direction - A bundle of axons - Comprised of axons, perineurium, endoneurium - Surrounded by epineurial blood vessel - Endoneurium: filler tissue between each individual axon - Nerve cell is synonym for neuron - Peripheral nerves = peripheral nervous system - Brain and spinal chord = central nervous system

Answer 93

* The spinal cord sends out spinal nerves * 4 sections: 1) Cervical (8 spinal nerves) 2) Thoracic (12 spinal nerves) 3) Lumbar 4) Sacral * Very important and fragile and not very big * Has to be protected * Protected by vertebrae * Needs to be a way to send nerves in and out * Individual vertebrae bones that have spaces through them * The spinal nerves go through these spaces between the vertebrae * Close to the spinal chord (medially), it's broken into 2 (dorsal root and ventral root) * Dorsal root has a bulge -> dorsal root ganglion (collection of cell bodies in the root) * Ventral root and dorsal root merge and become the spinal nerve * The spinal chord has meninges (dura mater on outside, pia mater on inside and arachnoid in the middle) * Mixed spinal nerve (motor and sensory fibers) * Spinal chord has gray stuff (gray matter) surrounded by white stuff (white matter) * Gray stuff has posterior and anterior horns * Sensory (afferent) info comes into the spinal chord from the dorsal part of the spinal chord (dorsal horn) * Motor (efferent) info leaves the spinal chord from the ventral part of the spinal chord (ventral horn)

Answer 94

- Parts of the body that are served by each spinal nerve - Front of head not served by a spinal nerve but instead served by something different - Ex: if touched in middle of chest -> you'll feel this due to T5 spinal nerve

Answer 95

- Condition where you get a rash and that rash is confined to one dermatome - It's extremely painful

Answer 96

1) Animals - Dorsal: to the back - Ventral: to the stomach - Rostral: to the head - Caudal: to the tail 2) Humans - Dorsal: top (brain) and back (spinal cord) - Ventral: bottom (brain) and front (spinal cord) - Rostral: towards the PFC - Caudal: towards the back of brain

Answer 97

- Ipsilateral: on the same side as… the noxious stimulus or injury - Contralateral: on the opposite side as… the noxious stimulus or injury

Answer 98

- Superior (above) - Inferior (below) - Anterior (in front of, toward the front) - Posterior (behind, toward the back)

Answer 99

Collection of cell bodies

Answer 100

* White matter: axons (nerve fibers travelling somewhere) that are myelinated (why it's white) * Gray matter is gray because that's the colour of neurons

Answer 101

- Both found in grey matter - Big neurons in the ventral horn - There are different laminae in the horns - Some have stated that neurons in different layers look different from each other

Answer 102

* There are different laminae in the dorsal and ventral horns * 1-6 laminae in dorsal horn * 7-10 laminae in the ventral horn * What's outside of laminae 1 is the dorsolateral fasciculus * Axons are going in and these are the sensory afferents coming into the spinal chord * Cell bodies start at laminae 1 * Laminae 1 & 2 are called substantia gelatinosa

Answer 103

* Nociceptor/sensory afferent neurons * AKA primary afferent because it's the first thing to fire * Primary afferents fire to some energy in the environment (heat, cold, touch, vibration, pain) * They send the info, pass through the dorsal root ganglion and enter in the dorsolateral fasciculus and then go to lamineas 1 & 2 (gelatinosis) and then they do 1 of 2 things: * They either synapse on what are known as 2nd order neurons (2nd neurons to fire - a spinal cord neuron) that get activated by a primary afferent neuron and cross the midline and go up to the higher levels of the brain (brain stem and thalamus) * Or it synapses on 2nd order neurons that never leave the spinal cord at all but instead project to deeper layers of the spinal cord (layers 5 & 6 - largely 5) and then there's a 3rd order neuron that crosses over and goes up to higher levels of the brain (brain stem and thalamus) * Eventually the info has to cross over to go up to the brain * This is the processing going on before the info is sent up

Answer 104

- Because the brain is built that way, everything crosses sides - Info from the right side of body goes to left side of brain and vice versa

Answer 105

- Peptidergic C fibers terminate in lamina 1 (large projection neurons) and outer lamina 2 (interneurons) - A-delta myelinated fibers terminate in laminae 1 and 5 - Nonpeptidergic C fibers terminate in inner lamina 2 (interneurons) - A-beta myelinated fibers terminate in PKCy+ neurons and lamina 5 - Splitting - the more splits we can make, maybe we can link up one type of population to one type of pain and another type of population to another type of pain

Answer 106

- Peptidergic C fibers (C fiber that contains its own peptide neurotransmitter) - A-delta myelinated fibers - Nonpeptidergic C fibers - A-beta myelinated fibers

Answer 107

Small protein

Answer 108

- “Peptidergic” (CGRP+) and IB4+ - For decades, this was the major distinction that people were making

Answer 109

* Defined by single-cell RNA-sequencing (gene expression) of DRG cells followed by principal components analysis (PCA; clustering) * AI found that there are 4 major groups: 1) NF = neurofilament heavy chain (Nefh)-expressing 2) NP = non-peptidergic 3) PEP = peptidergic 4) TH = tyrosine hydrolase-expressing * Then there were further splits that were made * Group came to the conclusion that the number of different categories is 11 * We thought there were 2 types of nociceptors but actually there are lots of types * Single-cell RNA-sequencing is a relatively new technique * We used to do this one molecule at a time * Now we can do it by looking at all the genes at the same time

Answer 110

* Neurogenic inflammation * When you activate a nociceptor, in addition of an action potential taking info into the spinal cord, there's also an axon reflex which ends up activating the other nerve terminals * What happens when the action potential turns the corner is that it causes the release of whatever neurons are in the nerve terminals * In the peptidergic nerve terminals, they release peptides (CGRP and Substance P) * These cause vasodilation/arteriole dilation, which makes your blood vessels leaky (the pores get bigger and stuff comes out) * One thing that comes out is plasma (the fluid that red and white blood cells swim in in the arteries) which causes inflammation/swelling and will also cause the infiltration of immune cells * If these immune cells start rushing in, this will also cause inflammation * Neurogenic inflammation: inflammation caused not by the injury but by the nervous system itself (by the nociceptors firing)

Answer 111

To send pain signals to the brain

Answer 112

Through a spinal reflex

Answer 113

* The nociceptor fires and then it goes into the spinal cord directly so it can direct your muscles to jerk your limb away from the noxious stimulus * Nothing has to go up to the brain or come down from the brain, everything goes into the spinal cord * Whatever part of the body the noxious stimulus arrived from is the part of the body that will jerk the body away

Answer 114

- Unknown - Potentially if the stimulus is acute and intense enough but not sure

Answer 115

* After the stimulus switches sides, it gets into the white matter and has to go up because that's where perception will occur * There are 2 routes to go up: dorsal column and antero-lateral column * Info goes up both ways * Dorsal column: located next to the dorsal horn in the inner part of the spinal cord * Antero: from anterior, similar to ventral -> located below ventral horn * This is one of the reasons why the original conception of surgical pain didn't work * Targeting both would involve interrupting major parts of the spinal chord

Answer 116

- Tracts are named based on where they start and end 1) Spinothalamic Tract - Tract from the spinal cord to the thalamus - Major touch pathway 2) Spinoreticular Tract - Pain has all kinds of effects on autonomic function and this is what this tract does - Reticulum: part of the brain and brain stem that's sort of diffuse and represents the whole central - Involved in basic housekeeping functions (breathing rate, heart rate, sleep-wake cycles) 3) Spinoparabrachial Tract - Tract that ends up in the limbic system - Parabrachial is in the pons - Emotional aspect of pain travels

Answer 117

White matter all travelling from the same place to the same place

Answer 118

- Above the neck: because all the nerves in the face are connected to each other and we have harder access to them - If you want to study pain on an animal, you have to inflict pain on an animal and it's harder to do this on the face than one the foot (can just use a heat grid) - We hence don't study pain in the face and head nearly as much - Viscera: it's harder to study the colon and the bladder than it is to study the foot

Answer 119

* Above the neck, there are trigeminal nerves * Trigeminal nerves are made up of 3 divisions: ophthalmic (V1), maxillary (V2) and mandibular (V3) * They have a trigeminal ganglion * The nerves that come from V1, V2, V3 are A deltas and Cs just like the spinal system * They end up not in the spinal cord but in the trigeminal spinal tract * This is connected into the spinal cord * The spinal cord grows into this * Different anatomy from spinal cord but same concept * Ascending pathways arise from spinal tract nucleus to reach the thalamus and cerebral cortex

Answer 120

* Visceral pain is complicated and is coming from all sorts of different places that are different from each other * It ultimately gets into the spinal cord through different nerves and ganglion * The organs have their own ganglia * Some of these are close to the organ itself and some are close to the spinal cord but not the dorsal ganglion * Some of it goes through the vagus nerve and into the brain directly and bypasses the spinal chord entirely

Answer 121

- Somatic = skin - When the info gets into the spinal cord, for somatic pain, it gets there very discretely - Just seeing where the C fiber axons go (pretty discrete) - Termination pattern of visceral neuron is completely diffuse and all over the place - This is why you can't localize visceral pain - You know it's in your abdomen somewhere but you can't exactly tell where - This is presumably because evolutionarily, somatic pain felt very important vs visceral pain - Finger on burning stove requires knowing where your finger is to move it off burning stove but stomach pain doesn't require muscle engagement because you can't do much about it

Answer 122

- Somatic (skin): - Stimuli: mechanical, thermal, inflammatory - Localisation: precise - Visceral: - Stimuli: ischaemia (lack of blood to an organ or part of body), distension, inflammatory - Ex: it turns out that you can take a red hot poker and put it in their colon and they will not feel pain in their colon, as the colon doesn't feel thermal pain - This is because if a fire actually reached your colon, you're dead -> there's no point for evolution to give your colon sensation of pain - The colon cares about pressure inside (wants to know if it's blocked -> constipation) so it wants to know when there's inflammation - Localisation: poor, referred to somatic structures

Answer 123

* Info coming from the viscera ends up terminating on the same 2nd order neurons as the skin muscle and joint * Visceral goes to the same place that the skin is going to * If you have a stomach ache, the problem is in your colon even though it sometimes feel like the pain is on the skin of your abdomen

Answer 124

- Referred pain because it's in a different location (ex: referred pain in foot from saline injection in shin) - Skin pain: localized - Muscle pain: localized and referred (skin and muscle) - Visceral pain: referred (skin, muscle, and viscera) - The size of the referred pain area depends on the intensity and duration of the actual muscle stimulus

Answer 125

* Studies using intramuscular hypertonic saline injections * Hypertonic saline = 6% saline * Saline is 0.9% (this is what's all through your body) * It's 0.9% because the ocean is 0.9% and we evolved from the ocean * Saline is bathing your cells * If you inject 6% saline it will hurt * Referred pain is when you inject somewhere in someone and they say it hurts elsewhere

Answer 126

- James Mackenzie (1909) - Physician that tortured a conscious subject with their abdominal cavity open - He noticed that if he pressed on the colon, the patient would feel pain and they would also refer to pain further away (10-12 inches away) from the local pressure

Answer 127

1) Lesions - Natural (disease and trauma) - We waited around for people to have a stroke or some sort of injury which we could then conclude damage to particular cortical area and then concluded what the symptoms were of this lesion - Induced (transcutaneous magnetic stimulation (TMS) and surgery) 2) Stimulation and Recordings - In animals and increasingly in humans - Direct (electrodes and optical imaging) - In animals we can implant electrodes - Indirect (electroencephalography (EEG)/event-related potentials (ERP) and magnetoencephalography (MEG) - In humans you can do EEG or MEG 3) Hemodynamic response - The one that has proven to be useful - Doesn't actually measure neuronal activity directly - position mission tomography (PET), single-photon emission computerized tomography (SPECT), fMRI - If an area of the brain is working harder, then you should be able to see that these neurons are pulling more oxygen out of the nearby blood vessels

Answer 128

- Most invasive technique = lesions - Least invasive technique = fMRI, then MEG + ERP - Different techniques occur in different places - fMRI is the most popular technique

Answer 129

- Primary and secondary somatosensory cortices (S1 & S2) - Anterior and mid-cingulate cortex (ACC) - Posterior parietal cortex (PPC) - Posterior cingulate cortex (PCC) - Basal ganglia - Hypothalamus - Thalamus - Amygdala - Parabrachial nuclei - Periaqueductal gray - Primary Motor Cortex (M1) - Supplementary motor cortex (SMA) - Insula - Prefrontal cortex (PFC)

Answer 130

- 6 brain areas: ACC, S1, S2, IC (insular cortex), thalamus, PFC - Normal subjects = people without pain - How these studies were run was very different - You can correlate their ratings with their cortical activities - When you do this, the pain matrix goes down, except for in the PFC

Answer 131

- S-D Aspects: localization of pain, quality of pain, intensity of pain - M-A Aspects: unpleasantness, drive to escape or attend to pain - Pain is a sensation and an emotion - Pain has a sensory discriminatory aspect and a motivation affect aspect

Answer 132

- Due to lesions of the insula, cingulate, or morphine - More commonly due to a stroke - With lesions to the insula or the cingulate, people will tell you they have pain and not necessarily do anything about it - Morphine: people say it doesn't kill the pain, so much as it makes them feel unbothered by it

Answer 133

- Sensory-discriminative = somatosensory cortex - Affective = anterior cingulate cortex (ACC), insula, nucleus accumbens, amygdala, parabrachial nucleus - Cognitive = prefrontal cortex - Inferential = hippocampus - Motivational = ventral tegmental area - Descending modulation (descending pathways) = periaqueductal gray and rostral ventromedial medulla

Answer 134

1) Cerebral cortex 2) Hypothalamus 3) Amygdala 4) Periaqueductal gray (PAG) in the Midbrain 5) Locus coeruleus (LC) in the Pons 6) Rostroventral medulla (RVM) in the Medulla 7) Dorsolateral funiculus (DLF) and ventrolateral funiculus (VLF) 8) Spinal cord

Answer 135

- To inhibit pain - It's for the brain to decide that it wants to suppress the info that would otherwise be sent up towards it

Answer 136

- Ed Perl - Pat Wall - Ron Melzack

Answer 137

- Specificity theory - Said that everything was very specific - Discovered nociceptors

Answer 138

- Probably the most famous pain researchers - Produced the gate-control theory (originally written on a napkin at a bar) - Argued that Perl is wrong and that pain is about patterns and not about specifiers doing specific things - Their idea is what people thought was true for very long

Answer 139

- Gate control theory built the field - Before the gate control theory there really weren't any pain researchers - There were only physiologists

Answer 140

- Ed Perl - There are nociceptors and a nociceptor by default is a primary afferent fiber -The more noxious the stimulus is the more it fires - In the periphery: there's a noxious stimulus (ex: in the skin) which turns into DRG nociceptors and then leads to the dorsal horn nociceptive neurons - Flaw in theory: there are other neurons, other primary afferents, that really do respond to pain but they don't have the properties shown in this theory

Answer 141

- Physiologists also find that there are low threshold DRG neurons that can get activated at a low threshold (meaning a non-noxious (innocuous) stimulus will make them fire, it's just that when you get in the noxious range, they'll fire faster) - These lead to WDR dorsal horn projection neurons

Answer 142

- Both noxious and innocuous stimuli are basically activating a whole bunch of primary afferents of different types and they have different firing patterns to that stimulation - It's the pattern of response of the primary afferents that's decoded somehow in the spinal chord - DRG neurons to dorsal horn neurons - You can tell how painful something is by tracking how much the DRG neurons are firing - May be hard to track what's painful

Answer 143

* 1965 * Pat wall (neurologist) and Ron Melzack (psychologist) * Published in a review paper * Almost certainly the most famous paper in the field (the paper that ultimately created the field of pain) * A model that people could prove * A lot more people got interested in pain and started calling themselves "pain researchers" * Melzack's contribution to this was the box on top of the circuit -> central control * He said he thinks the spinal chord is doing all of this but that the brain can send info down and modify whatever is happening in the spinal cord * The brain can either close the gate or open the gate whenever it wants * The circuit that Pat Wall provided is not actually correct (oversimplification of what's going on in the spinal cord) * Central control = descending modulatory systems * In the circuit there's 2 types of input (L: large fibers (A-beta) and S: small fibers (A-delta and Cs)) * These go towards T neurons * T neuron = Transmission/projection neurons (something that leaves the spinal cord and goes up) * When these T neurons fire, the more they fire, the more pain there's going to be * If the large fibers and small fibers are causing the projection neurons to fire then touch and pain will cause pain * SG = substancia gelatinosa neuron -> name for lamina 1 and 2 * This neuron inhibits the input from the large fiber to the transmission cell and the small fiber to the transmission cell * Idea is that the more the SG neurons fire, the less the large fiber will be able to excite the T cell, which is also true for the small fiber * The input from the large fiber to the SG is excitatory but the input from the small fibers is inhibitory * Let's say you only have touch info in the periphery, the large fibers will be activated but the small fibers won't -> if this happens the large fibers are going to excite the transmissionary fiber but because it's exciting the SG this then inhibits the excitation that would usually occur/ would have otherwise occur * The excitation of SG cancels out/prevents the excitation that would occur * So the large fiber will never be able to excite, the inhibition cancels out the excitation, so there is no pain * When the small fibers fire alone, the SG is now inhibited by the small fiber and because it's now inhibited, it will not inhibit the T neuron, and because the inhibition doesn't occur, then the excitation will occur * So the Transmission neuron will fire (pain will happen) * This system also deals with more and less * Gate control: gate open = pain, gate closed = no pain or less pain * This diagram correctly depicted that some of the afferents are going to superficial lamina and some are going to deeper lamina (where the projection neurons are) * Neurons when connected to other neurons can either excite them or inhibit them * + = excitatory synapse * - = inhibitory synapse making neuron less likely to fire

Answer 144

- Why if a part of your body is sore, you rub it (large fiber input) - If there's touch, there's large fiber input, which prevents T neurons from being excited - It also excites the SG which inhibits the small fibers of excitation - The more large fiber input there is, the less firing of the T neuron will happen

Answer 145

- Trephination - Theriac

Answer 146

- Method of treatment of pain in antiquity - Know of this due to finding the skulls - The idea was that disease was caused by bad spirits inhabiting your skull and the way the get them out was to make a hole/holes in the skull to get them out - Probably no anesthetic involved - Most are located in the parietal region, but they are also seen in frontal and even occipital regions - Did this work? - Most certainly not and probably made it worse - This is the kind of injury that easily gets infected and makes it worse - However, many examined skulls show evidence of bone growth attesting to the survival of the subjects

Answer 147

- Old treatment of pain that actually works, it actually reduces pain - Mix of roots, stems and barks, leaves, flowers, fruits and seeds, gums, oils and resins, animal parts and products, mineral substances - Active ingredient: opium poppy - Anything with enough opium poppy in it will be able to treat pain

Answer 148

1) Willow bark * If you take the bark of a willow tree and you boil it and drink it, this will lead to treating pain and reducing fever * How they knew this: Native people had tried and processed almost every plant in every way * Eventually the anecdotes pile up and then it becomes common knowledge for a tribe that bark treats pain and then becomes knowledge for everyone else 2) Opium poppy * Most of drug development today is based on trial and error * You have to be lucky to live in a part of the world that has access to these plants * In 2025, this is a lot of how we treat pain

Answer 149

- Very first pharmaceutical company built was the Merck KGaA in Germany (founded in 1668) - Purpose of the company: - They knew how to make morphine (start with opium poppy and turn it into morphine) - Problem with morphine is that everyone was making it up by themselves (problem: either too low or too high) - Too low = doesn't treat pain - Too high = death - Company that standardizes the dose of morphine for people so they don't take too much or too little

Answer 150

* 1st public demonstration of a surgery done with anesthetic was at the Ether Dome in the Massachusetts General Hospital in 1846 * Done with inhaled ether as a surgical anesthetic * Dentist (Morton) gave ether to patient that was getting a tumour removed from their neck * When slicing through their neck (by Warren), the patient didn't react and then woke up and felt like their neck had been scratched * The amount of surgeries that occurred with no anesthetic in the past * Strong men would hold the patient down and give them alcohol

Answer 151

* Opiate: a drug that's based somehow on the structure of opium * Opioid: a broader category that includes things in your body (ex: endorphins) * All opioids are opiates

Answer 152

1) Codeine 2) Oxycodone 3) Propoxyphene 4) Morphine 5) Hydromorphone 6) Methadone 7) Meperidine 8) Oxymorphone 9) Levorphanol 10) Fentanyl trasndermal system - They all can either be given as intramuscular injections or by mouth (per oral - PO) - Those with highest dosage: codeine, propoxyphene, meperidine - Those with lowest dosage: oxymorphone, methadone and levorphanol - All have similar half-life and durations of action (except methadone and levorphanol have much longer durations and half-lives) -> these last longer - If you mistakenly give someone too much of a drug, you're going to kill them - There's a wide difference in the doses and differences in the half-life - Half-life: how long it takes for the 10mg to turn into 5mg - Different types of opiates but they all do the same thing - Doesn't matter which one you use as long as you use the right amount

Answer 153

1) Subcutaneous (sc - right into the skin) 2) Intramuscular (im - in the muscle directly) 3) Intravenous (iv - in the vein, harder to do) ^ All injections (+ intra-arterial and intrathecal) 4) Transdermal (ex: patch - put it on top and hope it goes in) 5) Implantation (tube inside) 6) Otic (ear - topical, intracochlear, intratympanic) 7) Nasal (drops or spay) 8) Rectal/vaginal (suppositories, gel, tablets, ointments, pessaries) 9) Ocular (drops, ointments, implants, inserts, contact lens) 10) Oral (tablets, capsules, thin films, syrups, solutions) 11) Inhalation (dry powders, liquid sprays, aerosols) 12) Topical/transdermal (ointments, gel, cremes, patches, microneedles)

Answer 154

- We're all a donut or a sack of meat with a hole in the middle (mouth to anus) - Pathway from mouth is outside the body - For it to go through your mouth, it'll have to go through some sort of membrane - Also, drugs don't know where they're going, they go anywhere they can get and don't go right to the site of the pain - The only place that they can stick are places where they're designed to bind or stick to -> they bounce off of other places - Side effects are when a drug binds to a place that you don't want it to bind to - You can also try to put the drug where you want it to go and hope it gets absorbed in

Answer 155

- Some of these approaches are more invasive than others (may prefer a pill or patch) - People won't opt for the implantation if it's not necessary - The drug is going to take action quicker or slower depending on the route of administration (ex: blood-brain barrier) - If you want a drug to work faster, you want the drug to get to the blood faster, which can be done intravenously

Answer 156

* Pharmacologists either study pharmacodynamics or pharmacokinetics * Pharmacodynamics: what the drug does to the body * Pharmacokinetics: what the body does to the drug

Answer 157

- Acronym ADME - A: Absorption - What % of the drug gets in the bloodstream in the first place or in the brain - Different routes lead to different absorption - D: Distribution - M: Metabolism - Enzymes largely in your liver - The liver takes complicated molecules and break them down into simpler molecules - Metabolites are sometimes active and still produce effects - Example of drug where the drug has no effect at all and only the metabolites have an effect -> codeine - In pain, codeine has no effect on pain but the liver turns it into morphine - Morphine is codeine's active metabolite - There are genetic variants in the enzymes that metabolize codeine (some people are ultra-metabolizers of codeine and end up producing so much morphine with a regular dose of codeine which has led to their death) - There are also genetically poor metabolizers who don't turn codeine into morphine (25% of population) - E: Elimination - What happens to the metabolites? - They get eliminated - Either through breathing it out, pooping it out, peeing it out, or vomiting (less common) - Eventually the metabolites along with other molecules that your body isn't using end up in your bladder or colon

Answer 158

* Patients allowed to press a button to give themselves a dose of an opioid (ex: morphine) through an IV * Programmed to lock so that you can't just keep pressing the button * Good because patients used to have to beg a nurse to get more morphine * They were dependent on nurses to give them pain control * This requires a machine (costs money and only happens in developed countries and expensive hospitals) * When it first came out, everyone was worried that people were going to use more opiates than usual * The data shows that patients use way less (25-40% less) opiates

Answer 159

- Constipation (up to 80%) - Sedation (20-60%) - Myoclonic jerks (up to 60% at doses over 500mg/day) - Nausea or vomiting (15-30%) - Xerostomia (dry mouth) (common) - Pruritus (itching - 2-10% for spinal route and rare for oral route) - Respiratory depression (rare in chronic dosing) -> opiates can kill you which often occurs with this side effect (epidemic of people dying from this from opiates) - Urine retention (rare) - Confusion or hallucinations (no figures available) - Chronic opioid use leads to libido problems in men - This is an extremely problematic drug - If it were developed today it wouldn't be allowed - Only exists because it has been here forever

Answer 160

- Other things that the drug does that we didn't intend and usually don’t want - Due to the fact that the opiates or the drug is not only going to the place where you want but can also bind to other places with opioid receptors - Can also be given other things to treat side effects

Answer 161

- Acetaminophen (brand name: Tylenol) - Aspirin (brand names: Bayer, Bufferin, Ecotrin (325mg)) - Ibuprofen (brand names: Advil and Motrin IB) - Naproxen sodium (brand name: Aleve) - ^ Last 3 are non-steroidal anti-inflammatory drugs (NSAIDs) - OTC because you don't need a prescription for them - A lot of times, you're buying a combination of drugs (ex: dayquil = acetaminophen, and other drugs) - Mixing drugs together is one way that drug companies try to innovate and increase sales

Answer 162

- Non-steroidal anti-inflammatory drugs - Drugs that work against inflammation - Most well-known anti-inflammatory drug is steroids (these aren't steroids) - Most common in North America: aspirin, ibuprofen, naproxen sodium (pharmaceutical names) - These drugs have terrible side effects (especially with your stomach) - If these drugs were developed today, there's no way they would be approved

Answer 163

1) If pain occurs, there should be prompt oral administration of drugs in the following order: non-opioids (aspirin and paracetamol) +/- adjuvant 2) Then, as necessary, mild opioids (codeine) for mild to moderate pain, +/- non-opioid, +/- adjuvant 3) Then strong opioids such as morphine, for moderate to severe pain, +/- non-opioid, +/- adjuvant, until the patient is free of pain - Eventually, there's a drug that will control the pain but it will be very strong and thus extremely sedative - Struggle between the patient not being in pain but the patient being awake and able to speak to family - To calm fears and anxiety and manage side effects, additional drugs (“adjuvants”) should be used - To maintain freedom from pain, drugs should be given “by the clock” -> every 3-6hrs, rather than “on demand” - This 3-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective - Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective

Answer 164

- Ketamine for insufficient analgesic effects - Gabapentin for neuropathic pain - NSAIDs for nerve entrapment, compression - Benzodiazepine for muscle cramp

Answer 165

* Sometimes cancers are painful but sometimes they aren't * Eventually cancers get metastatic * The cancer spreads to your blood and then goes to your bone * Metastatic bone cancer is extremely painful

Answer 166

- Unique chemicals that are currently marketed in the US for pain - Broken down by molecule -> individual molecules used for pain - Cyclooxygenase inhibition (over the counter - 24 on the market) - Opioid receptor modulation (19 diff opiates on the market) - Voltage-gated sodium channel modulation (local anesthetics - 10 on the market) - Serotonin receptor agonists (migraine drugs - 9 on the market) - ^ 1-4 are the vast majority of drugs being sold - Most of these are willow bark and poppy juice - 5-12 (rest of the list are very rare)

Answer 167

- Include drugs (analgesics), physical therapy (ex: distraction techniques), psychological therapy (ex: stress management), occupational therapy (ex: work simplification) - Treatment of pain includes a combination of pharmacological and non-pharmacological treatments - A lot of psychological issues going on with pain that won't be treated with pharmacology methods

Answer 168

1) Surgical ("Interventionalist") - Ex: Neurectomy, cordotomy, deep brain stimulation - Surgical methods done by self-called "interventionalists" - The bar to get approval from the government to do these kinds of surgeries, is surprisingly low - This is because surgeons argue correctly that it would be unethical to do sham cuttings or use simulators - These are so invasive that no control is ethical - The evidence for a lot of this stuff is very thin - But surgeons are the most powerful people 2) Anesthesiological - Ex: Nerve blocks, epidural blockade, local anasthesia, lidocaine + - Pain doctors consist mostly of anesthesiologists - They do blocks - Some local anesthetic applied or injected very close to some nerve somewhere (ex: epidural -> go in right beside the spinal cord) - The targeting requires the training 3) Psychological - Ex: electromyograph (EMG) biofeedback, cognitive-behavioural pain management, hypnosis - Most commonly do cognitive behavioural pain management - CBT is currently the most common psychological treatment modality 4) Other - Ex: transcutaneous electrical nerve stimulation (TENS+), acupuncture, physical therapy - None of these are complementary methods - They're all perfectly standard treatment methods

Answer 169

* -otomy: a removal * -ectomy: a cut * A sympathectomy: you're cutting some part of the sympathetic system * Surgeons either go in and cut things or remove things that are thought to be harmful * Or they go in and put a stimulator to stimulate nerves that aren't firing on their own * They can also put in pumps to release chemicals

Answer 170

- Individual Practices: things you learn to do by yourself and for yourself - Ex: mindful (meditation, relaxation, yoga), spiritual (prayer, yoga, spiritual healing), energy based (massage, homeopathy, acupuncture), stimulation-based (TENS, aromatherapy, music), movement based (exercise, tai chi, yoga -> exercise is the winner of these treatments as it has lots of good evidence), mechanical/manipulative (chiropractic, osteopathy, massage), nutriceutical (vitamins, diet, herbal medicine) - Systems of Medicine: different from standard western medicine practices - Ex: homeopathy, chiropractic, osteopathy, naturopathy, mind-body healing - Allopathy is medicine that's informed by the rules of the scientific method as developed by the enlightenment in western psych - World Medicine Systems: - Ex: Native American Healing & other indigenous systems and Traditional Chinese Medicine (acupuncture and herbal medicine)

Answer 171

- Famous study by Stephens et al. (2009) on how swearing causes analgesia - Ps were asked for 5 words that they might use after hitting themselves on the thumb with a hammer and used the 1st swear word on the list - Found that swearing causes analgesia - Probably not replicated - People who swore had lower pain levels than those who didn't swear - Also showed women reported more pain in the control - Also, study by Guetin et al. (2011) on music and pain - Study that shows that music causes analgesia - Ps could choose their own music - Ps were lying down in their rooms with their eyes closed under minimum lighting so they felt at ease - Music through earphones - Can be a distraction and can change your mood - Distraction is probably the strongest analgesia there is - Levinson argues that people use music to self-manage their mood state and there's evidence that mood influences pain

Answer 172

- Flow diagram of what it would take you to do self-management of pain - Perceived importance and self-efficacy lead to readiness to change which lead to self-management behaviours (coping) - Ex of self-management behaviours: exercise, pacing, relaxation, positive self-statements, ignoring pain

Answer 173

- Probably not a good idea to give opiates or acetaminophen to babies (very dangerous for them) - Up until mid 80s, the standard medical training was that babies don't feel pain - In 1985, Jeffrey Lawson needed a surgery and they just gave him a paralytic and no analgesic because they thought babies don't feel pain - There's one class of babies that experience a lot more pain than most babies (premature babies in the NICU) - Premature babies aren't healthy and their medical monitoring requires blood draws - Drs use heel lances (sharp glass tube with sharp end) - Procedure: they poke the heel hard to try to get the blood drawn - Some pre-mature babies have this done many times a day and it hurts for them - Methods to relieve pain: - Sugar (sucrose and not splenda) - Suppling (may just be a distraction) - Kangaroo care + suppling - Kangaroo care (skin-to-skin contact between a baby and a bare chest) - Works best if it's the mother, then if it's any woman, then if it's the father

Answer 174

* John J. Bonica is regarded as the father of pain medicine * Before he became a dr he was a circus performer and wrestler * He was the author of the very 1st textbook on pain (The Management of Pain) * He founded the first multidisciplinary pain clinic in Seattle * He came up with the idea that pain would be better managed if it was managed by a team (psychology therapists, OT, PT) * Results from multidisciplinary clinics are better than just seeing primary care physician for pain * Chronic pain patient engaging with psychological therapies, educational programming, appropriate medical procedures, physical therapy, structured and alternative movement therapies

Answer 175

* This is usually talked about in the context of cancer * The intent is to cure patients with cancer * But at some point if it becomes clear that this will not work, the focus shifts from curative intent to palliative intent * Palliative: to make better * Palliative intent means to make someone comfortable, to manage pain symptoms * Palliative intent can happen in the hospital and can also occur in hospices * Hospices: places you go when you're going to die soon * Try to make people comfortable here * Big goal of palliation is pain control

Answer 176

* ~15-20 years ago there was a push that was successful in the US to make pain the 5th vital sign * 4 vital signs: pulse, blood pressure, temperature, respiratory rate * Vital sign: something that a paramedic or a nurse is required by law to measure and record * If you're a nurse filling out a patient's chart, this chart comprises a measure of these 5 things * These are things that have a bearing on your health * Pain = the patient's self-reported pain level (if the patient is capable of providing this rating) * Pain is different from the others because the other measures are objective whereas pain is self-reported

Answer 177

1) Personal Opinion (lowest in the pyramid) - Social media is here - What's floating around the internet 2) Expert opinion - Your doctor is here (barely) - Better than normal opinions - Is that person really an expert? -Primary care doctor may claim to be an expert on pain but they aren't - These doctors are generalists 3) Case reports - Written down report on treatment of a patient - Doctors have a bunch of people in their office and they may have one patient that they treat and it works 4) Case series - Ex: Doctor has 20 patients coming in their office for the last year for the same thing and got treated the same way and 14/20 got better 5) Case control studies 6) Cohort studies 7) Randomized Controlled Double Blind Studies - AKA RCTs (Randomized Controlled Trials) - A single RCT isn't worth much 8) Systematic Reviews and Meta-analyses - Combine a bunch of RCTs and come to an overall conclusion - The more RCTs the better

Answer 178

* How we know whether the treatments for pain work or not * New concept that came out of McMaster University * Medicine has been based on what doctors write down and what they teach in books * People acknowledged that this wasn't science-based * 2 things to know about treatment: 1) How does that treatment work? * If you know this, you can try to come up with better treatments 2) Does the treatment work? * This is a lot more complicated than you could imagine * Different types of evidence

Answer 179

- Classification system based on grades - 1a: evidence obtained from meta-analysis of RCTs - 1b: evidence obtained from at least one RCT - 2a: evidence obtained from at least one well-designed controlled study without randomization - 2b: evidence obtained from at least one other type of well-designed quasi-experimental study - 3: evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies - 4: evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

Answer 180

* Top of the line meta-analyses * A bunch of people that do meta-analyses together and they have come together to make up rules for how to conduct the best meta-analyses * Top line conclusion: it appears to work but not really well and that's what we know * They only count RCT evidence and none other * "Here's what the evidence we have today concludes about a particular topic"

Answer 181

1. Assesed for Eligibility (enrolment) 2. Randomized (or excluded) - Randomly assign patients with a random number 3. Allocated to intervention (treatment or control) 4. Received intervention (or didn't receive intervention -> dropped out before receiving intervention) - Biggest problem is people who are receiving the treatment and are supposed to come in to check-in with their pain levels but they don't show up anymore 5. Followed-up (or discontinued intervention or lost to follow-up) 6. Analyzed (or not analyzed) - Data is analyzed

Answer 182

- If they have more than one condition (comorbid) - If they only have a small amount of pain -> pain score is too low (want them to have pain above a certain level you may set) - If they're already on analgesics - If they've been in pain for a small amount of time (want them to have pain for a certain amount of time you may set) - Age (if they're too old or too young) - Mental illness (ex: schizophrenia) - Having a previous surgery - Addiction (ex: heroin addict)

Answer 183

- Many reasons for why this might happen - Ex: got a new job and moved, feeling much better, side effects were so bad that they hated the side effects more than the pain so they stopped taking the drug and feel too guilty to show up - May be able to tell based on how many dropped out of treatment vs control condition - You can assume new data based on the missing data (ex: they were on a downward trend before they dropped out so assume they are going down)

Answer 184

1) Parallel Design (“3 arm”) - Trial with 3 arms (3 groups) that are all being run in parallel - Often, in a 3-arm parallel design, you can add in an active control (a drug that you already have reason to believe works) 2) Crossover Design - Opposite of parallel design - Everyone gets both treatments - Advantage: you can compare the 2 treatments within the same person (more statistical power), you need less people (saves you money), patients like it a lot better (people hate parallel designs -> they don't like the idea that they won't get the drug) - Confound: carry-over effect (there's a period of time where we try to wash out the drug to try out the other, but maybe it doesn't fully wash out (has long term effects that affect the second drug) 3) Enriched Design - You start with the active dose and you keep increasing the dose until people either say it's working and their pain has gotten better or they say that it's not working and their side effects are getting worse - Only the people who are getting better stay in the trial - This isn't helpful because it could be placebo effect

Answer 185

1) Plot with Y axis = change in VAS and X axis = time (usually days or weeks - 3 groups: observation only (just observed nothing happened to them), placebo patch (got a patch and were told it was an analgesic), lidoderm (treatment condition) - Results: lidoderms go down and statistically beats both placebo patch and observers - Probably the most common presentation 2) Bar graph with Y axis = patient preference for treatment phase and X axis = type of treatment - People were exposed to both the lidoderm patch and placebo patch - They were then asked which on did you prefer? - 78% preferred lidoderm 3) Graph that shows how long Ps used the patch - They were asked how long did you use the patch - Weakest evidence because it's possible that shorter time on the patch means your problem got solved - What if only one of these measures were statistically significant? - Back in the day, the company would pick the one that was significant and tell the FDA only about this one and hide the fact that other insignificant findings were found - Also the reason why drug companies don't succeed as often

Answer 186

* Comes from cancer * Designed to look at the evidence that something does or doesn’t cause cancer * Ex: living near powerlines and cancer risk * Look at people who were either exposed or not exposed to cancorinogen * Wait and see who developed cancer and who didn't * On the numerator, you multiply the 2 numbers in support of the relationship (the idea that living near powerlines gives you cancer) * Then on the denominator, you multiply the 2 numbers in support of no relationship (the idea that living near powerlines doesn't give you cancer) * Then divide these 2 numbers and you have the odds ratio * Ex: if odds ratio = 3.86, then people in exposed population are nearly 4x as likely to get cancer as people in unexposed population * In human research, it's almost never possible to determine causation * This is what animal research is for * There's no causation without determining correlation first * This isn't testing a hypothesis statistically

Answer 187

Boxes would be labelled rows = drug vs placebo and columns = more vs less analgesia (determined by an arbitrary definition of work vs didn't work -> with analgesia this is "a 50% reduction in pain" (this would be indicative of analgesia))

Answer 188

* Type of meta-analysis * Invented by Dr. Forest * A way to plot all the odds ratios or relative risks of all the RCTs on the topic * When you see a meta-analysis, the meta-analysis is making a forest plot * All the estimates are odds ratios (CI in parentheses) * The plot is simply plotting those numbers * The box is the estimates and the lines are the 95% confidence intervals * Boxes are different sizes because the studies had different sizes * Weigh the boxes by their sizes * If the numbers are negative, it favours treatment over placebos * If the numbers are positive, it favours the placebo * In this study, all except one found that treatment was favoured * Diamond = weighted average of all these means * With forest plots, what's on the left and right changes (you always have to read the X axis) * Small one has big error bar due to being so small and big one has a small error bar due to being so big

Answer 189

* You plot the % of patients with some outcome on the drug on one axis and the % of patients with some outcome on the placebo on the other axis * Ex: plot where every dot represents an RCT that was comparing ibuprophen with placebo * If all dots are on the left (ibuprofen axis), then indicates that in every RCT, the results showed that ibuprophen outperformed placebo * Ex: plot comparing different drugs to placebo * If 2 of these drugs are right on the diagonal this would suggest that they didn't perform better than the placebos

Answer 190

- NNT = 1/(proportion benefiting from experimental intervention) - (proportion benefiting from a control intervention) - OR NNT = 1/(# of patients given active treatment achieving the target/total # of patients given the active treatment) - (# of patients given a control treatment achieving the target/total # of patients given the control treatment) - People think that if, for example, the NNT = 4, it means that as a clinician you need 4 patients - This isn't what it means - It means I need to treat 4 patients to make 1 better that wouldn't have gotten better by themselves - This tells you how good the treatment is but it doesn't tell you how many will get better - 1 in 4 is the number of patients that will get better due to the drug - The others may get better on their own or due to placebo

Answer 191

- NNTs range from 1 1/2 to 5 - Lowest NNT = Etoricoxib (NNT = 1.5) - Paracetamol (acetaminophen)/codeine: NNT = 2.25 - Ibuprophen: NNT = 2.5 - Morphine: NNT = ~3 - Paracetamol (acetaminophen): NNT = ~4 - Aspirin: NNT = ~4.5 - Highest NNT = Tramadol (NNT = 5)

Answer 192

* This is a very famous graph * Weighted by the # of people in the trial * NNTs range from 3 (opioids and botox) to 13 (Topical capsaicin - Qutenza) * Lidocaine patch: NNT = 5 * Capsaicin and SSRIs: NNT = 7 * Gabapentin/pregabatin have the biggest circles because there are more patients that have been in a clinical trial on this than any other drug * Drug companies often use clinical trials after the fact for marketing purposes * It had already been proven as good * Gabapentin is an approved drug yet 1 out of 6 people will get better due to the drug and others not necessarily due to drug * Yet Pfizer makes so much money out of this every year and all it does is reduce the pain from a 6 to a 3 for only 1 out of 6 users * Some of these drugs are maybe better (ex: amitriptyline NNT = 3)

Answer 193

- Oral sumatriptan single dose treatment for migraine has an NNT = 2.6 - Antidepressant for painful diabetic neuropathy = 2.9 - Paracetamol 1000mg single dose for postoperative pain has an NNT = 3.6 - What’s good about NNTs is that it's one number that you can use regardless of the treatment and its outcomes - Some treatments have sky high NNTs (ex: low dose aspirin for myocardial infarction (heart attack) has an NNT of 40) - Why use something with NNT of 40? - This is not a personal health intervention, this is a population drug intervention - Decreasing the total number of heart attacks in society which reduces healthcare costs for society - NNTs have to be taken into context: what's the purpose of treatment?

Answer 194

- Lowest NNH = most dangerous - Opioids have the lowest NNH -> how you can conclude that they're the most dangerous - Topical capsaicin: NNH (minor harm) = 3.9 and major harm = 4.7 - Gabapentin: NNH (minor harm) = 4.1 and major harm = 12.3 - Pregabalin: NNH (minor harm) = 4.3 - Tramadol: NNH (minor harm) = 7.2 and major harm = 10.8 - The perfect drug would be with a low NNT and a high NNH - Finnerup et al. (2010) graph looking at this found no drug in that quadrant

Answer 195

- Someone needs to come up with the decision or recommendation of what doctors need to try and in what order - Which treatments are recommended as first line, second line and third line - Base these decisions on few factors: quality of the drug, effect size, tolerability and safety (NNH), values and preferences, cost and resource allocation, strength of overall recommendation, and neuropathic pain conditions - 1st line drugs: - Serotonin-noradrenaline reuptake inhibitors (SNRIs) - Tricyclic antidepressants - Pregabalin, gabapentin - 2nd line drugs: - Tramadol - Capsaicin 8% patches - Lidocaine patches - 3rd line drugs: - Strong opioids - Botulinum toxin A - Table shows people prefer 2nd and 3rd line drugs, 2nd and 3rd line drugs being more expensive (cost and resources), and that 1st line drugs are more highly recommended - Irony: this ends up being subjective

Answer 196

- The biggest worldwide trade group/academic association dedicated to the study and treatment of pain - A lot of pain doctors are anesthesiologists - >7000 members - Multidisciplinary (anesthesiology, neuroscience, psychology, etc.) - 126 countries - 85 national chapters (including the Canadian Pain Society) - Publishes the journals, PAIN (since 1975) and Pain Reports - World Congress on Pain (since 1973) - Most members from Europe and Canada/US and least from Middle East Africa - Most members are anesthesiologists and least are from pharmacology discipline - Responsible for the definition of pain - PAIN is the primary journal in the field - Why there are not more neurologists and rheumatologists in IASP: - They have their own organizations - This organization is the one created by the anesthesiologists

Answer 197

- Highest % of studies' purpose is for intervention - Highest % of studies' subjects are human patients - Highest % of studies' stimulus is clinical - Highest % of studies' measure is behaviour/rating and lowest % is imaging - Highest % of total patient studies' clinical condition is chronic pain and then back pain and lowest % is spinal cord injury - Arthritis is much more common than neuropathic pain, so why are there more papers on neuropathic pain? - We have really good models of neuropathic pain in rodents but the models of arthritic pain are sketchy

Answer 198

* Measuring primary afferent fibers themselves * Electrophysiological Recording of Primary Afferent Fibers * This is the only thing that can be done in humans

Answer 199

* Technique: microneurography * Microneurography is very rarely done * You go into the foot or the leg and you poke a recording electrode directly into C fibers and you can record their activity * We can't go any higher than this level in humans because it's too invasive * People will let you poke them in their leg but not in their spine

Answer 200

Electrophysiological Recording of Primary Afferent Fibers

Answer 201

* With rodents under anesthetic * Should always be a little worried about what the anesthetic is doing to the data * Recording from neurons in the Dorsal Horn * These are 2nd order neurons * Not primary afferent, they're receiving the input from the primary afferent neurons and receive input from primary afferents that are arising from a particular part of the body * Technique: * Find a neuron in the receptive field of the part of the body you want to measure (in slide it's the left dorsal hip of rodent) * Reasonable chunk of skin * This is the part of the body that if you poke it'll respond * Recording electrode is in the spinal cord * Track action potentials per time * The dorsal horn neuron is tracking the temperature * The higher the temperature, the more noxious it is and the more firing there is * Press is more than brush and pinch is more than press and brush * Also responding to heat * Neuron is not specific to mechanical or heat, it's responding to both

Answer 202

- Major dorsal horn projection neuron types: 1) Wide dynamic range neuron (WDR) - Has input from A-betas, A-deltas, Cs - Input from large and small fibers - Seems to be positive (+) and negative (-) input - A-Beta, A-Delta and C all excite the spinothalamic tract neuron (T-neuron), but A-Beta also inhibits it - The dynamic range responds to innocuous in addition to noxious stimuli 2) Nociceptive-specific neuron (NS) - Has A-deltas and Cs (no A-betas) - Everything seems to be positive (+) - Both excite the spinothalamic tract neuron (T-neuron) - Because it's only getting excitement from A-deltas and Cs, they call it NSN (nociceptive specific neurons) 3) Low-threshold mechanosensitive neuron (LTM) - AKA “silent nociceptors” - Only respond to mechanical stimuli - Input to the LTM neurons: A-betas (large fibers) - Touch neurons - There's evidence that after injury (inflammation or nerve damage), these LTM neurons suddenly can register info in the noxious range too - They can add-on after injury and turn what would've been touch info into pain (what allodynia is) - The touch neurons suddenly turn into pain neurons and now when they fire they send pain signals to the brain - Silent nociceptors: before injury they aren't nociceptors (they're silent), but after injury they turn into nociceptors

Answer 203

- Anterior Cingulate: Limbic system emotional brain region - Responsible for pain unpleasantness - Not related to the location of the pain - Often lights up in FMRI studies - Can measure activity of nociceptive neuron in the anterior cingulate gyrus by placing electrode in neuron (on slide it's a lamina V pyramidal neuron) then squeezing the rodent on different parts of the body and measure how much the neuron is firing per second - Responses to painful mechanical stimuli show a whole-body receptive field for this neuron - It doesn't matter what part of the body you squeeze, that anterior cingulate will fire -> the receptive field of that anterior cingulate cell is the entire body - Recording electrode is just a very thin glass tube with fluid in it - After they're done with the recording, they can put a dye through the tube which goes into the neuron and stains it dark

Answer 204

- AKA Diffuse Noxious Inhibitory Controls/Conditioned Pain Modulation/Heterotopic Noxious Conditioning Stimulation (all of its names) - The idea that pain in one place can inhibit pain in another place - A thing that's been known to humanity for a long time - People know this to be true - Ex: getting punched in the arm relieving a headache - 1st people who studied it were in France and called it DNIC - Then was called Conditioned Pain Modulation (CPM - does not refer to conditioning learned in psych) - Most people call it this today - The strength of the CPM represents how well your descending modulatory systems are working - If you have a lot of descending modulation, an effective way of inhibiting pain endogenously (in your own body) then this will be reflected in having a lot of CPM - Not having CPM is a risk factor for developing chronic pain - If you're injured and are unable to inhibit the pain, this is what gives you the disease - Because CPM is non-invasive, it’s a good behavioural proxi in humans of the state of descending modulation - There's a lot of variability in CPM - 60% of people have CPM - 20% of people have no change - 20% of people get worse

Answer 205

- In a CPM experiment, you have 2 pain stimuli - You have the test stimulus that you want to see the change in - You also have the conditioning stimulus (another pain stimulus) - Ex: heat and cold stimuli - Get person's rating of the pain - Typical experiment: hot stimulus on one arm and then putting other arm in cold water and then presented with hot stimulus on arm again - The presence of cold pain on your right arm made the heat pain on your left arm less intense

Answer 206

- Take the ratings of pain stimulus before the conditioning stimulus - The healthy controls overall have CPM - Fibromyalgia patients don’t have CPM - Maybe the problem is that they're unable to inhibit that pain info with descending modulation - Has been replicated many times

Answer 207

- Measured CPM in the laboratory for a bunch of patients that were about to go under a drug for pain - Y axis: how well the CPM worked - If it worked well, the patients' CPM will be below 0 (analgesia) - If it got worse, the patients' CPM will be above 0 (hyperalgesia) - Most patients in their study are above 0 because they are likely to have chronic pain meaning they don't have analgesia but instead have hyperalgesia - Drug efficacy = how well the drug worked - There was a positive correlation between CPM and drug efficacy such that the drug worked better in people who didn't have CPM or had hyperalgesia instead of analgesia (in people who had impaired CPM) and it worked worse in the people who did have CPM - Why? - If the drug itself is working on descending modulation and your descending modulation is already working just fine, then maybe the drug won't work on anything

Answer 208

* The placement of electrodes on your skin in the general location of your skin * Tiny bit of current, not an electric shock * Enough current to make the neurons under the electrode fire action potentials they wouldn't have otherwise fired * The reason TENS is thought to work comes from gate-control theory * The terminals of A-betas are closer to the epidermis than the A-deltas and Cs * The purpose of conventional TENS is to activate non-nociceptive cutaneous afferents (A-beta) without concurrent activation of nociceptive (A-delta and C) or muscle afferents * The TENS unit is putting just enough electricity to be absorbed in the skin just far enough to activate A-betas but not the A-deltas and C fibers, so it doesn’t cause pain * Helps with pain because it's providing touch to your painful arm which helps inhibit pain * TENS units help (but not amazing) * It can be explained directly off of gate-control

Answer 209

* Nerve damage is ultimately physical destruction either in part or in whole of nerve fibers that would otherwise be sending afferent info about pain * If all the nerve fibers that are taking this info from one part of the body to the brain are injured, what you produce is phantom limb pain (because it's a complete nerve amputation of the limb, even if the tissue is still there) * Phantom limb pain is pretty rare * What's much more common is pain from partial nerve damage (some are crushed or severed and some are completely fine) * Ex: the 3 spinal nerves that connect to the hind paw of a rodent (L4, L5, L6) -> connect to sciatic nerve (nerve leaving from your foot and goes to your foot) * If we sever just L5, all the nerve fibers in this nerve will degenerate * But nerve fibers from L4 and L6 are still alive * Where's the pain coming from? Is it coming from the nerves that are dying or from those that are alive? * Good evidence for both * You can get pain from having too few primary afferents or too many or from dying ones changing the function of the ones that are still alive * Factors released during Wallerian degeneration of the injured fibers may affect function in uninjured nerve fibers * Commingling of injured and uninjured nerve fibers also occurs in peripheral target tissues such as skin

Answer 210

1) Peripheral sensitization - Happens in the periphery - Things that are released into the tissue that receives the injury - Inflammatory soup: a soup of different molecules that end up activating nociceptors to fire more than the tissue damage would predict 2) Central sensitization - Sensitization that occurs in the CNS - Either in the DRG or in the spinal cord - Gene transcription, then reversing inhibition, then enhancing synaptic strength (windup LTP), peptide up regulation

Answer 211

* Other sensations habituate while pain sensitizes * Perception of pain gets higher overtime (the longer the sensation is there)

Answer 212

- Using skin-nerve preparation, can run peripheral sensitization tests - Ex: can use a nano-stimulator to stimulate the receptive field and record from it - Ex: in one study they studied the number of impulses per second before giving bradykinin (BK) and after they gave BK - Found more impulses per second after giving BK - They also applied a thermode to the patch of skin from skin-nerve preparation and started at ~30 degrees and then amped up the heat - Number of impulses per second that the individual nociceptor had fired - Found that it doesn't really start to get going until you get to around 40 degrees - Found that the stimulus response curve to temperature has shifted to the left after BK - Seeing both allodynia and hyperalgesia electrophysiologically - Plateaus at nociceptors maximum firing rate - The same heat stimulus causing more firing in the nociceptor - More firing in the nociceptor = more pain - Only difference in these 2 conditions is the BK - BK is able to get the nociceptor to fire faster and get it to fire to stimulus it wouldn't fire to at all

Answer 213

- You take a piece of skin that you carefully rip off from an anesthetized animal and you get the skin while the animal's still alive and you tease out a nerve fiber that would have been running from the skin to the DRG to the spinal cord and you can put this in a bath and record from it - For a few hours, everything is more or less physiological as far as we can tell - Can run tests from it

Answer 214

- The subjectivity of pain - Cancer is perfectly objective - Can measure the tumour - There's nothing obviously objective to measure with pain

Answer 215

- Objective = verifiable - Subjective = emotional - Most objective to most subjective: 1. Chemistry 2. Biochemistry 3. Biology 4. Medicine 5. Psychology 6. Anthropology 7. History 8. Biography 9. Novel 10. Epic 11. Lyric - "Take, say, physics, which restricts itself to extremely simple questions. If a molecule becomes too complex, they hand it over to the chemists. If it becomes too complex for them, they hand it to biologists. And if the system is too complex for them, they hand it to psychologists ... and so on until it ends up in the hands of historians or novelists." - Noam Chomsky - "Art reduces to sociology which reduces to psychology"

Answer 216

- Subjective: feelings of tiredness with a physical appearance, ex: - Heavy feeling in the body and head - Tensed feeling in the body - Mild pain somewhere in the body - Objective: any practice induced reduction in the ability to exert muscle power or force, attributable to: - Impairment of muscle fibers OR - A decline in motorneuron input - Ex: give fatigued person a hand grip and they won't be able to use it as well

Answer 217

1) Verbal Pain Intensity Scale (aka Verbal Rating Scale - VRS) - You pick an adjective that you think most identifies your pain (ex: no pain, mild pain, moderate pain, severe pain, very severe pain, worst possible pain) - You could turn these into numbers - Problem: you would have to accept the fact that the difference between mild and moderate is the same as moderate and severe - We don't know if this is true in people's minds 2) 0-10 Numeric Pain Intensity Scale (aka Numeric Rating Scale - NRS) - Numeric rating scale is almost always an 11 point scale - The producers of Big Hero 6 made the big mistake of making a 1-10 scale rather than a 0-10 scale accounting for when people aren't in pain - Uses 2 adjectives = pegs - Need to describe what a 0 is and describe what a 10 is and then let them pick a number - Everyone agrees on 0 pain - Adjectives on the 10 depends - Use of different pegs might make a difference - People aren't always thinking about it in a clear way and it's hard to do - How much pain can I imagine? What is the worst pain? - Between subjects, scales are terrible - There's no way to tell whether your 4 is my 4 - Where scales tend to work: if you told me your pain is a 4 but last week it was a 6, this is useful info - It's hard to believe your interpretation of the scale has changed since last week - People generally give the same rating over and over again (reliable) 3) Visual Analogue Scale (VAS) - Arguably the best - Horizontal line with "no pain" on one end and "worst possible pain" on the other end - Ask people to put a vertical line through the horizontal line where your pain is - Initially without number (researchers would use ruler on 10cm line to measure their line) - Not giving Ps a number 4) "FACES" Scale - Has faces with numbers and written descriptors beneath all illustrating different levels of pain - Pediatric purpose - Words aren't for the kids but for adults to explain it to kids - Kids understand pictures of people that are unhappy - Ask them to point to the picture that's like how they're feeling

Answer 218

- People remember the number they gave you last time and they might want to be sending you a message - Ex: if they gave you a 6 and they didn't get the prescription they wanted, then they'll amp it up to a 9 to get their prescription - Or they feel bad for doctor trying and give a lower number to show there's some improvement in pain when there isn't - You can sort of memorize where you drew the line but it's not as accurate - More pure

Answer 219

- Face 0 smiling: the opposite of pain isn't happiness, the opposite of pain is neutralness - You can not have pain and not be happy - New face of scales start neutral and get worse

Answer 220

- Questions you're asking: - Ex: when? (right now, average in the last week, maximum in the last week, etc.) - How could patients average their pain levels in the last week - Asking them very difficult questions - Issue of context: - In what context? (at rest, when standing, in the morning, etc.) - Often with pain syndrome, what you're doing greatly influences your levels of pain - You can ask people specifically in particular contexts - Can you even explain to people what you're asking them to do: - Issues with "pegs" (“worst possible pain”, “worst pain imaginable”, “pain as bad as it can be”, “unbearable”, “excruciating”, etc.) - Ex: trying to explain worse possible pain in English to someone who doesn't speak English or trying to explain it to a kid

Answer 221

* We need ratings * Ex: if I want to know how much your back hurts, then I'll ask you with a rating scale

Answer 222

- Uses 2 VASs - One of them asks about intensity and the other one about unpleasantness - Ex: one scale is from no pain to most intense imaginable and the other scale is from not unpleasant to most unpleasant imaginable - Mostly these are correlated - Visceral pain is usually more unpleasant than intensity

Answer 223

- Scales using 0-10 ratings with very detailed descriptions of each level - Ex: 0-10 scale of pain severity with description of experience at each severity level - Problem with these: the descriptions are completely arbitrary and they put them in a specific order (who says that's the order of these descriptions?) - Someone's asserting that the descriptions on the higher numbers are worse than the descriptions on the lower numbers - You can't just come up with a scale - You have to validate these and show people that it works

Answer 224

1) Pain Ratings as a Communications Strategy * What a person giving you a rating is aiming at is probably not the same thing as why you're asking them for a rating * You want an objective depiction of their pain * Patients usually are sending you a message about what they want from you * Want to be taken seriously and want good treatment * Patients will often say their pain is an 11 on a scale of 0-10 or it's "too serious for numbers" 2) Pegs * This has been used to explain why women are more sensitive to pain * It's true that they're more sensitive to pain * If we're using the peg "worst pain imaginable" on a VAS scale, people substitute the worst pain with the worst pain they've ever experienced themselves * Women will hence often put childbirth which is much more painful than most pain experiences of males * Women therefore probably have much bigger scales than men * When using these scales, it hence often seems like men are experiencing greater pain, but it's only because the pain women are feeling is much smaller relative to their much larger pain scale that they've experienced in real-life * Although it seems like men are experiencing greater pain, women are actually experiencing greater pain

Answer 225

* Asked people that had these pain experiences to rate them and asked people that hadn't had these experiences to estimate them through their imagination * Findings show that people imagine these to hurt much more than they do * One exception: childbirth * People have rated this lower than it actually hurts * Closest approximation to experienced rating was for sprained ankle, athletic injury, menstrual cramps and ingrown toenail * Furthest approximations to experienced rating were for electric shock, dog bite or small mammal bite and stepping on nail or glass in bare feet

Answer 226

- Ratings from Montreal General Hospital patients - Most painful: 1) Causalgia (8.5) 2) Digit amputation (8.25) 3) Childbirth (no training = 7.5 and training = 6.8) - Least painful: 1) Sprained ankle (3.25) 2) Laceration (3.4) 3) Arthritis (3.9)

Answer 227

- Ratings from chronic pain patients - Comparing clinical pain to experimental pain (temperature from thermode) - Most painful: 1) Childbirth (8.75) 2) 51 degree Celsius thermode (7.5) 3) Causalgia (6.75) - Least painful: 1) 43 degree Celsius thermode (2.75) 2) 45 degree Celsius thermode (2.9) 3) Myofascial pain (4.25)

Answer 228

- Ratings from 115 University of Florida undergraduates - Most painful: 1) Dental drilling (without anesthetic) (7.75) 2) Fall from 6-foot ladder onto cement (7.5) 3) Boiling water spill on hand (7.1) - Least painful: 1) Throat examination during check-up (1.75) 2) Dental examination (1.8) 3) Mosquito bite (1.9)

Answer 229

- Ratings from 187 University of Florida undergraduates - Most painful: 1) Childbirth (9.25) 2) Knife wound (8.9) 3) Cancer (advanced) (8.75) - Least painful: 1) Eye exam (1) 2) Mosquito bite (1.5) 3) Walking on gravel (1.75)

Answer 230

- These painful events differ in things other than pain intensity: - Differ in their duration - Digit amputation is very bad, but it only hurts for as long as it lasts (couple hours?) - Neuralgia can last months - Childbirth and labour pain goes up and down in pain throughout time - Some pains last longer than others, some are shorter, some come and go - Also if comparing experimental pain to clinical pain, a 51 degree thermode you can only apply to someone for a few seconds because it'll cause a burn - So issue with comparing this for a few seconds compared to longer chronic pain

Answer 231

- Most to least: - Functioning (anxiety/depression, sleep disturbance, cognitive) - Allodynia (punctate, dynamic, cold, heat) - Ongoing pain (burning, lancinating, stabbing) - Hyperalgesia (mechanical, thermal) - Even if you get a pain score (ex: clinical pain score of 8), and you could trust the overall number, you don't know what's driving this pain - How much of it is spontaneous or ongoing pain, how much of it is allodynia - Patients often don't sleep because of the pain and it makes their brain foggy and their anxiety and depression is worse and these will all factor into their pain number - Not only about the pain - This is telling us what we want to know but with a lot of ambiguity - Pain ratings have lots of problems but it's the best system we have right now

Answer 232

* Instantiations of ratings * Use on babies * This is a rating scale where the person in pain is not self-reporting * This is now a rating by others (almost always a nurse) * Used pretty commonly * FLACC: 1) Face: 0 = no particular expression or smile, 1= occasional grimace or frown, withdrawn, disinterested, 2 = frequent to constant frown, clenched jaw, quivering chin 2) Legs: 0 = normal position or relaxed, 1 = uneasy, restless, tense, 2 = kicking, or legs drawn up 3) Activity: 0 = lying quietly, normal position, moves easily, 1 = squirming, shifting back and forth, tense, 2 = arched, rigid, or jerking 4) Cry: 0 = no crying (awake or asleep), 1 = moans or whimpers, occasional complaint, 2 = crying steadily, screams or sobs, frequent complaints 5) Consolability: 0 = content, relaxed, 1 = reassured by occasional touching, hugging, or being talked to, distractible, 2 = difficult to console or comfort

Answer 233

* Another way of rating pain of someone else * Paul Ekman was the first to have the insight that emotional expressions are pretty constant across cultures, individuals, species * The face has a finite number of muscles that can only move in certain ways * FACS: Facial Action Coding System * He coded all the muscles on the face, what they do and what the result is on the face * Score their facial expression * Found that rage is a reliable sequence of facial muscles doing a certain set of things * You can look for changes in the face that are caused by specific musculature * Video-ing the person and then later someone can turn their facial expressions into numbers * Prkachin (1992) depicted the facial expressions and facial muscle movements that depict increasing amount of pain * Demonstrated a sequence of facial changes showing the emergence of the 4 principal facial actions: 1) Onset of action 2) Brow lowering, orbit tightening, and levator contraction 3) Brow lowering, orbit tightening, and eyelid closing 4) Mouth stretch (not consistently related to pain)

Answer 234

* Ron Melzack at McGill * Started by coming up with a whole bunch of descriptors that anyone anywhere have used to describe pain (whole bunch of adjectives) * Then divided those into categories * Main categories: sensory, affective and evaluative * Temporal adjectives: what pain does through time * Change in intensity over a small amount of time * Spatial: pain moving from place to place on the body * Punctate pressure: pressure at a particular point * Incisive pressure: pressure at a particular point that goes through the skin * Constrictive pressure: when you put pressure on something * Traction pressure: when you pull on something * He then asked both doctors and patients to put them in order within each category * Where the most severe adjective should go at the bottom and least severe should go at the top * Very good concordance between doctors and patients

Answer 235

* Temporal (between 1 and 3 in intensity): 1) Flickering (least) 2) Quivering 3) Pulsing 4) Throbbing 5) Beating 6) Pounding (most) * Spatial (between 2 and 4): 1) Jumping 2) Flashing 3) Shooting * Punctate pressure (between 1 and 4): 1) Pricking 2) Boring 3) Drilling 4) Stabbing 5) Lancinating * Incisive pressure (between 3 and 4): 1) Sharp 2) Cutting 3) Lacerating * Constrictive pressure (between 1 and 4): 1) Pinching 2) Pressing 3) Gnawing 4) Cramping 5) Crushing * Traction pressure (between 2 and 4): 1) Tugging 2) Pulling 3) Wrenching * Thermal (between 2 and 5): 1) Hot 2) Burning 3) Scalding 4) Searing * Brightness (between 1 and 3): 1) Tingling 2) Itchy 3) Smarting 4) Stinging * Dullness (between 1 and 3): 1) Dull 2) Sore 3) Hurting 4) Aching 5) Heavy * Miscellaneous (between 1 and 4): 1) Tender 2) Taut 3) Rasping 4) Splitting

Answer 236

- Tension (between 2 and 3): 1) Tiring 2) Exhausting - Autonomic (between 2 and 4): 1) Sickening 2) Suffocating - Fear (between 3 and 5): 1) Fearful 2) Frightful 3) Terrifying - Punishment (between 3 and 5): 1) Punishing 2) Grueling 3) Cruel 4) Vicious 5) Killing - Miscellaneous (between 3 and 4): 1) Wretched 2) Blinding

Answer 237

1) Mild (least intense) 2) Annoying 3) Discomforting 4) Troublesome 5) Miserable 6) Distressing 7) Intense 8) Horrible 9) Unbearable 10) Excruciating

Answer 238

* Melzack & Katz (2012) * He turned the Pain Descriptors by Intensity into the McGill Pain Questionnaire * 20 categories of adjectives and you pick the one that's most representative of the pain that you have * Put down where on your body the pain is happening * PPI: present pain index * Use 6-point verbal rating scale (VRS) for this * These adjectives would provide a signature that doctors could diagnose what problem that you have * This is very popular but it doesn't really work * But it works well for neuropathic pain that has a lot of heat components and electrical components to it where people use a lot of relevant adjectives for it * Inflammatory pain is very dull * You can tell the difference between these 2 from this questionnaire * This has as many citations or more than the gate control theory * He had the most cited pain research career ever

Answer 239

* Melzack & Katz (2012) * Short form of McGill Pain Questionnaire * Now people use the short form of this questionnaire * It's kind of a different thing * List of 15 of the adjectives that people rate (from 0 to 3, none = 0, mild = 1, moderate = 2, severe = 3) * Why did Melzack want to make a short form of the MPQ? Why is there a need for short forms of questionnaires? * In clinical settings, people don't have time to let patients take 10 mins on this * Original MPQ takes 10 mins and the short form takes ~1 min * Scientists like the original MPQ but clinicians like the short form

Answer 240

* Bouhassira, D. (2005) * Douleur Neuropathique 4 * Consists of 4 questions * Consists of a patient interview and a patient examination * 10 points total * You get a point for each item you answer yes to and then get a score out of 10

Answer 241

Fancy word for numbness

Answer 242

* Haegg (2007) * Has one section about pain (section 1 - pain intensity) * Asking people how much pain they have in the presence of pain killers * Kind of getting at pain intensity * Rest of the sections are about disability * Demonstrates the impact of the pain on disability

Answer 243

- Catastrophizing is a combination of rumination, magnification, and helplessness - Rumination: can't stop thinking about something - Magnification: building something up to being bigger than it is - Helplessness: feeling like you can't do anything about it

Answer 244

* Sullivan et al. (1995) * Super important * Developed at McGill * Short scale * 13 Questions * Meant to quantify catastrophizing * Either respond 0 = not at all, 1 = to a slight degree, 2 = to a moderate degree, 3 = to a great degree, 4 = all the time * You can catastrophize about things other than pain but this is about pain * Pain catastrophizing is both a trait and a state * There are a lot of psychological constructs that can predict pain * None works as well as this scale * This has the best predictive power

Answer 245

* Sometimes rating scales are aimed at particular disease states * Specific, not general * Specifically developed for arthritis * Measures 3 things: pain, stiffness, and disability * Section A (pain): for arthritis sufferers these will all cause very different ratings * Ex: going up stairs is very hard for people with Knee OA

Answer 246

* Svendsen et al. (2007) * Threshold and tolerance * Strange thing happening in the pain world: * People got very frustrated with ratings and thought maybe they could get useful info by doing lots of thresholds and ratings and doing it carefully and systematically (QST) * 2 ways to do QST: at the bedside (faster) or true QST (everything is perfectly calibrated and repeatable) * Ways to fake it at the bedside

Answer 247

1) Mechanical stimuli: - Dynamic Touch - Static Touch - Punctate stimuli - Method: - Stroking skin with a paintbrush/cotton swab - Gentle pressure with fingertip - Pinprick 2) Thermal stimuli - Cold - Warm - Method: - Metallic thermal roller kept at 20 degrees Celsius - Acetone/menthol - Metallic thermal roller kept at 40 degrees Celsius

Answer 248

1) Mechanical stimuli: - Tactile detection threshold - Tactile pain threshold - Pressure pain threshold - Pressure pain tolerance threshold - Method: - Von Frey Hair - Pressure Alogometry 2) Thermal stimuli - Cold detection threshold - Warm detection threshold - Cold pain threshold - Heat pain threshold - Heat tolerance threshold - Method: - Thermotest (using a thermode)

Answer 249

* If you're going to do QST, you have to consider that you'll apply stimuli at different pain intensities * In what order do you present stimuli? * Psychophysics: * There are ways and orders to do things * Up-down games (Gracely & Eliav, 2009) * Sensory detection regions: start small and go up until detection and then start high and go down until no detection * Pain threshold region: go up in intensity until pain is felt

Answer 250

- 4 subjects were tested for their pain thresholds - Line represents skin temperature (extremities are colder than core) - Tested their cool threshold, warm threshold, cold pain threshold, heat pain threshold - Findings: - Cool threshold: 31.1 degrees Celsius - Warm threshold: 37.7 degrees Celsius - Cold pain threshold: 13.8 degrees Celsius - Heat pain threshold: 43.5 degrees Celsius - People won’t call it pain until it goes down to about 14 degrees and until it gets hot to up to 43.5 degrees - Something that's just a bit more or less hot than 44 degrees: hot tubs - Evolutionarily heat pain is at 43.5 degrees because proteins start to breakdown higher than that (they denature) - If your skin gets to that temperature, then your core gets to that temp and proteins breaking down leads to death - Evolutionarily cold pain is at 14 degrees because frostbite and core being too cold (hypothermic) which leads to death

Answer 251

- Quantitative Thermal Sensory Testing of Inflamed Skin - Heat pain thresholds (degrees Celsius) in human models of experimental inflammation - Testing what certain injuries will do to your heat pain threshold 1) Burn: - Baseline = 44.5 - Inflamed skin = 39.7 - Change in threshold = -4.8 2) Capsaicin (injection): - Baseline = 42.5 - Inflamed skin = 33.7 - Change in threshold = -8.8 3) UV - Baseline = 44.5 - Inflamed skin = 36.7 - Change in threshold = -7.8 4) Freeze - Baseline = 42.5 - Inflamed skin = 37.1 - Change in threshold = -5.4 5) Mustard oil - Baseline = 42.1 - Inflamed skin = 36.5 - Change in threshold = -5.6 - In all of these cases, these caused the threshold to go down by 4.8 to 8.8 degrees - People's ratings may or may not correspond to how hyperalgesic they've become

Answer 252

* Experiment that did QST on a neuropathic pain patient * 3 things were done: * Used a cotton wisp * Used a Qtip * Used a paint brush * Dynamic mechanical allodynia * Didn't look for pain threshold * They simply did this on the side of the body of the patient with pain and on the unaffected side of the body * On affected side of the body (in pain) they had mechanical allodynia * What's surprising: the pain rating was the same in each case even through using different tools

Answer 253

* Rolke et al. (2006) * Pinnacle of QST: data that were generated by a bunch of German pain researchers * Being able to do what the McGill pain questionnaire couldn't do * Can we use QST to differentiate one type of pain from another type of pain * Splitting exercise * 14 QST types * They trained everyone in this network very seriously * Made sure everyone was using these precisely in the same way * Gave these to non-pain patients * Got a normal distribution of all of these pain thresholds * An individual pain patient had a problem if they were above or below each of these * Studied 2 patients with postherpetic neuralgia * These have the same diseases but have 2 complete different QSTs * Maybe these people have completely different diseases * Looking back, this effort largely failed * Turns out that QST is really good at determining who has neuropathy but not good at determining who has neuropathic pain * Doesn't tell you anything about their pain, just tells you about the diseases they have that causes their pain

Answer 254

* If you pay people a bit more money, you can get them to agree to let them test their pain directly in the muscle * You can electrically stimulate the muscle, do deep mechanical in the muscle and inject chemicals (all of these activating the muscle nociceptor and triggering exogenous muscle pain) * Chemical (ex: hypertonic saline, bradykinin, capsaicin, glutamate, substance p) * Mechanical (pressure and tourniquet pressure) * Electrical (intramuscular and intraneural) * Miscellaneous (heated isotonic saline and focused ultrasound) * You can also test visceral pain in people (ex: inflating balloons in their colon, oesophagus, or bladder)

Answer 255

- Self-report (through scales and interviews) - Observe behaviour and infer - Indirect physiology

Answer 256

* Pain measurements are subjective * People hate this * Everyone thinks that life, the world and pain research would be better if we had some sort of objective biomarker for pain * Biomarker: something you can measure the levels, size or density of * You can infer how much pain people were in from that biomarker without asking them anything * Problem: you would only be certain that something is a biomarker if it agrees with self-report * Dependent on agreement with self-report * Some people are incapable of self-report (ex: babies, people with dementia) * People also lie sometimes (however #1 rule is believe the patient) -> patients in general won't go through the trouble of driving to the hospital and telling you they're in pain when they're not * But sometimes they would (ex: maybe they're an opioid addict, man lying about not being in pain, legal actions -> getting money for pain and suffering) * There are circumstances where there's reason to believe people are lying * Biomarkers would solve the problem

Answer 257

- Tissue Damage (bigger wounds don’t necessarily mean more pain) - Cardiovascular (ex: heart rate, blood pressure, heart rate variability) -> it's true sometimes that people in pain have higher heart rates and increased blood pressure but not always true - Stress-Related (ex: cortisol and galvanic skin response) - Neural (ex: EEG, microneurography, imaging (functional, structural, chemical)) -> a lot of people are putting their money on brain imaging - Chemical (in blood or CSF) (ex: substance P, b-endorphin, cystatin C, C reactive protein, nerve growth factor) -> chemicals in the blood that have been indicated as being pain biomarkers - Molecular (ex: DNA variants and mRNA levels) - Problem with DNA variants: you have a DNA variant from the moment of conception and that doesn't tell you very much (it's always there) but biomarkers are used to tell you what's going on right now - Problem with mRNA: invasive, it's specific to the tissue in question (DRG, spinal cord, cingulate, insula)

Answer 258

- Rated pain rating on a VAS - Wide range of ratings - Took people with the 6 highest ratings and 6 lowest ratings in an imager - High raters had high activation (in SI and ACC) - Low raters had low activation - Their brains agreed with their ratings - Evidence that could be used as a biomarker

Answer 259

* The jury is still out on this * People range on a continuum between fMRI will maybe be a biomarker it just has to improve a little and others who say fMRI won't work for pain

Answer 260

- Studied the brain activation of Ps with physically-induced pain, hypnotically-induced pain and imagined pain - Found there was pretty big overlap (especially between PI pain and HI pain) suggesting that the same areas of the brain are going to activate if you experience physically-induced pain and are hypnotized to imagine it

Answer 261

- Can conduct causation experiments (can't do a causation experiment in humans, only correlation which is useful but causation is better and impossible to keep everything the same in every one thing for humans but in rats and mice, you can do essentially the same thing in all -> can hold things constant) - 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 or off at will - Can control environmental pre-exposures (ex: housing, diet) - Cheaper, faster, less highly regulated - No malingering (to try and get more drugs), no stoicism/machismo, no demand characteristics (confound of human experiments where people sort of intuit what the right answer in an experiment is and they supply it to increase the chances that the research will work and the experimenter will be happy)

Answer 262

- Most common to least common: 1) Rat (800) 2) Mouse (600) 3) Dog (500) 4) Cat (300) 5) Rabbit (200) * In the 70s, these 5 species were pretty common in pain research * In 1980-1985, the rat took off and became very popular in pain research * Why rats? * They're small which means they're cheap (they cost less to feed, you can house them in a much smaller space -> can fit them in a room) * Later the mouse took off and became very popular and caught up to rats * #1 species in biomedical research * Something that happened in the late 1990s for this to happen: transgenetics (alter gene expressions) * There was a while where that technology only worked with mice * So a lot of people switched over from rats to mice

Answer 263

- “The best material model of a cat is another cat, preferably the same cat.” - Arturo Rosenblueth (1945) - Meaning it's hard to model things with things that aren't the same - They’re the “wrong” species - They don’t talk - They’re prey (rats and mice are prey species and they have reason to hide their pain from us as we're much bigger) - They’re a lot tougher than we are (not used to comfort in the way humans are, put up with a lot and the kind of things that'll get us to complain, they'll need more to complain) - Ethical issues (ex: deontological vs consequentialist ethics)

Answer 264

- Deontological Ethics: the normative ethical position that judges the morality of an action based on the action’s adherence to a rule or rules - Relies on rules put out prior - If there's a rule that you shouldn't inflict pain on animals, then you can't inflict pain on animals - Consequentialist Ethics: the normative ethical position holding that the consequences of one’s conduct are the ultimate basis for any judgment about the rightness of that conduct - Utilitarianists are a subset of consequentialists - Whether you do something depends on the consequences of that conduct - What matters are the consequences

Answer 265

- Types of pain measurement in rodents: 1) Chemical 2) Cold 3) Electrical 4) Heat 5) Mechanical 6) Spontaneous (pay attention to ear position changes, orbital tightening, cheek bulging, nose bulging, and whisker changes)

Answer 266

* Heat used to be the dominant type of measurement in 1980s and 90s * We spend a lot less time measuring heat overtime and spend a lot more time measuring mechanical overtime * Mechanical allodynia and pain is a much more important clinical problem (much harder to avoid) * Whereas heat hyperalgesia and allodynia is easier to avoid

Answer 267

- Hot-plate test - Tail-flick test - Hargreave's test

Answer 268

- von Frey filaments - Randall-Selitto test - Weight bearing (indirect) - Grip force (indirect) - Gait changes (indirect)

Answer 269

- Writhing test - Formalin test

Answer 270

- Thermal Assay - Hot plate analgesia meter - Put a rat or mouse on a hot plate - What happens when you put a rat on 50 degrees plate - 2 seconds after you put them on the plate, nothing happens - Why? - Their skin is at ~ 32 degrees - It takes a few seconds before hind paw skin gets to 50 degrees - They'll usually pick up the hind paw and shake it really fast or they pick up their paw and put it in their mouth - As soon as the animal does a jump, lick or shake, you take them off the hot plate - The ones with the longer latencies had the longest thresholds

Answer 271

- Tail-flick analgesia meter - 2 ways of doing this: 1) Shine a heat light on the rats tail 2) Dip their tail in hot water (50 degrees Celsius) - As soon as their tail gets to the heat threshold, they'll flick their tail

Answer 272

- Tail-flick test is a reflex - Hot-plate test is not a reflex because they're thinking to themselves this is no longer a warm, this is a pain, what should I do? - 2 ways of measuring acute thermal pain: 1) Only requires the spinal cord: tail-flick test 2) Requires the brain supra spinal: hot-plate test

Answer 273

- AKA “radiant heat paw-withdrawal” test or “toe-toaster” test (not really) - Invented by Ken Hargreaves - IITC Plantar Test Analgesia Meter System - You put animals on a glass floor and once they stop moving, then you shine a high intensity heat lamp aimed at the plantar surface of the hind paw and you measure the amount of time it takes for the animal to hop away - The hot plate test, you don't have any control over the left or right paw because they're both on the hot plate - This test you can isolate either paw and choose to test the ipsilateral or contralateral pain - No one knows if this is spinal (reflex) or supra spinal (brain)

Answer 274

* Bioseb von Frey Filament Set * Von Frey filaments were meant for humans to test neurological functioning in humans * It was realized that if you use smaller fibers, then you can do the same thing in mice that you do in humans * Set of fibers that are calibrated such that when they bend, they're exerting a particular amount of force and no more force than that * You find the fiber that cause withdrawals 50% of the time * Can test mechanical allodynia where they withdraw with smaller fibers after they're given an injury

Answer 275

* IITC Digital Randall-Selitto Paw Pressure Test * Another way of measuring mechanical pain * Generally only works with rats since rats allow people to hold them in position necessary for this test * A force will drop on the rats paw and the force gets bigger and bigger and eventually the force gets big enough that the rat squeaks or wiggles away which indicates their pain threshold * Von Frey and Randall-Selitto are direct ways of measuring mechanical stimulation

Answer 276

- Mechanical assay - Positioning the mouse so it has to put its weight on its hind paws - Measures how much weight the mouse is putting on the right vs the left hind paw

Answer 277

- Mechanical assay - If the mouse is holding onto something and you pull them on the tail, they'll hold on for a while - Measure how much time they can hold on for

Answer 278

* Chemical Assay * Test developed in 1950s * Abdominal constriction test * Inject a chemical substance in their belly (either acetic acid, magnesium sulfate, hyper-/hypotonic saline, bradykinin, etc.) * This causes the animal to have abdominal pains * This only lasts about 30 mins but you can stop the pain easily with aspirin * Can identify abdominal pain by the way the mouse drags their belly to the floor

Answer 279

* Chemical assay * Inject 5% formalin substance in the hind paw and it causes inflammation * The nociceptive behaviour is licking -> the animals lick their hind paw * The more they lick the more pain they're in * Measure C-fiber response and DH neuron response * Early/acute phase and late/tonic phase * Also interphase/quiescent period * People are more interested in late phase because whenever something lasts longer, it's a good comparator to clinical pain

Answer 280

* More modern techniques * This is what people generally do today * Inflammatory Thermal Hyperalgesia (inject chemical substance in hind paw then do Hargreaves' test) * Inflammatory Mechanical Allodynia (inject chemical substance in hind paw then do von Frey filaments test) * Inflammatory Cold Allodynia (inject chemical substance in hind paw then inject acetone -> if you bubble a drop of acetone on the skin, it'll immediately evaporate and cool the skin -> cool under normal circumstances but hurts mouse with cold allodynia) * For inflammatory pain, you want to inject an inflammogen that produces effects that last from days to weeks * Terms allodynia and hyperalgesia are not right, because we're measuring thresholds and not allodynia or hyperalgesia * Mechanical and cold = allodynia * Thermal = hyperalgesia * What they're referred to in the field

Answer 281

- Carrageenan - Complete Freund’s adjuvant (CFA) - Zymosan - Mustard oil

Answer 282

* Surgical * Measures: * Thermal hyperalgesia * Mechanical allodynia * Cold allodynia * Different ways of causing injuries to the nerves from the foot * Interested in the sciatic nerve because it serves the foot * You can put a cuff, create ligatures or cut some but not all of the sciatic nerve as it branches out to go out to the foot * Sciatic nerve breaks into 3 * If you cut all of these, you get phantom limb pain * Neuropathic pain is caused by partial nerve injury * Causes thermal hyperalgesia, mechanical allodynia, cold allodynia

Answer 283

* Another nerve that comes from the foot: the saphenous nerve * If you want no info to go from the foot to the spinal cord, you have to cut the sciatica and saphenous * Behaviour that this causes is autotomy (mice starts biting off their toes and you measure this by counting how many flanges have come off) * Create wounds by excessive self-grooming with automutilation (autotomy) of denervated limb -> high autonomy score following nerve transections * Autotomy studies not allowed to be done anymore except for in one pain lab in the world * This is not done much anymore because there's lots of blood that comes from this (messy and disturbing)

Answer 284

- Chronic neuropathic assays 1) Sciatic Nerve Transection (ScNT) - Nature of injury: transection and ligating of sciatic nerve - Clinical correlate: nerve trauma, iatrogenic nerve injury 2) Partial Sciatic Nerve Ligation (PSL) - Nature of injury: partial ligation of sciatic nerve - Clinical correlate: partial peripheral nerve injury 3) Spinal nerve ligation (SNL) - Nature of injury: ligation of the L5 and L6 spinal nerves - Clinical correlate: proximal peripheral nerve damage (ex: after disc prolapse) 4) Spared Nerve Injury (SNI) - Nature of injury: ligation and transection of 2 of 3 distal sciatic nerve branches - Clinical correlate: partial peripheral nerve damage 5) Chronic constriction injury (CCI) - Nature of injury: loose ligature of the sciatic nerve with chromic gut suture - Clinical correlate: nerve entrapment (ex: carpel tunnel syndrome) 6) Sciatic inflammatory neuropathy - Nature of injury: perineurial injection of immune activator (zymosan or CFA) - Clinical correlate: peripheral neuritis 7) Peripheral nerve demyelination - Nature of injury: Immune or toxin-mediated demyelination - Clinical correlate: demyelination (ex: diabetic neuropathy) 8) Diabetic neuropathy - Nature of injury: Streptocotocin, diet, genetic models (can give animals diabetes through diet, genetic models, and injecting streptocotocin) - Clinical correlate: Diabetic neuropathy 9) Viral neuropathy (neuropathy from virus) - Nature of injury: herpes simplex virus, varicella zoster virus, HIV (gp120) - Clinical correlate: zoster-associated pain, postherpetic neuralgia, HIV-associated neuropathy 10) Drug-induced neuropathy - Nature of injury: Vincristine, paclitaxel, ciplatin (3 of the most common chemotherapeutics) - Clinical correlate: polyneuropathy caused by tumour chemotherapy - It would be better to use higher doses of these to kill the cancer but we can’t because they cause neuropathic pain

Answer 285

- Depending on age and gender - Back pain - Headache - Osteoarthritis

Answer 286

- Back pain - Headache - Osteoarthritis - Diabetic Neuropathy - Post-Herpetic Neuralgia - Fribomyalgia et al. - These are the things we're trying to model in animals

Answer 287

- Is injecting something inflammatory or cutting through nerves in mice's hindpaw really osteoarthritis? - The Problem with “Better” Algesiometric Assays: * It's possible to make a better pain assay (pain testing) * Animal model of vulvodynia (one of the most common pain syndromes) (Farmer et al., 2011) * Syndrome where the symptom largely is allodynia of the vulvar vestibule (of the vulva) * Affects ~20% of pregnant women * A better assay * Women with vulvodynia have a fair share of yeast infections * Giving mice yeast infections and then treating the yeast infection *Confirm that it's gone and then give another yeast infection * After 3 rounds of yeast infections, mice become allodynic * No one has ever used this assay because it's very long * 90 days to get only 40% of mice to show allodynia * A lot of time and work and expensive

Answer 288

1. Reflexive vs conditioned measures - All our measures are not like human clinical pain 2. Pain-affected measures (ex: sleep, anxiety, attention) - We haven't measured this in animals for most of history 3. Symptom epidemiology vs dependent measure use - Disconnect between the symptoms common in humans and symptoms common in animals

Answer 289

- People have come up with the idea of using conditioning methods to get the animal to think about the pain and have it make some decisions - Operant (Reinforcement) Conditioning: - Learned escape from pain from electric shock and from noxious heat/cold - Learned analgesic self-administration - Motivational conflict (between pain vs food/water) - Method of measuring or inferring pain by using operant conditioning - Inject carrageenan in mice's cheek - Would expect this to create mechanical or heat allodynia - Made a machine where the animal can go get a sweetened solution (reward solution) but to do so, it has to press its inflamed cheek on a heated coil (Neubert et al., 2005) - If the animal drinks less of the reward solution than it would without the heated coil, you can infer that it hurts to drink the solution so it's doing it less - Problem: this is complicated - Maybe the animal is drinking less of the solution because it's in pain or maybe it's not thirsty or maybe it doesn't like the sweetened solution as much, or maybe it's too sedated - Classical (Pavlovian) Conditioning: - Conditioned place avoidance (to chamber where pain is experienced) - Conditioned place preference (to analgesic-paired chamber) - Training phase where you put the rat or mouse into another of these chambers and you put it in there and let it walk around for a while (King et al., 2009) - Left and right of chamber is very different so rat can tell the difference - On one side you give them an analgesic and on another you give them a saline - Then eventually you open the door and let them choose where to go - If the animal spends more time in the analgesic side, then the animal must be in pain because why else would they be there - Conotoxin worked against von frey mechanical allodynia, compared to sham surgery and baseline surgery - Conotoxin is not a drug that gets you high and the rat preferred this side so sciatic nerve ligation (SNL) causes pain because if the rat prefers this side, there's no other reason to explain this other than pain - Problem: could be pain, or could be memory or movement

Answer 290

- You can measure this in animals and people have started measuring these things too - Modern pain research doesn't only try to measure pain but also these other comorbidities - Anxiety: Suzuki et al. (2007) ran a study that seems to demonstrate heightened anxiety in mice in pain in an open field test and elevated plus maze test - Attention: Millecamps et al. (2004) found significantly lower attention level in colitic mice compared to healthy mice - Sleep: Anderson & Tufik (2003) found mice in pain experienced significantly lower sleep efficiency than mice who got a sham

Answer 291

Prevalence of chronic pain symptoms in humans (Backonja & Stacey, 2004): 1) Spontaneous pain (continuous and/or paroxysmal) = 96% 2) Mechanical hypersensitivity = 64% 3) Thermal hypersensitivity = 38% - If you ask how bothersome these are, they also come up in this order Prevalence of dependent measures in animal models (Mogil & Crager, 2004): 1) Thermal hypersensitivity = 48% 2) Mechanical hypersensitivity = 42% 3) Spontaneous pain = 10% (claim to measure this 10% of the time (doesn't mean they actually are measuring it))

Answer 292

- A measure of spontaneous pain in mice - A way of measuring pain in mice the same way you do it in babies - 5 action units as defined by the facial action coding scale by Eckman - Looks at orbital tightening (eyes closing), nose bulge, cheek bulge, ear position, and whisker change coded/on a scale of 0 = not visible, 1 = somewhat visible, 2 = very visible - Then give the mouse a score from 0-10 - This works pretty well - Works so well that there are now grimace scales for 12 other mammals

Answer 293

- Mouse - Rat - Cat - Horse - Bunny - Otter - Lamb - Monkey - Sheep - Donkey - Pig - Cow - Ferret

Answer 294

- Mammals meet all criteria - Evidence that birds do most of these - Amphibians and reptiles have about 1/2 of these

Answer 295

* Clifford Woolf discovered central sensitization when he was in London * He published this study in 1983 * Sole-authored study * He was testing behaviourally and recording from rats and was measuring the flexor reflex of the leg (movement of the leg when they try to withdraw from some noxious stimulus) * Found that the threshold for that rat to withdraw from a mechanical stimulus, after the injury plummets down * After a few hours, they're extremely allodynic * He was measuring from WDR (2nd order) neurons in the spinal cord and before the burn injury they fire and after the injury they fire more and then it lasts for a lot longer * The surprise: he also found when recording WDR neurons in spinal cord following a noxious stimulus before and after a burn injury to the hind paw that the neurons were firing on the contralateral side as well * Injury was on the left side but when he simulated the other side of the body, he also got a firing response * Only way to explain that WDR neurons are also being activated by stimuli on the other side of the body is if the WDR neurons themselves had changed * The 2nd order neurons had to change such that a stimulus that normally wouldn't be painful before the injury would fire * This was revolutionary in 1983 * People thought changes in the periphery causes changes in the periphery but not in the CNS * If the changes found here in the flexor reflex parallel changes in the sensory input to the brain then pain hypersensitivity following injury may be due to changes within the CNS as well as at the site of the injury

Answer 296

* Electrophysiological recordings can measure peripheral sensitization and central sensitization * If there's only peripheral sensitization, then regardless of where you're recording from (peripheral or CNS), you're going to see the same thing * After sensitization, you're going to get more firing * All things being equal, even if there's no sensitization, the periphery fires faster * You would expect to see a similar pattern of responding peripherally and centrally * If there's only central sensitization, you wouldn't see any changes in the periphery * In central sensitization, it's the spinal cord that has changed * In peripheral sensitization, the nociceptor will be activated more often

Answer 297

* Part of Central Sensitization * You can measure this in people * This is what it would look like in a rat or a mouse * Every second, they're given the stimulus (maybe a pinch or heat pulse) * The spinal cord neuron you're recording from is firing * As you go further, that same neuron is firing more times * Temporal summation: summation in time * "Wind-up": that stimulus is winding up * If the stimuli are far enough apart such that they don't produce wind up (ex: 4 seconds apart), then you'll have a normal rate of firing * However if you're doing this many times in a short period of time (ex: 1 second apart) then the pain intensity adds up and becomes more intense with time (with the same stimulus) and the pain threshold goes down

Answer 298

* If you put many noxious stimuli close enough to each other that the stimuli summate with each other, then the ratings goes up and up and by the end the ratings are way above their threshold * Their second order neurons are simply firing more to the stimulus

Answer 299

* Sensitization produces hyperalgesia and allodynia * Primary hyperalgesia: the thing that happens at the site of injury * You can easily show that within the zone of injury, you get hyperalgesia and allodynia * Can get it for heat and mechanical stimuli * If you get away from the site of injury and enter the secondary zone (uninjured tissue) you can show mechanical allodynia and hyperalgesia but not heat

Answer 300

* Secondary hyperalgesia is mechanical only * 2 types of mechanical stimuli: poking (static) vs brushing (dynamic) * 2 types of secondary hyperalgesia: 1) Stroking hyperalgesia (allodynia) * Adequate stimulus: light stroking * Area: small * Duration: short * Central sensitization 2) Punctate hyperalgesia (static hyperalgesia) * Adequate stimulus: punctate stimuli * Area: large * Duration: long * Central sensitization * How they measure this, they give someone an injury and then start poking them from areas further away from the injury and draw out a map * From this they can draw a circle or oval * In doing these experiments they found that if they use stroking stimuli, the area of hyperalgesia doesn’t go as far * But if they use static punctate hyperalgesia, it goes further * The evidence that it's central sensitization, is mirror pain * Seeing allodynia and hyperalgesia on the other side of the body from the site of the injury and local desensitization/analgesia doesn’t block it

Answer 301

1) Rubor: redness (ruby) 2) Calor: heat (calorie) 3) Tumor: swelling (tumour) 4) Dolor: pain (douleur) 5) Loss of function - These all happen until you form a scab

Answer 302

- Because inflammation either causes or exacerbates: - Neurological diseases - Diabetes - Cancer - Cardiovascular - Alzheimer's disease - Pulmonary diseases - Arthritis - Autoimmune diseases - All of these things are happening as a side product of the immune system - It's the chronic low level inflammation that you can’t see that's the root of all evil - The obvious inflammation that you get after injury is probably the good one

Answer 303

- Ibuprofen (41%) - Acetaminophen (25%) - Aspirin (18%) - Naproxen (10%) - Other (5%)

Answer 304

* Derives from the bark of the willow tree * Chemical that comes from the bark of the willow tree is salicylic acid * Bayer company figured out how to turn salicylic acid into acetylsalicylic acid (ASA) * This was much gentler on your stomach than taking salicylic acid

Answer 305

- Meyer et al. (2012) - From coolest temperatures to hottest - TRPA1 ion channel responds to cinnamon, horseradish, and garlic, mustard oil - TRPM8 ion channel responds to mint/menthol - TRPV4 ion channel responds to BAA - TRPV3 ion channel responds to camphor - TRPV1 ion channel responds to chili peppers, capsaicin, protons

Answer 306

* David Julius * Won the nobel prize for it in 2021 * TRPV1 will activate to capsaicin * It can be blocked by resiniferatoxin * People are testing resiniferatoxin as an analgesic, found evidence that it works as an analgesic in dogs * There to respond to heat (anything 43 degrees or up will activate it) * Not just heat that activates it, but also protons (acid) * State associated with decreases in pH: inflammation, when tissues get acidic, partially because of the wound itself * Inflamed tissue is acidic * Once TRPV1 was discovered, people realized there are all sorts of receptors that affect TRPV1's excitability * Even if heat isn't there, all of this stuff can still activate TRPV1 * TRPV1 is also found in the olfactory bulb * Side effect that you may predict if something's in the olfactory bulb and you're going to block it: might interfere with smell * If you don't smell very well, then you don't taste very well * There was a time when there were 23 different drug companies in the world trying to develop drugs to block TRPV1 * Plants would want to evolve the ability to develop TRPV1 so animals leave them alone * A lot of plants want to be eaten by animals (especially birds) because the animal eats the plant including the seeds, flies out somewhere else and then poops out the plant somewhere else, covered in fertilizer which helps it grow somewhere new * The chili pepper plant does indeed want to be eaten but specifically wants to be eaten by birds, because it figured out that there's something about bird biology that the TRPV1 in birds responds to heat and protons in a normal way but don’t respond to capsaicin, so they can consume capsaicin * Example of co-evolution

Answer 307

* Transduction of Mechanical Pain * Mechanical pain has been much harder to understand * Today we also don't really understand mechanical pain * Ardem Patapoutian won the Nobel prize in 2021 for piezo * Piezo is the mechanical touch transducer * Also the gene that is suspected to be involved in masochism * It's been very hard to figure out the mechanical pain transducer, it may or may not be TACAN or TRP or TMC or DEG/ENaC * Everyone is working hard to figure out that any one of these is the mechanical transducer

Answer 308

- Mast Cells secrete 5HT (binds to 5HT), Histamine (binds to H1), PGE2 (binds to EP - part of COX), Bradykinin (binds to B2/B1) - Macrophages secrete Bradynikin (binds to B2/B1), IL1-Beta (binds to IL1-R), NGF (binds to TrkA)

Answer 309

Transformation of info from the environment into neural firing

Answer 310

- Heat - Cold - Touch - Cell lysis - Chemical (acids, bases, irritants)

Answer 311

- Cannabinoids receptors in the Rostral Ventromedial Medulla - Serotonergic mechanism (serotonin) - Odd that for such a popular drug, we don't know the mechanism or whether it binds to a receptor and which one

Answer 312

Cancer deaths

Answer 313

1) Gastritis Erosive (38%) 2) Dyspepsia (27%) 3) Gastric Ulcer 4) Gastritis (14%) ... 12) Erosive Esophagitis and Hiatus Hernia (6%) 13) Diarrhea, Nausea, Duodenal Ulcer (5%) 14) Upper Respiratory Tract Infection (4%)

Answer 314

1) Cancer (cancer pain) 2) Stroke (shoulder pain) 3) Diabetes (painful diabetic neuropathy) 4) Trauma (causalgia) 5) Shingles (post-herpetic neuralgia) 6) Stroke (post-stroke pain) 7) Surgery (chronic post-surgical pain ~7%) 8) Fracture (complex regional pain disorder)

Answer 315

- Organismic: - Genetic background - Sex - Psychological traits - Age (infants feel most pain and elderly women) - Circadian rhythms - Environmental: - Past experiences - Gender - Psychological states - Diet - Social factors

Answer 316

- Most heritable clinical pain (between 50 and 60%): 1) Rheumatoid Arthritis 2) Menstrual Pain 3) Migraine 4) Back/Neck Pain 5) IBS - Most heritable experimental pain (50-55%): 1) Punctate Hyperalgesia Area 2) Cold-Pressor Pain Intensity 3) Heat Pain Threshold

Answer 317

Most to least (between 65 and 75%) 1) Acetic Acid Constriction Test 2) Paw Withdrawal Test 3) Tail-Clip Test 4) von Frey Test 5) Autotomy

Answer 318

* Famous study (hidden-open study) * Placebo effect was being instituted * At min 25 using a hidden design, people were either given saline in which case the placebo continued or they were given proglumide which blocks CCK which lead to placebo getting even stronger * Means CCK is working in the opposite direction of placebo so it’s producing nocebo * Placebo and nocebo are working simultaneously but in opposite directions * If you do something in a negative direction to placebo, then you can infer nocebo effect * Proglumide is a blocker of CCK * Enhancing placebo is the equivalent of blocking nocebo * They concluded the proglumide was blocking nocebo therefore the CCK

Answer 319

- Subjectivity vs objectivity of measure (pain or depression vs. wound healing or Parkinson’s) - Nature of the verbal suggestion (“It can be either a placebo or a painkiller” to “It’s a powerful painkiller”) - Previous experience - Belief/expectation/desire of patient and clinician - Patient-clinician interaction (the “therapeutic context”): - “Bedside manner" (enthusiasm, reassurance, empathy, communication) - White coats - Deep voices - Physical properties of placebo itself: - Sham surgery > i.v. placebo > i.m. placebo > big pill > small pill - Expensive pill > cheap pill - Personality variables (ex: trait optimism)

Answer 320

* Lester Grinspoon "Marihuana Reconsidered" * In the 1960s with the counterculture flower power ideology, cannabis started to come back * This was political * People using cannabis were against political control and the Vietnam war * This book is a story of anecdotes of people coming to him about how cannabis helped them with their medical conditions * He wrote this book stating that we should think about cannabis again and that there's something important to it * In 1960s THC was first identified from hash by an Israeli scientist * 4/20 was the day Mekoulom wrote his paper on THC * In the early 1970s, now pharmacies had a molecule * It was approved for treatment for patients with HIV experiencing vomiting and for appetite stimulation * It was approved for HIV because AIDS patients went to physicians and said if they consumed cannabis, their appetite came back * Also for cancer patients going through chemotherapy * Nurses were allowing them to slip out the back and smoke cannabis because it was helping them with their nausea

Answer 321

* The idea was that people were not only starting to think about the potential medical purposes but they started rethinking the risk of these plants and extracts * Looking at these as products of abuse and misuse * Back then it was believed morphine wasn't that addictive if used properly * Pharma companies had started to recognize that these extracts had potentially really good purposes for treating pain * Isn't it a human right for people to get relief of pain? * Were starting to allow people with chronic non-cancer pain to be prescribed powerful drugs like oxycodone * The companies ignored the signals that these substances had high abuse potentials * "Pseudo-addiction" * Ignoring the addictive signals patients showed * Eventually couldn't ignore how many people were dying from these

Answer 322

* The cannabis story mimics the opioid story in some ways * Canada was one of the earliest countries to try to regulate this * Had to come up with a cultivation source * Licensed companies to grow cannabis in underground mines so people had no ability to access them * But at this time, the Canadian government said it had to be 5% THC (very low) * Patients were upset with this * By 2013, the Canadian government allows for more than one producer of weed and started to lighten up the regulations * Selling dried flower products to patients * Started going up 9%, then 12%, then became moister and started to taste better * In 2016, this allowed patients to grow their own cannabis * Given seeds by the producer * Had a limited amount of cannabis plants they could grow * This spiraled into an abuse risk because people would combine multiple growth licenses and growing large crops * In 2018, the legalization of non-medical cannabis use was made legal * Canada has not seen massive medical health concerns with this * What has happened is that people that were already using cannabis pre-legalization were still using it after legalization * People were scared that the younger pop would be using it but this hasn't been the case * We can now buy cannabis oil legally with a known amount of the chemical compounds for recreational purposes * Alcohol is far more dangerous than any of these compounds * Yet there are places you can go and consume alcohol (bars), but no such place like that for cannabis * Med doctors hated medical cannabis

Answer 323

* Set up a cannabis smoking lab * Showed that if you gave patients a pipe that they would smoke 25mg of cannabis (small amount) * Varied THC levels from control placebo to 6-9% * Took the puff and monitored them * Let them go home with the pipe and a prescribed amount of cannabis and told to do this 3x/week (promised they wouldn't smoke other stuff) * These were not regular users * Had to demonstrate that they have tried and failed all other pain management methods * This took about 2-3 months * Findings: * 9% THC was good for sleep, pain control and mood * First time anyone had shown that smoking a small dose of cannabis 3x/day helped relieve pain * THC was the active ingredient * THC and CBD are the interesting compounds * These are not patentable or licensable * No ones interested in doing these trials because you can't own that knowledge

Answer 324

* Nobody's ever really done a large-scale RCT with a cannabis product to show whether it works (efficacy and safety) * In 2021 the IASP conducted a presidential task force… * Advising pain clinicians of the world that they don't endorse the use of cannabis and cannibinoids for pain relief * "Reviews of preclinical research and clinical safety and efficacy of cannabis and cannabinoids for pain relief have identified important research gaps. Due to the lack of high-quality clinical evidence...."

Answer 325

* 2 months after the IASP's statement of not endorsing this type of research, the BMJ publishes another study * Their recommendation was that they had weak evidence for the use of cannabis but that if standard care is not sufficient, we suggest offering a trial of non-inhaled medical cannabis or cannabinoids fir people living with chronic cancer or non-cancer pain * Peer-reviewed study (task force was not this) * One of the main reasons these 2 differed: * This study had patient engagement and patients said if all else fails, patients said they want cannabis * IASP didn't use patient considerations

Answer 326

The psychology of pain

Answer 327

Diabetes is one thing that can cause ectotopic firing

Answer 328

- Stress is mild - Stress is chronic - After injury - After prolonged exposure to opioids

Answer 329

- Mu, Delta and Kappa - They're all inhibitory - When opioid receptors are activated, the neuron responsible for them is inhibited - Eventually, ion channels are inhibited or excited and the net result of all of this is inhibition

Answer 330

1) Mu - Agonist: Morphiceptin, DAGO (DAMGO), Normorphine, Sufentanyl - Antagonist: Naloxone (in high enough doses will also block delta and kappa) - Agonist effects: analgesia, Respiratory depression, mitosis (squinting), reduced GI motility (constipation - most common), nausea, vomiting, euphoria 2) Delta - Agonist: Deltorphin, DPDPE, DADLE - Antagonist: ICI 154,126, ICI 174,846 - Agonist effects: Analgesia 3) Kappa - Agonist: U 50,488, Trifluadom - Antagonist: MR2266 - Agonist effects: Analgesia, Respiratory depression (weak), mitosis, dysphoria (opposite of euphoria - people feel bad and blame it on the drug)

Answer 331

* Euphoria (fancy word for feeling good or feeling high) * Reason why people may take the drug dependent of whether or not the analgesia is working

Answer 332

- Opioid Receptors are Everywhere - They're in all different parts of the brain and in other places as well - Find them in the intestine - This specifically explains the constipation - Drugs go everywhere and if there are receptors everywhere they can bind to these - Opioids are dirty (as pharmacologists call them) - Dirty drugs are drugs that bind to receptors in lots of places - Some people believe all drugs become dirty overtime

Answer 333

* Receptors don't evolve to be activated by plant products but by things floating around * There are 3 genes: * POMC * PENK * PDYN * These produce beta endorphin, leu and met-enkephalin, and dynorphin A * Endorphin binds equally well to mu and delta * The enkephalins bind more or equally to delta than mu * Dynorphin A binds to Kappa * They all start with Tyr-Gly-Gly-Phe amino acid sequence * Endomorphins a bit different from this * Endomorphins are very potent and remarkably selective to mu * No one to this day has been able to find a gene that codes endomorphin 1 and 2 * POMC is a gene that produces a bunch of peptides depending on alternative splicing (beta endorphin is just one of these proteins)

Answer 334

* We know how opioids work probably better than any other analgesic based on this research * Had a preparation * Rat that's anesthetized * Doesn't feel the surgery but light anesthetic enough for the tail to flick as a reflex when a light is shining on it * The computer can both record from neurons in the RVM and turn the heat lamp on at appropriate times and tell whether the tail flicked or not * If the rat is flicking its tail = feels pain * With respect to pain there are 3 types of neurons: * Neutral cells * On-cells: right before the rat flicks its tail, they turn on * Once there's pain, these cells which are quiet turn on * A few milliseconds before the tail is flicked, the rat feels pain and that's when these fire * Off-cells: always firing * With DAMGO, the rat is becoming analgesic * Once the rat has DAMGO, the heat lamp is unable to stop the off-cell firing (there's analgesia) * From this data it appears that it's the firing of on-cells that causes pain and the firing of off-cells that causes analgesia

Answer 335

* The Eastern conception of Acupuncture relies on idea that there are energy meridians that are mapped onto the body and there are specific points on the meridians (acu points) * Specific acu points correspond to different organs * Don't have to be near the organ * If you have stomach pain, you can stick a needle in the knee if the meridian there is responsible for the stomach, then it should treat the stomach * There's not a shred of modern western evidence that this is true * But there's a lot of evidence that acupuncture is clinically effective * Most powerful of all acupuncture points: point in the web between thumb and index (very painful) * Teacher got both acu and oxycodone * Found that the analgesia of acu was better/stronger but oxycodone lasted longer and was less painful during the process * Explanations for how it works: * Opioid hypothesis: * You can show acute effects in rats and mice * Rats and mice don’t receive needle acupunture, instead they get electrode acupuncture which stimulates the tissue in approx the same way that a needle would * Analgesia is completely blocked by naloxone * If you do electro acupuncture at low frequency its mu dependent and of you do it at high frequency, then its kappa dependent and in the middle its mu, delta and kappa

Answer 336

* When you're a chronic pain patient and doctors say they'll put them on antidepressants, patients often have a negative reaction * Although a lot of patients have depression, many don't and don’t understand why we prescribe these * Treatment of chronic pain is given antidepressant for much lower doses * No treatment lag that we see for psychological disorders * Amitriptyline has a great NNT but has horrible side effects (ex: loss of libido): * Tricyclic antidepressant * 1st generation of antidepressants * SNRI: * 3rd generation of antidepressants * Serotonin noradrenaline/norepinephrine reuptake inhibitor * Better for chronic pain than SSRIs * Implies norepinephrine is more important than serotonin * SSRI: * Serotonin-selective reuptake inhibitor * 2nd generation of antidepressants * Selectively bind to serotonin pumps and inhibit these pumps so the serotonin will just float around * Agonist of serotonin * Makes for more serotonin * Norepinephrine: * PAG goes to locus sirolimus * Has a projection neuron that releases norepinephrine in the spinal cord * Norepinephrine and serotonin activate the interneuron which inhibits the pre-synaptic neuron * How descending modulation closes the gate/inhibits pain

Answer 337

* There are cannabinoid receptors in the brain * There because they have endogenous ligands of their own (ex: AEA and 2-AG) * CB1 receptors are very dense (all over the brain and spinal cord) * CB2 receptors are a little in the brain and spinal cord but mostly in the periphery * CBD: we're unsure * May do stuff but we don't know * THC: active ingredient in marijuana * Mostly binding to CB1 * Why it has the psychoactive effects that it has because it mostly binds in the brain * Evidence that cannabinoids work for pain is close to none (Barakji et al., 2023) * For chronic pain, it doesn’t look like these are great for it

Answer 338

* As of 2009, the US market was 27 billion * Has gone up since then * Most to least prevalent drugs: 1) Strong opioids (295) 2) NSAIDs (28%) 3) Anticonvulsants (ex: Pregabalin and gabapentin - 13%) 4) Antidepressants (11%) 5) Weak opioids (7%) 6) COX2 inhibitors (7%) 7) Local anaesthetics (5%)

Answer 339

* Phase 0 (year 1-4): everything that happens before a clinical trial * Pre-clinical research * Anything happening in animals, cell lines, etc. * Based on the strength of pre-clinical data, drug developers will say they want to clinically test a particular compound for a particular disease state * Clinical trials are typically in 3 phases * Phase 1 (year 3-6): not interested and usually doesn't collect data on if the drug worked for what it's designed to work for * About is my drug going to kill people or not * Usually the animal data will suggest whether it is deadly or not * Typically pay undergrads a lot of money to take the drug * In healthy volunteers without the disease * Phase 2 (year 5-9): actually look at if the drug works and beats placebo * Done in patients in a small number * If it beats placebo in phase 2, then they run 1 or 2 phase 3 studies * Phase 3 (year 8-12): * Phase 3 studies have lots of people in them * Can be very expensive * If the 3rd trial doesn't work, then it's either over or you go back and try to see what went wrong * If it works, they send their research over to the FDA * Every country has an FDA or EMA equivalent * Often won’t go to Canada to develop a drug, due to smaller market * Usually will go to FDA or EMA (US or Europe) Most countries will follow what the FDA says (very important) * After FDA approval, then market introduction

Answer 340

- Haematology has the highest success rate - Oncology has the lowest success rate

Answer 341

- Data can be more optimistic than reality because usually based on clinical trails that were published - Clinical trials are only published when they worked - If they didn't work, then they're put in a file drawer and are never seen - There's all sorts of motivation for the drug company and scientists to publish a study that works - For studies that don’t work, no one will get - The literature is biased towards things working - Most of the things that end up in the literature is that these drugs work - To address the file drawer problem, governments have started making it mandatory to: 1) Register the protocol of your trial 2) Pre-decide your primary outcome 3) After the trial is over, you have 12 months to at least put the results of the trial online even if you don't publish your findings (on the same website that you registered your study) - There's no reinforcement mechanism - Nothing that the government can do to make them put the results - Also if small clinic failed, probably went out of business and no employees to put the results online

Answer 342

1) Failure of NK1 agonists 2) Success of Prialt but has to be an intrafecal injection - Will only happen if someone has a lot of pain which won't happen for a very long time - Used for end-stage cancer patients who don't respond to anything else - This hence doesn't make any money - Succeeded but failed in that it didn't make anyone any money (cost a lot to develop) 3) Tanezumab - Situation where drugs pass the phase 3 of their trial but drug supervisors still say no - Tanezumab beat placebo (success) but because of the side effect problem, this didn't happen - Made people so much better but Pfizer suspended the project because it came to light that a small number of people's pain was better but their OA got dramatically worse 4) Anti-CGRP Monoclonal Antibodies and Gepants - 2 types of CGRPs: - Monoclonal antibodies - Administered by regular subcutaneous injection - Gepants: 2 pills (rimegepant and ubrogepant) - For treatment of acute migraine - Mabs are preventive or prophylactic treatment (preventing the disease from occurring) - Chronic migraine (if you get X numbers of migraines per month) - Cut-off: 14 per month - If you have this and respond to mabs, then it takes the 14 and brings it down to 11 - They work by either inhibiting CGRP and they do this in the dura of the brain

Answer 343

1) HSAN, Type V -no pain -no other symptoms -loss-of-function mutation 2) Paroxysmal Extreme Pain Disorder -pain and erythema -rectum and back of thighs -usually only in babies -gain-of-function mutation 3) Primary Erythromelalgia -pain and erythema -hands and feet -gain-of-function mutation - This discovery led to 20+ drug companies trying to create Nav 1.7 antagonists - Teacher has always been skeptical about this - Gene is expressed everywhere and also it's present from the moment you're born - So how could it be in one place and not another and how could it go away - There must be other genes involved

Answer 344

- Nav 1.1 (CNS, PNS, Cardiac muscle) - Nav 1.2 (CNS, PNS) - Nav 1.3 (CNS, PNS) - Nav 1.4 (Skeletal muscle) - Nav 1.5 (Cardiac muscle, skeletal muscle, brain) - Nav 1.6 (CNS, PNS) - Nav 1.7 (PNS) - Nav 1.8 (PNS) - Nav 1.9 (PNS)

Answer 345

Celecoxib (pfizer drug)

Answer 346

- December 1998: Celecoxib (Celebrex) approved - May 1999: Rofecoxib (Vioxx) approved - November 2001: valdecoxib (Bextra) approved - April 2002: Cardiovascular risk warning added to Rofecoxib - Sept 2004: Rofecoxib withdrawn from market - Dec 2004: Cardiovascular risk in CABG patients added to valdecoxib - Dec 2004: Cardiovascular risk warning added to celecoxib - April 2005: valdecoxib (Bextra) withdrawn from market

Answer 347

* Cox-1 is an enzyme that is constitutively expressed * It's always made, is always there * Needs to be there all the time because it's involved in housekeeping functions * It's important that it always be there so it always is * Cox-2 is an inducible enzyme * It's only produced when it's needed * The gene that codes this enzyme is only expressed when needed * It's inflammation that causes it to be expressed * Where: in the mast cells * Mast cells in the presence of inflammation will start to release PGE2 * The more Cox-2 expression you have in the mast cell, the more PGE2 you're going to release which leads to inflammation * The drugs we're using now are blocking both * But if we want an analgesic, we only want to block Cox-2 and leave cox-1 alone

Answer 348

1) Leukemia 2) AIDS 3) NSAID toxicity 4) Multiple myeloma 5) Asthma 6) Cervical cancer 7) Hodgkin's disease

Answer 349

- PGE2 - To the extent to which it binds to the EP receptor

Answer 350

1) Ibuprofen (41%) 2) Acetaminophen (25%) 3) Aspirin (18%) 4) Naproxen (10%) 5) Other (5%)