Midterm 1 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