Lec. 2 (pain treatment + research)

Question 1

Trephination

Answer 1

The oldest treatment for pain known in the history of mankind. It was found on archeological sites all around the world. Ancient people believed that pain was due to evil spirits living in the head, and a hole in the skull would allow them to get out. Of course, it didn’t work, and was extremely painful in itself (because no anesthetics/analgesics at the time). Still, many of the skulls found show evidence of healing. The holes varied in their shape, location, size, and number.

Question 2

Theriac

Answer 2

An ancient treatment of pain which contained many different plant extracts and animal parts (varied in different geographical locations, depending on available ingredients). People at the time didn’t know what exactly in it made it work, so they The one we consider today to be the active ingredient is papaver somniverum (opium poppy), the original opioid.

Question 3

The 2 most common pain-relieving plants in history

Answer 3

Since the Ancient Times, the 2 most common pain treatments were Willow Bark (which contains a compound from which aspirin was synthesized; and most modern-day painkillers are inspired from its chemical structure), and the opium poppy (which led to the synthesis of all known opiods today, like morphine, heroin, etc.)

Question 4

Morphine and the Pharmaceutical Company

Answer 4

Buisness model: in 1668, it was hard to standardize the dose of morphine (between no effect and OD). The chemists of the Merck KGaA company (the 1rst pharmaceutical company) found a way to synthesize morphine in a way where it was easy to control the dosage. This was useful enough to start a buisness on it. Then, the chemists continued experimenting to try to find new drugs. To this day, pharmaceutics is the most profitable industry in the world (except maybe tech nowadays)

Question 5

1rst anesthesia

Answer 5

The Ether Dome at the Massachusetts General Hospital in Boston was the site of the first public demonstration of the use of inhaled ether as a surgical anesthetic on 16 October 1846. The surgeon John Collins Warren removed part of a tumor from Edward Abbott’s neck. After Warren had finished, and Abbott regained consciousness, Warren asked
the patient how he felt. Reportedly, Abbott said, “Feels as if my neck’s been scratched”. It was a first in the history of the world (the best people could do until then was getting patients drunk). But ether was dangerous (mortality rate of 1/100, compared to 1/100000 with modern anesthetics).

Question 6

Opiates vs opioids

Answer 6

Opiates are the synthesized versions of the natural opioids (opiates are manifactured opioids). What is commonly used as a pain-relieving treatment nowaday are opiates.

Question 7

Table of opiates compared to morphine

Answer 7

The table shows the doses of common opiates (injected or taken orally) needed to be equivalent to 10mg of morphine (injected intra-muscularly). For example, 1mg of methadone or oxymorphone has the same analgesic properties as 10mg of morphine. 130mg of codeine are necessary to achieve that effect (and 15mg of oxycodone). The table also shows the half-life of the medications, and the duration of their action. Fentanyl has a duration of action of 48-72h (it’s the one that lasts the longest of the table, morphine lasts 3-4h). Finally, the table also indicates some comments about the uses of each medication (ex. what it can be combined with).

Question 8

Routes of drug administration

Answer 8

The main difference between the different possible routes is in the timing: for certain routes, the drug takes longer to show an effect. Fastest are IV and inhaling (for getting to the brain quickly). For some drugs, the speed matters less. It’s easier to do an IM or SC injection than an IV (so, it’s a trade-off). Patches are probably the slowest, but also the easiest to use.

Question 9

How is the necessary dosage established?

Answer 9

Drugs don’t know where they’re going, so you need to inject more than the minimal required dose for the area if you want the drug to actually make it to the area and still have an effect (drug diffuses and has no effect on most of the body, only bind to some receptors).

Question 10

Pharmacodynamics vs. pharmacokinetics

Answer 10

• Pharmacokinetics: what the body does to the drug (this is essential to know how much of the drug to administer).
• Pharmacodynamics: what the drug does to the body (ex. what receptors it binds to)

Question 11

ADME in pharmacokinetics

Answer 11

• Absorption (through stomach, skin, airways… To get to the blood. Remember: we are donuts, the interior of the intestines is outside of our body - so an oral drug is not inside our body until it is digested)
• Distribution (when it reaches the bloodstream, it can diffuse everywhere in the body)
• Metabolism (the liver releases enzymes to break the foreign drug down)
• Elimination (urine, etc.)
  All of these steps can be optimized, so that the drug lasts the longest while causing minimal side effects. This is what most pharmacology is about.

Question 12

Patient-Controlled Analgesia (PCA)

Answer 12

Patient goes into surgery and in the recovery unit, where they can administer themselves the drug as soon as they’re in pain. The doses are programmed into the machine (the doses are controlled so that you don’t OD). Patients prefer this method and they also end up losing less morphine than when it’s administered by nurses and doctors. The only downside is that they’re expensive (for this reason, it’s not common in Canada).

Question 13

Opiate side effects

Answer 13

Most common one (up to 80% prevalence) is constipation, which makes it the most problematic one (constipation can actually cause higher pain than the original pain that was being treated, causing people to stop treatment). Nausea, vomiting, dray mouth (xerostomia) and sedation are also pretty common. Respiratory depression is the msot dangerous one, but it is very rare in chronic dosing.

Question 14

Why do drugs have side effects?

Answer 14

Because drugs go everywhere (any receptor they fit in). There are a lot of opioid receptors in the body, and in many areas of the brain, so many parts of the body can be affected by the drug in ways that they were not intended to be.

Question 15

How do you die from opiate usage?

Answer 15

Dying from side effects is rare. The most common death caused by opiates is OD, which usually happens when people take a much higher dose than they’re used to (for example in street drugs, when they’re laced with something else, like fentanyl, which is extremely potent). The one side effect that causes the main concern is addiction, which can then indirectly lead to the use of street drugs, which are more dangerous (less reliable) than prescribed ones.

Question 16

The problem with side effects

Answer 16

The side effects can be treated seperately - but the more drugs you take, the more at risk you are at having dangerous interactions (and even more side effects). It also increases your risk of developing an addiction to one of these drugs, for example if the drug causes severe withdrawal side effects (causing the person to take them constantly).

Question 17

Classes of drugs

Answer 17

There are 3 classes of drugs: prescription drugs (most often from doctor, but sometimes by nurses or other medical professionals), back-of-the-counter (not on the shelves; you need to ask the pharmacist who will determine if it’s safe for you, but there’s no need for a prescription), and OTC (you can buy from the shelves of any pharmavy or health store, they have a good safety profile)

Question 18

OTC analgesics

Answer 18

2 main classes: acetaminophen (not a NSDAI because it’s a pure an analgesic, without any anti-inflammatory properties) and NSAIDs (aspirin, ibuprofen, and naproxen sodium). Drugs often mix different active ingredients, so only if there are 4 common analgesic ingredients, there are many more oral OTC drugs.

Question 19

Should NSAIDs be OTCs?

Answer 19

Some drugs are just OTC because they’ve been around long enough (if they were discovered today, they would need a prescription), like the 4 common analgesics: aspirin (Bayer, Bufferin, Ecotrin), ibuprofen (Advil, Motrin IB), acetaminophen (Tylenol), and naproxen sodium (Aleve). These were shown to cause mortality in chronic patients.

Question 20

The WHO Analgesic Ladder for Cancer Painn

Answer 20

The WHO created an algorithm in 2007 for doctors to follow when adminestering drugs to treat pain for cancer patients. The first thing you try is a non-opioid (aspirin or acetaminophen), then a weak opioid (codeine), then finally a strong opioid (morphine). These can be mixed with other drugs (ex. anti-anxiety), and should be administered every 3-6h and not on demand. This three-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective.

Question 21

Analgesic-anesthetic trade-off

Answer 21

There is an opioid dose that will relieve all cancer pain, but that dose can be dangerous, and it sedates most people. It’s a trade-off between pain and coma. A high enough dose become an anesthetic.
For example, Putin’s army released a very strong opioid (trhough the air) in the church where a terrorist Chechen group was taking cover. The drug sedated them all, allowing for the armed forces to arrest them (while wearing gas masks).

Question 22

Current Analgesic Categories (US in 2018)

Answer 22

The category of analgesic that has the most active pharmaceutical ingredients (API) in it is cyclooygenase inhibitors (OTCs, with 24 API, including aspirin, acetaminophen, ibuprofen, etc). Opioid receptor modulators have 19 API (morphine, oxycodone, codeine, fentanyl…). Voltage-gated sodium channel modulators are anesthetics and include 10 APIs that often end with “-caine” (like cocaine, lidocaine, etc.). At the bottom of the table, with only 1 API per category, we fing SNARE inhibitors, adrenergic receptor antagonists, etc.

Question 23

Difference “-otomy” and “-ectomy”

Answer 23

-“otomy”: cutting it
-“ectomy”: taking it out entirely

Question 24

Problems with interventionalism

Answer 24

Pain takes a lot of routes to get to the brain: if you cut one, it doesn’t really solve the problem. Also, there’s no evidence that it works - and it would be unethical to come up with evidence. So, is it just a placebo effect? The thing is, people really want to believe that it works, but it doesn’t come without its risks, so it might not be the best thing to do.

Question 25

Complementary and Alternative Medicine (CAM) for Pain

Answer 25

The NIH has a whole institute devoted to the study of CAM (because of a senator once that had a wife that was healed by a naturopath, and so he wanted to legitimize it and have an institute that shows it works). But even when the institute proves smth to be a fluke, people who practice CAM generally don’t care (they woulnd’t practice it otherwise). A lot of alternative medicine is probably just placebo. Some of it maybe has some benefit, but it’s hard to prove. Some of it are jsut scams. Once Western medecine provides evidence for the efficacy of some CAM treatment (and start using it, ex. some plant in a new drug), it ceases to be CAM.

Question 26

Unconventional Analgesic Modalities

Answer 26

• There was one study (not replicated yet) that showed that the use of swear words (compared to no sound or simply screaming) has an analgesic effect.
• Music can be analgesic (this was replicated numerous times). It works better if you like the music, and if it’s exciting rather than relaxing.

Question 27

Self-Management of Pain

Answer 27

With chronic pain, unfortunately, not much helps. You just have to cope with it. This often angers patients, because they go to the doctor so that they can help them, but then they have to manage themselves. Accepting it is a journey that a lot of patients need to take.

Question 28

Story of Jeffrey Lawson, 1985

Answer 28

Jeffrey was born prematurely and had a heart defect; heneeded surgery. In 1985, doctors believed that babies didn’t feel pain, so he didn’t get any anelgesic or anesthetic (so he had open-heart surgery without anesthetic(, and he died a few hours later. His mother was a journalist and wrote an article on it. Soon after, doctors started using anesthetics on babies and manage post-OP pain.

Question 29

Analgesics used for babies today

Answer 29

• Sugar (sucrose - artificial sweeteners don’t work). For some reason, it works in babies (but it doesn’t in adults)
• Breastfeeding
• Kangaroo care (skin-to-skin contact): most effective when it’s the mother, but it also works with other people (father, nurse, volunteer…). It doesn’t make the pain go completely away, but it’s better than nothing.

Question 30

Heel prick for babies

Answer 30

The only way to get enough blood to make a blood test (this is necessary, esp. for premature babies). Some babies in the NICU have this done several dozens times a day (so, it hurts a lot). You can’t give them morphine or other drugs that are dangerous for babies, so you need to find alternatives. But how do you measure pain in babies?

Question 31

Multidisciplinary Pain Clinics

Answer 31

Created by John J. Bonica in the 1950s. until then, people went to their primary doctor, who then referred them to a specialist, then to another if it didn’t work, etc. In a multidisciplinary pain clinic, a team of different professionals (ex. primary doctor, phsyical therapist, etc.) decide on the appropriate advice and medication (personalized treatment for each patient).

Question 32

Multidisciplinary pain management (possible steps)

Answer 32

• Educational programming
• Physical therapies (structured and alternative movement therapies)
• Appropriate medical procedures
• Psychological therapies
  All these are ultimately decided by the patient manager (usually the primary care physician), and depend on the chronic pain patient.

Question 33

Palliative and Hospice Pain Care (cancer example)

Answer 33

The first thing they try to do is to cure you, but it often doesn’t work, and it shifts to an attempt to treat it (try to make things not as bad: palliative care, at home or at a hospital). Palliative care try to makes limited remaining time as comfortable as possible.

Question 34

Cancer pain

Answer 34

Some types of cancers are painful from the beginning, and some types are not painful at all in themselves. However, cancer metastasizes (metastatic cancer is always painful, because it spreads to the bones, muscles, etc.). At some point, all cancer patients have pain.

Question 35

The vital signs

Answer 35

Vital sign: you need this thing to be in a particular range to be alive. Vital signs are the things that nurses are required to document every time they check on a patient (to write it on the chart). They are so vital that you have to document them. Not only doctors can measure them, so it’s practical. The 4 commo vital signs are pulse, blood pressure (BP), temperature, and respiratory rate (pain is sometimes considered the 5th vital sign).

Question 36

Pain as the 5th vital sign

Answer 36

There was a movement in the 1990s advocating for nurses to also record pain levels when doing their check-ups.The problem with this is that pain is subjective, you don’t have any machine to measure it. It’s a good idea, although if your pulse or BP falls out of a certain range, you could die, but this wouldn’t be the case for pain.

Question 37

Evidence-based medicine

Answer 37

Evidence-based medicine only dates back from the 1980s, and most GPs today are barely at the “expert opinion” level. A primary doctor is not an expert (that’s the concept of a GP - know a little bit about as many things as possible). There are only a few experts in the world, in any field. Today, doctors still do whatever they want, but people generally argue that the things that are done to patients should have some evidence of efficacy. People agree in principle. Evidence-based medicine is easier said then done, some things don’t have enough RCTs, ex. there have never been a large RCT on dental floss, because why pay for one when everyone already uses it?

Question 38

Classification of evidence levels

Answer 38

From bottom to top (least good to best):
- personal opinion (this includes social media)
- Expert opinion
- Case reports (Doctors write about a certain patient - it’s better then expert opinion because it’s written down, you’re sure everything there is to know is there)
- Case series (series of case reports)
- Case control studies (experiments)
- Cohort studies
- Randomized controlled double-blind study (best kind of experiment, but only 1 is never enough evidence)
- Systematic reviews and meta-analyses (analysis of multiple RCTs)

Question 39

The Cochrane Collaboration

Answer 39

Organization that collects meta-analyses for every RCTs that have been made (every drug/treatment, every possible pain modulator, etc.), they put everything in clear statistical terms. It strives for a standardization of evidence-based medicine. They follow a strict method for all their meta-analyses.

Question 40

Randomized Controlled Trials (RCTs) steps

Answer 40

• Assess for eligibility
• Random assignment of treatment or placebo (made with a random number generator). Remember: the safest place to be is in a placebo group (you could still get results, but no side effects)
• For each group: intervention (taking treatment/placebo),m and then follow up. Some people don’t show up, or stop taking the drug at some point (as much as 30% are lost).
• Analysis of results (it’s often placebo vs. drug, but it can be comparison of 2 drugs)

Question 41

What are common “exclusion criteria” for pain trials?

Answer 41

• Not feeling pain (although rare), or not being a chronic pain patient
• Being already under treatment (some people are still allowed to participate, as long as they stop treatment long enough before the start of the trial)
• Having specific comorbidities
• Pregnancy/ breastfeeding/ wanting to get pregnant (you never know when a drug is going to be a teratogen)
• Having a certain age: for example, not babies (also, there are many treatments for pain that haven’t been tested for children, we just assume they work if it works in adults)

Question 42

Does it matter why people choose to stop participating?

Answer 42

Yes. For example, if they choose to do so because they experienced too many side effects. Also, some people could maybe have stopped because it worked so well they didn’t need it anymore. Most of the time though, people jsut lose interest because the drug didn’t work for them.

Question 43

What do you do with the data you already collected from a participant that stopped the treatment?

Answer 43

Some people cheat and still use the data, even though it’s incomplete, as they would any other data (they assume their results are the same as the last time they answered follow-up questions, or they assume whatever trend their data was following, ex. pain levels going gradually down, is not going to change). However, the data is often used in itself, to show that the participant chose to stop the treatment. There are all kinds of statistical models that help figure out what to do with that data.

Question 44

RCT designs - parallel “3 arm” design

Answer 44

Participants are randomly assigned to 1 of 3 conditions: experimental treatment, active control, and placebo treatment. The active control is a drug that already exists to treat the problem the experimental treatment is trying to treat. 3 arm trial costs 50% more than a 2 arms one.

Question 45

RCT designs - enriched design

Answer 45

At the beginning, everyone gets the experimental drug. Some people drop out if the drug has no effect on them, or if it creates too much side effects, you drop out. The people remaining have a good profile. Then randomly you cut back on the drug for some people (without them knowing), to see the effects. This might be considered cheating: you are pre-selecting people who the drug works for. That may be a too small percentage of the population to make it a widely distributed drug.

Question 46

RCT designs - crossover design

Answer 46

People start the trial with either the placebo or the drug. After the end of this first period, there is a rest time so that the drug can wash out of the body. Finally, treatment starts again, but this time people get the one they didn’t have before (either the drug or the placebo), so that everyone gets the drug and the placebo at some point.

Question 47

Crossover design pros and cons

Answer 47

• Pros: Better because everyone gets the drug, makes people hopeful. Also accounts for individual differences, everyone is exactly the same. Allows for within-subject statistical analysis, which allows for greater statistical power. So, it’s just more powerful statistically, so you can use a smaller sample (so it can become cheaper).
• Cons: It takes twice as long, so it might make it actually more expensive. Also, you’re assuming the drug has completely washed out (what if one of the drug has long-term effect? Or if it cures the problem entirely?)

Question 48

Pain clinical trial results (possible graphs)

Answer 48

• Change in pain levels in function of hours (with 2 curves: placebo and experimental drug)
• Patient preference for treatment (in %, comparison exerimental drug vs. placebo)
• Median number of days it took people to stop participating in the trial when they did (if you like the drug, you usually keep taking it)

Question 49

What if only one of the measures from a clinical trial is statistically significant?

Answer 49

The ability to analyze measures differently and have only one that is statistically significant lead to some cheating. The FDA + European Medicines Agency (MDA) are the most important agencies that decide what medication can go in the market. They have a new rule that companies now need to decide before the trial what statistical analysis they’re going to use (most of the time it’s change in pain levels through time). If the primary doesn’t work, it can lead to more research, but the drug can’t be accepted.

Question 50

Odds ratio (relative risk)

Answer 50

An odds ratio is the odds that the treatment works vs. that it didn’t work. This was originally used for cancer research (whether exposure to power lines makes you more likely to get cancer - or maybe if it protects you from cancer). For pain research, the row labels would be experimental drug vs. placebo; and the columns would be pain levels decreased vs. stayed the same. What they’re interested in is the decrease in pain, not the actual level of pain each person has (because no one is in 0 pain).

Question 51

Forest plots

Answer 51

Shows the meta-analysis of RCTs, in terms of the odds ratio. If the CI for the overall result doens’t encompass 0, the conclusion of the meta-analysis is that the drug is effective (significant result). The meta-analysis is there to resolve the discrepancies between different RCTs, showing their trustworthiness (sample size), their confidence intervals, etc. In the forest plot, each study is weighed in importance based on their sample sizes. They are palced on a scale of -20 to 20, with -20 favoring the drug and 20 favoring the placebo (and 0 no difference).

Question 52

L’Abbe Plots

Answer 52

RCTs are represented by dots of different sizes according to sample sizes, or drugs are represented by dots of different sizes according to the number of RCTs on them (sometimes the dots aren’t drawn in different sizes). The dots are compared to a diagonal that represents the 0-difference line between placebo and drug. The two axes of the graph are “percent with at least 50% pain relief with drug” (Y) and “percent with at least 50% pain relief with placebo” (X).

Question 53

Number-Needed-to-Treat (NNT)

Answer 53

The NNT is 1 over (the proportion benefiting from experimental intervention) - (proportion benefiting from a control experiment). This emans that the NNT is the number of people you need to treat so that 1 person (that wouldn’t have responded to the placebo) responds favorably to the drug. A high NNT number can be considered good or bad depending on context.

Question 54

NNTs for postoperative pain drugs

Answer 54

Drugs that end in “-coxib” (ex. etoricoxib, valdecoxib, etc.) have low NNTs in general. Most drugs (including acetaminophen, codeine, ibuprofen, naproxen, and morphine) are in the 2-3 NNT range. Aspirin has an NNT of around 4.5

Question 55

NNTs for Neuropathic Pain

Answer 55

Botox has a low NNT but doesn’t have a lot of papers on it. Opioids have an NNT of around 3. Gabapentin has an NNT of 6 (it’s quite big, but since it doesn’t do much harm, and it can help some people, it’s widely used). Also, a lot of papers were published on it as a marketing strategy from Pfizer (doctors trust widely tested drugs more, and it was a way to keep it in journals). Topical capsaicin has an NNT of 12, which is very large.

Question 56

NNTs of certain drugs for specific health problems

Answer 56

• Ulcers are now know to be due to a bacterial infection. Antiobiotics work almost everytime, meaning they have a very low NNT (1.1-1.8)
• Sumatriptan works well for migraines (NNT= 2.6)
• Antidepressants work well for painflu diabetic neuropathy (NNT = 2.9)
• Paracetamol works pretty well for postoperative pain (NNT = 3.6)

Question 57

Can drugs with very high NNTs for a specific condition be worth it?

Answer 57

Yes - but again, it depends on context. For example, aspirin for myocardial infarction has a high NNT (40: you need to treat 40 people with aspirin to prevent 1 heart attack). However, it’s still widely prescribed by doctors, because it’s cheap - the population is big enough, and 1/40 is already good (it’s a public health initiative - heart attacks cost more than aspirin to the healthcare system). So things with high NNT can be worth doing, not just for 1 patient, but for the population in general

Question 58

Number-Needed-To-Harm (NNH)

Answer 58

Same concept as NNT, but the other way around: it’s the number of patients you have to treat for one of them to develop a harmful side effect. You want the NNT to be as low as possible, and the NNH to be as high as possible. Gabapentin has an NNH of around 17, and capsaicin has an NNH of around 12.

Question 59

GRADE Recommendations

Answer 59

After a RCT is made, doctors meet to give a score to the trial. They quantify the effect size (NNT, odds ratio), safety, preference (ex. patient prefer patches than injections), and cost. No one is saying how to weigh these things against each other. At the end of the meeting, they just come up with a strength recommendation, and what type of conditions they recommend the drug for (if the drug should be a
1rst, 2nd, or 3rd-line treatment). Consensus is based on whatever the doctors choose. The irony is that the RCT data is found scientifically but the recommendations are subjective - but how could it be any other way? Computers? But how to weigh every aspect?

Question 60

The International Association for the Study of Pain (IASP)

Answer 60

• > 7000 members
• multidisciplinary (anesthesiology, neuroscience, psychology, etc.). Still, it’s mostly anesthesiologists, because it was originally founded by them. Anesthesiologists are the most interested in pain, and other specialists have their own associations that talk about various topics (including pain but not only)
• 126 countries
• 85 national chapters (including the Canadian Pain Society)
• publishes the journals PAIN (since 1975) and Pain Reports
• Yearly World Congress on Pain (since 1973)

Question 61

What is published in the journal PAIN?

Answer 61

• Purpose: most frequent is intervention
• Subject: most frequent is human patient
• Clinical condition: most frequent is chronic pain, followed by back pain (least frequent is spinal cord injury)
• Stimulus: most frequent is clinical
• Measure: Behavior

Question 62

Why are there more papers on neuropathic pain than arthritis when arthritis is more common?

Answer 62

Arthritis is more common than neuropathic pain, but there are more papers on neuropathic pain, because there are good animal models of neuropathic pain, but not very good models for arthritis, so neuropathic pain is more practical to study. It’s like the story of the guy that lost his keys at night but looks on the other side of the road than where he lost them, because that’s where the light is. That’s the only thing we can do in research, search what we can even if something else might be more useful.