I have a new term to add to the English language, ebolasmacked, a derivative of the British term gobsmacked. Ebolasmacked defines my life the last few weeks since Ebola, or at last preparations for Ebola, have taken a huge bite out of my time with many interesting twists and turns. I think this is maybe the 9th outbreak (HIV, MERS, SARS, Legionella, H1N1, Avian flu, West Nile, MRSA) of my career and it has certainly generated more hysteria relative to the risk than any to date. Many of my usual pastimes, like SBM (as this essay will no doubt demonstrate), have had to take a back seat to preparing for what should be a very unlikely, but very disruptive, event. We do not want to get caught with our hazmats down should a case of Ebola come through the door.
What makes life interesting, among other things, is the constant realization that the more you know the more there is to know. I like Richard Dawkins’ metaphor in Climbing Mount Improbable where he pictures scientific progress as a series of false summits extending into infinity. It sure seems that way. Every time I think I understand a topic, I find there is still more to learn.
My Dad told me when I graduated from medical school that half of everything I had just learned was probably not true, the only problem is that you didn’t know which half. It was partially true. There have been ideas that have been abandoned since I was an intern, the most famous being that ulcers were due to stress and diet. But a new paradigm has been the exception, not the rule.
The last thirty years have been more about refining knowledge about the complexity of disease and its treatment and, perhaps equally importantly, having a better understanding of the all slings and arrows of outrageous fortune that can make the results of a clinical trial suspect.
There are a series of false summits in medicine, but each is only a foot above the preceding summit, more a series of very long, never-ending steps in an ever-more refined and sophisticated understanding of disease. Recently, as an example, my gaster was flabbered to discover there are now 36 interleukins. Where did all those come from? There were, like, six last time I looked. As the national ID meetings last week demonstrated, yet again there are a never-ending series of fine points for processes about which I thought I had a good understanding.
It is one of the characteristics of pseudo-medicine of which I am jealous. Each practitioner sits at the summit of a perfect mountain, albeit one make of made of fog, delusion, and unicorn tears, with a perfect and never-changing concept of disease and its treatment.
I think I have a good understanding of the placebo effect, although perhaps I should say I have my understanding of the placebo effect. The comments will no doubt suggest mine is not a universal interpretation, but given the enormity of my ego, I think it is the correct one in clinical medicine.
I have multiple posts on the topic, so rather than repeat myself, although I do love to quote me, the one liner is: there is no placebo effect. Placebo (I know, I have gone beyond one line) are beer goggles, improving subjective end points with no change in objective endpoints. My archetype is from Penn and Teller’s BS episode where a lady reports her pain is better after treatment with a giant magnet that is actually a painted gutter downspout.
But why are some people prone to having a placebo effect, a subjective improvement, to a worthless intervention like homeopathy or acupuncture? Or a ‘real’ placebo as is used in a clinical trial?
Genes and placebo
I recently came across “Outsmarting the Placebo Effect” in Science, a short review of the genetic underpinnings of the placebo response. It is interesting, although early work.
The point of the article was to review the attempts to identify people who were prone to the placebo effect. There are compelling economic reasons to do this. If you are designing a clinical trial you want to know if your therapy is better than placebo. The greater the placebo effect in an intervention, the larger the number of patients need to be enrolled to demonstrate efficacy and the bigger the trial the more it will cost. If you can minimize the placebo response, you can move to smaller, less expensive and faster trials to show a new therapy is effective.
Dr. Kathryn Hall has found a relationship between the enzyme catechol-O-methyltrasferase (COMT) and a placebo response. The COMT enzyme breaks down catecholamines, which are neurotransmitters.
The COMT gene comes in two polymorphisms, with either a valine (val) or a methionine (met) amino acid at position 158. Since genes come in pairs, people can be val/val, val-met, or met/met. The met/met form of the enzyme has less activity, leads to more dopamine and:
has been correlated with variations in memory function, cognition, attentional processing, affect , confirmation bias , pain processing and sensitivity. Met/met individuals have higher levels of performance in cognitive tests, which measure executive function as well as increased sensitivity to experimental and chronic pain relative to val/met and val/val individuals.
Which combination of the genes is present is associated with perception of pain as people with met/met sense pain more acutely than those with the val/val form of the gene. But even more curious for this blog, met/met carriers also respond more to placebo.
They had patients from a previous study of irritable bowel syndrome who were treated with waitlist, sham acupuncture offered in a no frills businesslike way (a limited placebo), and a:
limited placebo arm augmented with a supportive warm provider who expressed confidence in the effectiveness of the treatment (‘‘augmented placebo’’).
In the original study, the more placebo offered, the better the response in the IBS-SSS score:
IBS-SSS includes abdominal pain severity, abdominal pain frequency, abdominal distention severity, dissatisfaction with bowel habits, and disruption of quality of life.
So they went back and genotyped everyone and looked at their response and their genotype. It was a nice, linear relationship: met/met with the most response on the IBS-SSS, the val/val had the least and the val-met right in the middle.
And there is more:
Significantly more drug-specific as well as general side effects were reported from homozygous carriers of the Val158 variant during medication as well as placebo treatment compared to the other genotype groups. Val158/Val158 carriers also had significantly higher scores in the somatosensory amplification scale (SSAS) and the BMQ (beliefs about medicine questionnaire). Together these data demonstrate potential genetic and psychological variables predicting nocebo responses after drug and placebo intake, which might be utilized to minimize nocebo effects in clinical trials and medical practice.
I recognize that genes are not destiny and that the final understanding will be far more complicated, especially in an organ as complex as the brain. Well, some brains. The ID literature is growing with reports of various polymophisms in Toll-like receptors and other proteins and the resultant increase or decrease in the risk of infections. My personal favorite is:
Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.
Translation: have the wrong snot, increase your risk of meningitis and death. And this is but one among hundreds of subtle variations in genes that alter our risk for disease. As Willie said “The fault lies not in the stars, but in ourselves.”
This leads to an alternative, and a testable, partial explanation for the continued popularity and loyalty to what should be worthless pseudo-medical interventions. It is not the innumerable flaws of the modern medicine or the wonderful bedside manner of pseudo-medical providers. It could be that there is a subset of the population that is predisposed to the perceived benefit of a pseudo-medicine and are receiving continuous positive reinforcement every time they get, say, an acupuncture treatment. It could also explain why so many different forms of acupuncture all have the same effects. It is not the beloved endorphins in the spinal fluid, instead acupuncturists are all stimulating the placebo centers in the predisposed. It would be interesting to know the COMT composition of regulars in a chiropractic or acupuncture clinic. Perhaps there is a preponderance of met/met polymorphisms in these practices.
And it would be interesting to know how the val/val patients respond to standard therapy as well since:
Despite their best efforts, many a warm and caring physician has had patients that seemed to derive minimum benefit from their empathic attentions. Our findings that val/val patients are less influenced by the placebo treatment, regardless of whether it is delivered in an augmented or limited context, potentially shed some light on this clinical challenge.
What is the distribution in somatosizers? Chronic pain patients? Or the distribution in TAM attendees or the commenters to this blog. I would love to know my own genotype, as well as how much Neanderthal DNA I have and where my genes come from. When asked my ethnic background, a popular question in Minnesota (Crislip. Where’s that name from?) I like to say my ancestors came from Hadar.
As I think I have mentioned in the past I am sometimes skeptical of free will and consciousness, suspicious that both are an illusion. So I am biased in favor of studies like this that point to variations in the meat machine that could alter its function. It is interesting to think about, and great grist for beer-fueled late night discussions.
Of Mice and Pain
The May 2nd Science had an article called “Male Scent May Compromise Biomedical Studies” and reviews how mice respond to pain.
Dr. Jeffrey Mogil studies pain in mice. Mice exhibit less pain response if there is someone in the room, even if that someone is a cutout of Paris Hilton. But even more curious, animals demonstrate even less pain response if there is a male in the room. Then they refined that response even more. It is the smell of the male that the mice were responding to:
So he told the people in his lab to place their worn T-shirts near injected animals and then leave the room. Even when the humans weren’t present, the results were the same. Rats and mice showed about a 36% lower score on the grimace scale when exposed to male versus female T-shirts, the team reported online this week in Nature Methods. (Female mice were slightly more sensitive to the effect). Placing a woman’s T-shirt next to a man’s T-shirt negated the impact. Bedding material from unfamiliar male mice and guinea pigs, as well as pet beds slept in by unsterilized male cats and dogs, produced the same response: Male odors seemed to act like painkillers.
He hypothesized that it is an evolved response to being potentially hunted. To show pain is to show weakness and make it more likely you will be attacked.
Does this apply to humans? Interesting question. Humans are not mice although it is estimated we can detect a trillion (not a typo) smells and those of you with teenaged boys know that is not an underestimate.
I think back to acupuncture pain studies and wonder what the gender of the acupuncturists was and if the gender of the therapist could have made a difference in pain. It is an interesting potential confounding variable, and would make for an interesting review of the acupuncture literature. Does the published literature demonstrate better results from male vs. female acupuncturists?
I remember one pain study, and I can’t locate it on the web or my drive (so many references to find that particular needle in the pdf stack), where several acupuncturists were used in a trial and only one had a consistent positive improvement on patient pain scores. I wish I could find the study as I wonder about the gender of the acupuncturists and perhaps the one with the better results was a more manly man, a user, perhaps, of Old Spice.
Acupuncture could be an excellent modality to tease out any effects on pain due to the gender of the provider. A researcher would not have worry about any real physiologic effects. It is reasonably clear that the features most associated with responding to acupuncture are knowing you are receiving acupuncture and believing or being told that acupuncture works.
Have male and female acupuncturists apply real and sham acupuncture (as if there is a difference) in a neutral manner and double blind methodology. If there is a gender difference due the provider and patients’ pain it would be very interesting.
Another step up.
Now back to Ebola preparations.