Table S4 has the blinding information, including "Bang's Blinding Index" (Fun new thing I learned). They assess the success of blinding in not only the participants but the CO-PI and the joint evaluators. The TL:DR is that there was some breakdown of blinding, with the index being 0.28 (ideally you want it between -.2 and 0.2, in favor of simulation. So perhaps blinding could at least partly explain the results.
Thanks for this post; I enjoyed it. I'm not fully sure I fully understand your point about the relationship of vagal-nerve stimulation to the placebo effect, though. Are you arguing that:
1. the placebo effect is clearly real, but our knowledge of its mechanisms is less that what we would like.
2. pharmaceuticals clearly can have a direct chemical effect in addition to their potential placebo effect
3. vagal-nerve stimulation, since it doesn't involve drugs, is probably operating by some of the same mechanisms as the placebo effect.
If so, I'm going to try and push back on #3 a bit. The human brain is arguably the final frontier of biology, and neural signaling seems intricately involved with the functioning of essentially every organ system. Altering that functioning electrically doesn't seem very different from doing so chemically, and thus wouldn't seem to have any more of an intrinsic connection to the placebo effect than a drug intervention would. Happy to go into it a bit further if desired.
We are seeing a proliferation of implantable devices to treat a variety of diseases using studies with questionable endpoints and questionable controls. It is hard not to see commercial interests rather than science driving this trend. Some patients are also inclined to see medical devices as having magical healing effects.
A colleague of mine once affectionately referred to this as "Gizmo Idolatry"
In the field of EP, the FDA required ICD manufacturers in the 1990s to show that ICDs reduce all-cause mortality as a condition for approval. Now devices just as expensive and invasive are approved using questionable subjective and surrogate endpoints.
In EP, we also learned about the power of the placebo effect from the randomized North American Vasovagal Pacemaker studies (VPS). VPS-I randomized patients with frequent vasovagal syncope to pacemaker or no pacemaker and showed pronounced reduction in the pacemaker group.
However, the apparent therapeutic effect disappeared in VPS-II in which all patients had a pacemaker implanted and were randomized to pacemaker on or off in a blinded fashion.
Dr. Cifu thank you for this post as it hits home in many ways for me. I truly enjoy this substack and of all the things I read daily in my inbox - I always look for the Sensible medicine email - always a value add and great to have civil and not nasty political debates. I don't' always agree with all the takes but I enjoy reading the "opposite view" as it expands my learning .I often share with other clinician friends that learn something and make changes in their practice and are enlightened by your analysis. Your work is important and as my Dad would say even one person can change the world. So keep it up!
In regards to this specific article, I wanted to comment on the content and how it totally hit home to me. Hopefully this won't be too rambling! Back when I was in college I had a professor who talked about how your "mind" and how you thought could improve outcomes in illness. (this was the mid 80s) At first, as a young didactic trained science major, I was skeptical. But over the years of living, practicing pharmacy (clinical practicing Pharma D in ambulatory, hospital, teaching, research and managed care), reading about therapeutics (and non western medicine especially) and as a patient myself at various times, I have come to respect this approach as a very important component in health and maybe the most important. When I went through breast cancer therapy years ago I had an amazing MD that used these techniques in addition to other medical metrics to manage my care. He became the most important person in my recovery . He was my oncologist Dr Fetting at JHU (who was also trained as a psychiatrist which I found out years later but didn't know at the time). His attentiveness, engagement, calm demeanor and caring totally changed my mental framework especially the first few years "post" treatment where most of the "support" from those around you has diminished because you are "well". but in reality it is a very fragile time. I give him a significant amount of credit for my mental and physical recovery and my lack of recurrence (20. years this year) Since then I discovered A "resort/spa" that focuses a lot on mindfulness as its main mantra for a healthy life; and I truly believe these types of approaches where we focus on these aspects of our health actually are more important than many other biological solutions. Our western society has gotten so focused on tech and science and driven away from spiritual/emotional health (mainly bc we don't truly understand or cant figure out how to measure it) that we have taken away an important part of healing. The community doctor who knows your family, knows and actually cares about you ,who can connect your history instead of looking at an error filled EMR and who actually does physical exams and listens to you is a true healer. As I always say the art of medicine is hard to put a price on and non clinicians often do not understand this. Hopefully in western medicine we will realize this and start to incorporate other "non scientist" types in medical care again and start to explore this more. To help this move forward, I believe liberal arts college degrees should be required for medical school acceptance not just science courses. We need family doctors not AI computers. Anyone who truly thinks AI will replace real medicine are misguided administrators. I pray this wont take very long to figure out - but it make take a long time for those non clinical admins to understand. Again, thanks for this post.
Dr. Cifu, don't you think the study design answers your question about whether or not the patients knew if they were in the active arm? "When the device was active, stimulation intensity was set to an upper comfort level..."
I read that part half a dozen times. If one could feel the stimulation, then the whole reason for going through the hassle of the sham would be a waste. I am giving them the benefit of the doubt but... not sure if that is warranted.
Thanks for sharing this interesting study, Dr. Cifu. I wrote an article about VNS a couple of years ago. Dr. Greg Plotnikoff (one of my favorite go-to sources, a truly remarkable physician) spoke with me at length about the results he was seeing in some of his patients with inflammatory conditions by using a handheld VNS device (no implantation required). One of his quotes has stuck with me: "For people who have struggled with stress and chronic inflammation for years, it offers proof to the body and mind that another state is possible." https://experiencelife.lifetime.life/article/how-to-reset-your-vagus-nerve-and-find-calm/
Interesting article to highlight. I do have concerns about the risks associated with very expensive biological drugs and the traditional DMARDs. Definitely seems to be a worthy intervention for RA patients. I like the swim in Lake Michigan approach.
Table S4 has the blinding information, including "Bang's Blinding Index" (Fun new thing I learned). They assess the success of blinding in not only the participants but the CO-PI and the joint evaluators. The TL:DR is that there was some breakdown of blinding, with the index being 0.28 (ideally you want it between -.2 and 0.2, in favor of simulation. So perhaps blinding could at least partly explain the results.
Yes!!!!! Thanks.
Thanks for this post; I enjoyed it. I'm not fully sure I fully understand your point about the relationship of vagal-nerve stimulation to the placebo effect, though. Are you arguing that:
1. the placebo effect is clearly real, but our knowledge of its mechanisms is less that what we would like.
2. pharmaceuticals clearly can have a direct chemical effect in addition to their potential placebo effect
3. vagal-nerve stimulation, since it doesn't involve drugs, is probably operating by some of the same mechanisms as the placebo effect.
If so, I'm going to try and push back on #3 a bit. The human brain is arguably the final frontier of biology, and neural signaling seems intricately involved with the functioning of essentially every organ system. Altering that functioning electrically doesn't seem very different from doing so chemically, and thus wouldn't seem to have any more of an intrinsic connection to the placebo effect than a drug intervention would. Happy to go into it a bit further if desired.
Joel
We are seeing a proliferation of implantable devices to treat a variety of diseases using studies with questionable endpoints and questionable controls. It is hard not to see commercial interests rather than science driving this trend. Some patients are also inclined to see medical devices as having magical healing effects.
A colleague of mine once affectionately referred to this as "Gizmo Idolatry"
https://jamanetwork.com/journals/jama/fullarticle/181743
In the field of EP, the FDA required ICD manufacturers in the 1990s to show that ICDs reduce all-cause mortality as a condition for approval. Now devices just as expensive and invasive are approved using questionable subjective and surrogate endpoints.
In EP, we also learned about the power of the placebo effect from the randomized North American Vasovagal Pacemaker studies (VPS). VPS-I randomized patients with frequent vasovagal syncope to pacemaker or no pacemaker and showed pronounced reduction in the pacemaker group.
https://pubmed.ncbi.nlm.nih.gov/9935002/
However, the apparent therapeutic effect disappeared in VPS-II in which all patients had a pacemaker implanted and were randomized to pacemaker on or off in a blinded fashion.
https://jamanetwork.com/journals/jama/fullarticle/196492
As a result, pacemakers are now used for this indication only in rare, exceptional circumstances.
We should assume that any implantable medical device will have a strong placebo effect and plan clinical trials accordingly.
Dr. Cifu thank you for this post as it hits home in many ways for me. I truly enjoy this substack and of all the things I read daily in my inbox - I always look for the Sensible medicine email - always a value add and great to have civil and not nasty political debates. I don't' always agree with all the takes but I enjoy reading the "opposite view" as it expands my learning .I often share with other clinician friends that learn something and make changes in their practice and are enlightened by your analysis. Your work is important and as my Dad would say even one person can change the world. So keep it up!
In regards to this specific article, I wanted to comment on the content and how it totally hit home to me. Hopefully this won't be too rambling! Back when I was in college I had a professor who talked about how your "mind" and how you thought could improve outcomes in illness. (this was the mid 80s) At first, as a young didactic trained science major, I was skeptical. But over the years of living, practicing pharmacy (clinical practicing Pharma D in ambulatory, hospital, teaching, research and managed care), reading about therapeutics (and non western medicine especially) and as a patient myself at various times, I have come to respect this approach as a very important component in health and maybe the most important. When I went through breast cancer therapy years ago I had an amazing MD that used these techniques in addition to other medical metrics to manage my care. He became the most important person in my recovery . He was my oncologist Dr Fetting at JHU (who was also trained as a psychiatrist which I found out years later but didn't know at the time). His attentiveness, engagement, calm demeanor and caring totally changed my mental framework especially the first few years "post" treatment where most of the "support" from those around you has diminished because you are "well". but in reality it is a very fragile time. I give him a significant amount of credit for my mental and physical recovery and my lack of recurrence (20. years this year) Since then I discovered A "resort/spa" that focuses a lot on mindfulness as its main mantra for a healthy life; and I truly believe these types of approaches where we focus on these aspects of our health actually are more important than many other biological solutions. Our western society has gotten so focused on tech and science and driven away from spiritual/emotional health (mainly bc we don't truly understand or cant figure out how to measure it) that we have taken away an important part of healing. The community doctor who knows your family, knows and actually cares about you ,who can connect your history instead of looking at an error filled EMR and who actually does physical exams and listens to you is a true healer. As I always say the art of medicine is hard to put a price on and non clinicians often do not understand this. Hopefully in western medicine we will realize this and start to incorporate other "non scientist" types in medical care again and start to explore this more. To help this move forward, I believe liberal arts college degrees should be required for medical school acceptance not just science courses. We need family doctors not AI computers. Anyone who truly thinks AI will replace real medicine are misguided administrators. I pray this wont take very long to figure out - but it make take a long time for those non clinical admins to understand. Again, thanks for this post.
Thanks for the kind words and the REALLY thoughtful comment.
Dr. Cifu, don't you think the study design answers your question about whether or not the patients knew if they were in the active arm? "When the device was active, stimulation intensity was set to an upper comfort level..."
I read that part half a dozen times. If one could feel the stimulation, then the whole reason for going through the hassle of the sham would be a waste. I am giving them the benefit of the doubt but... not sure if that is warranted.
Thanks for sharing this interesting study, Dr. Cifu. I wrote an article about VNS a couple of years ago. Dr. Greg Plotnikoff (one of my favorite go-to sources, a truly remarkable physician) spoke with me at length about the results he was seeing in some of his patients with inflammatory conditions by using a handheld VNS device (no implantation required). One of his quotes has stuck with me: "For people who have struggled with stress and chronic inflammation for years, it offers proof to the body and mind that another state is possible." https://experiencelife.lifetime.life/article/how-to-reset-your-vagus-nerve-and-find-calm/
Thanks for the reference.
Interesting article to highlight. I do have concerns about the risks associated with very expensive biological drugs and the traditional DMARDs. Definitely seems to be a worthy intervention for RA patients. I like the swim in Lake Michigan approach.