>> Okay. We've almost made it to the end of the day, so sorry if I bore you. Hopefully I don't. [Laughs] I'm going to be talking today in this last talk about "Acupuncture". And for me it's been a really nice journey to be in this field for the last 25 years, and sort of see how things have changed and how the pendulum has kind of swung back and forth. As Dan talked about in the beginning like fibromyalgia in the early days wasn't even considered a real condition. And so acupuncture also has gone through a period where it's been discredited and there's been a lot of controversy around it. And there's been a lot of people who don't understand what acupuncture is, and what the research actually has shown about acupuncture. And hopefully, what I present to you today might be some information that you may not normally experience or have been experienced getting exposure to. So when we talk about acupuncture, we're actually talking about a component from traditional Chinese medicine. And there's a lot of different things that are considered alternative or complementary. But the term nowadays is called "integrative". So we call these therapies "integrative interventions". And so acupuncture is part of the mind body class of products interventions. And how often are we using these things? So this is a survey that's kind of old, but there's not really a more recent one. This was one that was done in 2007. And you can see that there's a lot of different mind/body therapies. There's prayer, there's meditation, there's massage. And actually, acupuncture here is very low utilized. There's not very many people that have gone to use acupuncture in 2007. But still it's estimated that about four billion dollars have been spent that year in out-of-pocket expenses for this. So this is not something that you typically go to your primary care physician and say, "Hey, I'd like to try acupuncture." They may not even know where to send you, where to go to get acupuncture. So a lot of what -- it's surprising to me that acupuncture has still been around over the years, because many of these people are paying for this out-of-pocket rather than getting reimbursed. So what is acupuncture? Has anyone had an acupuncture treatment in the audience? All right; wow there's quite a few of us. Okay, so that's good. So you can see the acupuncture needles there. You've got a handle and a needle that gets inserted into the skin. So these needles are not like a blood-drawing needle like a hypodermic-type needle to draw blood. They're solid, they're not hollow. They're designed to not puncture veins or arteries, so you get very little bleeding with this. And many times, you don't even experience the needle getting inserted into the body at all. So many times, the experience can be actually quite comforting. And so acupuncture is a part -- it's not the whole thing, it's a part of traditional Chinese and East Asian medicine. And so it includes things like Tai chi. So we heard others today talk about how exercise is very important, and getting the body moving and getting motion is a very important thing. And so Tai chi is a component of Asian medicine; and so that's a movement exercise. There's [inaudible], which involves massage. And so then there's also acupuncture, which is a component which may be part of the intervention that you would get exposed to. So with acupuncture, there's typically manipulation of the needle. Once it's inserted, it might be a manual manipulation. There might be thermal manipulation where they put an herb called "moxa" on the needle and light it, and that will give heat that then gets penetrated into the body. There might be electrical acupuncture where they run electric current through the needles. And there's also chemical acupuncture where there's an injection of herbal substances into the body, which isn't done in the US, but is very commonly prescribed in Korea. So there are different theories behind acupuncture. And each time acupuncture has been introduced into a culture, it's been changed. So acupuncture in China is different from Korea, is different from the acupuncture that you will find in Japan, and also in Europe and in France. But typically, it involves this concept of meridians and channels where the substance called "chi" is thought to flow. And chi doesn't really translate very well into the Western language, but chi is basically in essence you can think of it as an energy or a function of the body. If you're functioning well, if you've got energy, if you're vital, then you're thought to have good chi and good health. So you may not believe that and that's quite all right if you don't, but let's just see what the research kind of shows behind acupuncture, and what it has shown us. So here I'm plotting a paper that came out in [inaudible] a couple years ago, which I think is quite interesting. So it's plotting the number of publications in acupuncture over the last 20 years. And what you can see in the black circles are acupuncture research. So you can see that over the last 20 years, the number of acupuncture research articles has increased almost four and a half fold from 1995. And then as you can see in the triangles on the lower part -- the triangles on the low slope there, those are actually just biomedical articles. So you can see the number of acupuncture research studies has increased dramatically and has outpaced actually the amount of research studies that have been done in more biomedicine, more generic biomedical literature. Interestingly, before the 1970s, there were no research articles on acupuncture really to be thought of; and it actually happened that when Richard Nixon went to China and gave some lectures there, one of his news staff members had a case of appendicitis while he was in China. And they actually did an appendectomy on him, and used acupuncture as the analgesic for him. And he had such a nice response that he wrote an article when he got back to the United States, and that just basically set off this trajectory of increasing in acupuncture research. So now I'm going to go through to what I think is more of the definitive clinical trials that actually show that acupuncture is effective for chronic pain. And these trials are part of this acupuncture trialist collaborative, which is a group of many researchers throughout the world that have decided to pool the clinical research data from protocols that were standardized and generalized across the sites. And so this acupuncture trial's collaborative was basically designed to answer two questions, each of the two primary questions. One of them was, you know, "Is acupuncture better than standard care? Is it better than usual care that people are getting for their chronic pain?" This is a very real-world situation. A patient may come to the practitioner and says, "Am I going to benefit from this?" So that's question one. Question two is more of a methodological or mechanistic kind of research question and that's asking, "Is acupuncture better than sham treatment? So that's like is acupuncture better than a placebo control?" So why I think these studies are most definitive is because of the numbers of patients that were in this trial. So they combined data from over 29 clinical studies; 17,922 patients. So this is very, very well-powered. Over 20 of the trials had sham controls, so that's going to answer research question two; there was about 5,000 patients in those studies. And 18 of the trials involved the non-acupuncture control, so that's like the usual care or waitlist control. And those studies had over 14,000 patients in them, so very well-powered studies. So the types of non-acupuncture controls that were used were variable. So some of them involved no additional intervention, some involved wait listing, some involved an intention control, like an education, for example; or it involved usual care that the patients might be experiencing. And so this next slide I'm going to show is a forest plot of the facts of acupuncture, versus usual care or no acupuncture controls for low back and neck pain. And I don't know if you know what this type of a plot shows, but it's called a "forest plot". And the vertical line that's centered around the zero delineates whether the study favored the control, or whether it favored acupuncture. And what you can see on the rows are individual studies. And the dot in the middle is the mean value. And then the whiskers represent the precision around that mean value. And so if the whiskers cross the vertical zero line, then that study sort of failed to show a significant difference between the control intervention, which in our case is usual care, or versus acupuncture. And so as you can see on the study, many of these trials are shifted to the right, and that means that they're favoring acupuncture versus usual care or no acupuncture controls; so that's for low back pain and neck pain. Here's the same thing for osteoarthritis pain, again showing a favorable response to acupuncture versus no acupuncture control. And here's headache and migraine, again showing a favorable response to acupuncture versus the control. So this is a summary of those slides. And it lists the effect size and the P value. And I think the P value is very impressive. All these studies have a P value of less than .01. But what I think is really remarkable is the effect size there is .4 to .57. So in the terms of a clinically meaningful effect, that's a moderate effect size, which is very, very respectable for this intervention. So that sort of says that acupuncture is effective, that it's useful when you compare it to no treatment or usual care, which is I think the actual situation that most patients are in, they don't really care so much about whether acupuncture is different from a placebo or not; they're more interested in getting relief. And so this data, I think, is fuel for that argument. But for those of you that are interested in placebo controlled studies, what does the clinical trial's results suggest about placebo controls? So you may be wondering, "How do you control for acupuncture? What is a placebo for acupuncture?" And it turns out there's no gold standard placebo control that we actually have in our hands. There are a number of different ways that you can go about fooling someone into thinking that they've got an acupuncture treatment. One of the more common ways is using a non-penetrating needle. And so what you can see there is the person's hand with a Band-Aid on it. And they would insert the needle into the Band-Aid. And the needle is actually blunt, so it doesn't actually penetrate the skin. But when you press down, the needle retracts into the handle just like a stage dagger retracts when you get stabbed with a stage dagger. So it looks like the needle is going in, but it really isn't penetrating the skin at all. So that's called the "[inaudible] needle", because he's the one who invented it. And that's a very commonly used sham treatment. There's also studies where you just prick the skin to make them feel like they've got needle inserted, and they've been blindfolded so they can't see what's going on. So there's a number of different ways that you can control for placebo effects. So let's see what the clinical trials look like now. So these are the same conditions. This is low back pain and neck pain again. And so in these studies, again you can see the preponderance for all of these clinical trials. The mean effect, or the dot, is shifted to the right of the vertical line at zero, showing that it's favoring acupuncture. That's for low back pain. This is for osteoarthritis of the knee. So again, some of the studies are crossing zero, which means they're not showing a difference between acupuncture and control. But you can see that the preponderance of the data is shifted to the right for osteoarthritis. And then you can also see that again also with headache and migraine. So this is a summary now looking at the same conditions. We haven't changed the active ingredient in our active group, it's still acupuncture; we've only changed the control group, which was the placebo control. And here you can see the effect sizes are much smaller. They're on the smallest range from .15 to .23; but they still are statistically significant. So the critics in the acupuncture field -- and there are many, many critics out there, say that this is just not a clinically meaningful effect, that this effect size isn't worth studying and it isn't worth offering for patients. But I would argue that the placebo-controlled study isn't necessarily the real-world setting that the patient experiences. I don't think when the patient goes to the doctor that the patient says, "Give me something that's not sham acupuncture," they just want pain relief. And I think that's something that's kind of overlooked. So the conclusions from these clinical trials is that acupuncture is effective for chronic pain, and it has a moderate effect size. And the effect of the needling is statistically significant; it's smaller than effect size. But it suggests that there are factors other than the needling, then, that are key at reducing pain. It's not just the needling that's involved in the pain reduction, it has an effect, but it's not quite as large as the effect of the nonspecific contextual factors that go around the intervention. So now I'd like to go into some studies which might -- one study which might show why you might need so many people to show a difference between [inaudible] or real acupuncture and sham acupuncture. And this is a study which we did in 2003, which showed that fibromyalgia patients are not all identical. So even though individuals that get a label of chronic pain and get a diagnosis of like knee osteoarthritis or fibromyalgia, they're not all homogeneous. There's actually quite a lot of variability even within the clinical diagnosis. Like what we've been talking about today is conditions like fibromyalgia is just the tip of the iceberg. Many osteoarthritis of the knee patients have conditions going on within themselves that are indicative of centralized pain and fibromyalgia pain. And so in this study, we show that there were three different types of fibromyalgia patients, and some of them could be -- you could categorize them as conditions of anxiety and depression, as well as QST measures, which is this MRS score on the right. You can find type one individuals have very less -- very low amounts of tenderness, whereas type three individuals have quite high amounts of tenderness. And so that sort of behooves us to ask the question about, "Should we actually design the treatment to best target the pathology in the patient?" And so this is an article that came out in 2001 by the late Mitchell Max and Clifford Woolf. And they were some of the first individuals to really suggest that, "If we could actually more accurately pinpoint the pathology of the patient, we might be more able to design a treatment to target them." And so we wanted to do that with acupuncture. And so these are results from the acupuncture clinical trial that Dan talked about. This is the third acupuncture study that was funded by NIH to look at the treatment of acupuncture for fibromyalgia. And here we've just reanalyzed the data in a way to look to see if there was a difference in responsiveness to the treatment based on the sensitivity of the individual person. And so what I'm plotting here is the sham group is on the upper left and the [inaudible] or acupuncture group -- two acupunctures on the upper right. And what I'm plotting on the Y axis is their clinical pain response to acupuncture, which is increasing treatments go along on the right. And you can see that interestingly in the sham group, as they get more sensitive to needling sensations, they get a very dramatic increase in their pain reduction; so they get a very dramatic decrease in their pain. Now, look at the real acupuncture group in the same scale. They actually show a very remarkably different phenotype, even it looks like in the [inaudible] group as they get more sensitive to the needling, they actually get worse with the acupuncture. And that's something that many therapists will sell to you, that if you treat an acupuncture patient and they have fibromyalgia, you're not going to stimulate the needle very strongly, you're not going to get a really strong sensation because they actually don't like it so much. And so if you look at the rest of -- the whole rest of the continuum, you can see there's a dramatic difference between whether someone responds to sham acupuncture treatment versus real acupuncture treatment, based on how tender they are to the thumb, as well as how sensitive they are to needling. And to bring this home, that means that if you target the right patient with the right treatment, it might require less individuals. So for the acupuncture trialist collaborative that required 1,900 to even 7,000 people in your trial to power a statistically significant difference between [inaudible] or real acupuncture and sham acupuncture. But if we limited this to the patients who had high pressure pain thresholds, we'd only need 280 to show a difference between real and sham acupuncture. So actually, I think there's a lot more that we don't understand about this intervention. And as the research progresses, I think we're getting a more clear understanding about who's more likely to benefit from this treatment and who's not. I'd like to segue now into some more mechanistic studies, which I think are important for chronic pain. There have been a number of trials that have looked in the brain to see how acupuncture affects brain activity. And this is a meta-analysis of 34 fMRI studies, and they've shown that yes indeed, acupuncture needling can increase brain activity, specifically in the insula, the mid-singular cortex, and the thalamus. And these are areas which sham acupuncture doesn't always get. Look at sham acupuncture of the blue regions and the green is the overlap. So you can see that there are some areas of the brain which show similar activations with the sham treatment as the [inaudible], but there are definitely some areas which are showing differences between real and sham acupuncture. We did a study here at the University of Michigan that showed that acupuncture was quite effective at changing brain opioid receptor binding. And I think this is important given the recent climate of the opioid epidemic that we're having. And there are many that have proposed that acupuncture might be an effective tool to help reduce the craving in people who are addicted to opioids, and maybe reduce the long-term dependence on opioids as well. I'd like to highlight another study by my colleague, Vitaly Napadow in chronic carpal tunnel pain patients. He did a study where he gave carpal tunnel patients -- local acupuncture was in one group, so acupuncture designed of the wrist where the carpal tunnel is; and then another group got distal acupuncture, which you may not be aware of, but there's a theory that if you have the pain, say, in your wrist, if you treat the ankle on the opposite side, that might be effective at helping. Very counterintuitive, but it actually has been borne out in research that that might be effective. And then the third group got sham acupuncture. And what was remarkable in Vitaly's study was he found that both the local acupuncture treatment affected brain structural connectivity in the area of the sensory cortex around the wrist with local acupuncture. He found that acupuncture in the ankle distally affected connectivity in local structures in the S1 leg area, but that then had an effect on carpal tunnel pathology in the wrist even. So that's really remarkable. And it suggests that local and distal acupuncture might have differing effects on pain in the wrist, where local acupuncture effects S1 or sensory cortex area in the wrist, which then is involved in healing of pain in the wrist, whereas the distal acupuncture works via another mechanism. So I like this slide here, it's kind of funny. "You've got to be kidding, your back still hurts?" [Laughter] So you have stuck needles everywhere. So it may not be too critical exactly where the needles are placed, but I think it is very important to have skin penetration, and I think it has an effect. But has this really changed the way healthcare is given? Has this research actually ever, you know, changed the way patients are treated? So the Acupuncture Trials Collaborative did a lot of studies in Germany. And actually the German Healthcare System was funding a lot of these large clinical trials of acupuncture. And what's interesting is that actually the studies resulted in a large increase in the number of treatments that patients were getting with acupuncture; it increased about 20%. The German Healthcare System will pay for these treatments now. They will pay for low back pain; they will pay for knee osteoarthritis. Similar effects were seen in the UK following these studies. So the United Kingdom's National Institute for Health and Care and Excellence recommends now acupuncture for low back pain and for headache. So that's a nice response to the research. So what about the National Institutes -- what about the United States and the National Institutes of Health? So interestingly, the NIH has funded a lot of the basic and the clinical research in acupuncture. And there's a specific institute, NCCIH, which is funding a lot of this research. It's unfortunate to know that the American College of Rheumatology, actually in 2012, their recommendations, which is kind of remarkable, they say that, "Treatment with acupuncture is conditionally recommended only when the patient with knee OA has chronic to moderate to severe pain, and is unwilling or contraindicated to undergo arthoplasty." So that's kind of dramatic. So I would be shifting a little bit away from that. I think that acupuncture is quite effective for knee OA, and is definitely something that I would recommend a patient to try, at least. And I think it's worth trying because it's quite safe. And this is something that can't be said for some of the interventions that we have. So this is just one study, which was published in 2004, and very large trial, 97,000 patients, 7,000 physicians, in Germany treating low back pain, OA, and headache. So these patients received on the order of eight sessions that exceeded, which means they got over 760,000 actual separate treatments. They had about 7,000 mild adverse events. These were involving needle pains and hematoma, which is very common; and those very quickly resolve. But of those 760,000 treatments, there were only six serious adverse events. And the most common were pneumothorax. There were two that -- two pneumothorax events, which were due to inappropriate protocol. Most acupuncturists know not to insert needles into the back -- perpendicular to the back, because then you can penetrate the lung and cause a pneumothorax. So that's kind of something that you wouldn't see normally at all. And then the other serious adverse events were just maybe related to the acupuncture. So I would say that's pretty good. You know, out of 760,000 treatments, only six were serious adverse events; and a lot of those could have been prevented with accurate protocol. So I think acupuncture has barriers. There's definitely -- increased access is really needed. How many of you know where to go to get an acupuncture treatment if you're interested? So some people do. That's great. Not everyone does. And so I would suggest if you're interested in getting acupuncture, there's a board, the National Certification Commission for Acupuncture and Oriental Medicine, NCCAOM, is a website that you can go to, and you can click on find an acupuncture who's board certified in your zip code. And I think this is an intervention that we need to be actually putting more on the front line. Many times when people seek out acupuncture, it's after they've tried everything else; they've tried surgeries, they've tried all sorts of drugs, they've tried everything. And they're at their wits end and they're like, "Okay, I'm now going to try acupuncture." You know, it's amazing that this therapy is still around, because the acupuncturists have been treating the dregs, you know, for many, many years. [Laughter] And the effects can be seen, because it's still around. So in summary, I'd like to say that acupuncture I think is effective at reducing pain. I think it's more than simply placebo. I think it alters brain function and structure, which we've touched upon a little bit. I hope you understand that acupuncture is quite safe. Outside of the US, acupuncture has been fairly well-incorporated into clinical guidelines. And I do think acupuncture access is needed, especially in this post-opioid era of pain control. And I'd like to thank the team. And I'd like to point out Noah Zucker, who was a medical student at the University of Michigan here, and he did some of the analysis of the needling sensitivity and did a very nice oral presentation at a conference. And I worked with him for a number of months, and he did very well and I was very happy to mentor him. And finally, I'll end. There's an acupuncture research meeting in Vermont in a couple weeks. If anyone is interested in learning about how acupuncture is changing and getting more incorporated into healthcare, that's going to be a topic at the conference. So thank you very much for listening. [Applause]