Chronic Pain Chronicles with Dr Karmy

Episode 4: Regenerative Medicine in Pain Management - Is it a medical breakthrough or a scam?

• Dr Grigory Karmy • Season 1 • Episode 4

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An in-depth discussion of the most popular regenerative medicine approaches to chronic pain management in Ontario. Approaches discussed include Prolotherapy, Prolozone, nSTRIDE, PRP, and autologous stem cell injections. The pros and cons of each approach is discussed to help you decide whether or not you want to dip your toes into one of these approaches.

Tune in to learn about which regenerative pain treatment is the right fit for you!

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Dr Karmy:

There is at least a possibility that these treatments slow down the aging or reverse aging related processes.

Raveena:

Welcome to Chronic Pain Chronicles with Dr. Karmy, where we embark on a journey to uncover the transformative potential of regenerative medicine and chronic pain management. I'm Raveena, your host and guide through the intricacies of this evolving field. Today we confront a pressing issue, the intersection of chronic pain and innovative treatment options. With approximately 20 percent of the population grappling with chronic pain, finding effective long term solutions is needed more than ever. Today, we'll explore the latest advancements in regenerative treatments from prolotherapy to stem cell injections and delve into their potential to revolutionize pain management. As we navigate the landscape of pain management, we're privileged to be joined by Dr. Grigory Karmy, a seasoned expert in pain management with over 20 years of medical experience.

Dr Karmy:

Hello, this is Dr. Karmy, and I just wanted to share some thoughts on regenerative medicine. So, for starters, what is regenerative medicine? Regenerative medicine is a field of medicine where you are trying to stimulate your body to heal faster or to regenerate tissues like cartilage, for example, in a damaged knee. Regenerative medicine is not limited to pain and musculoskeletal system. There are a number of studies for all, any number of disorders ranging from heart to neurological system, conditions like multiple sclerosis., however, for the purposes of this podcast, I'm going to focus on what I know the best, which is musculoskeletal conditions. There's also an advantage that the best research and the most amount of research has been done in musculoskeletal conditions. First of all, obviously, the premise is that is very appealing. We're all getting old. We all sustain injuries. Osteoarthritis is thought of as a wear and tear condition where cartilages become worn out over time. There's any number of other Other things that wear out in our body, including discs, wouldn't it be nice to reverse that process? Wouldn't it be nice to reverse aging of our musculoskeletal system? Instead of covering up the wear and tear by maybe giving a patient some pills that reduce pain or giving a patient some injections that reduce pain, or doing a procedure to destroy the nerves that send pain signals, wouldn't it be better to just fix the problem? So, clearly, that is a very Attractive solution. However, like anything else in life, things are not as straightforward as they seem. Also, I guess a disclaimer, what I'm going to talk about is evidence based, in the sense that there are some studies to support the things I'm going to say. However, there's a difference between having some studies and being able to prove that something is actually a certain way in medicine. And certainly for most treatments that we use in pain management, and we're not just limiting it to regenerative medicine, the evidence to support these treatments is relatively weak. Uh, there's a number of reasons for that. One of them being that just generally speaking, biologically, different people are different and often respond to different forms of treatment. This is more so in pain than any other field in my experience. Also there's the issue of incentives. A lot of treatments in pain, and that includes regenerative medicine, cannot be patented. The usual business model in medicine is that you develop a drug, you spend maybe a billion dollars developing it, and that includes a lot of that money going towards studies to prove that it works, to prove that it's not dangerous. And then for the next 20 years. Your drug is protected. You are the only company that can manufacture it and then you make all your money back and then some. The problem with most approaches to pain management is that then one cannot patent them. So there's really no business case to be made for a company to do a Very large study and often in pain management to prove anything definitively, you do need very large double blind controlled trials. Well, if you're not going to spend hundreds of millions of dollars, or even tens of millions of dollars on a big study. If once you complete the study, there's no way for you to recoup your investment and make some money. So what happens for most pain management studies, and I'm talking in general, I'm excluding drugs because drugs and pain management is a business model. What happens is typically there's some small studies run by individual clinics or individual researchers in university invariably the number of patients is relatively small and It's very hard to prove anything with a small study or what often ends up happening is you have one study coming out Showing that the given treatment works, and then you have another study coming up Giving you the opposite conclusion, and that's just the weakness of the field in general also, there's a very Very large placebo effect for most pain treatments. We don't see it as much in pain clinic because a lot of patients have tried a number of other treatments before they came to the clinic and failed to have a response. So there isn't necessarily a larger expectation that what we are going to do will help them, If you take just a general pain patient, not a pain clinic patient, there is a huge placebo effect. In other words, if patients expect to get better from a given treatment, even if the treatment is ineffective. A lot of patients do get better. I was looking at a study for a new migraine medication that came out and they claimed and I'm making up numbers a little bit I might be off a little, but in any case, if I remember correctly, it was about 55 percent response rate to this drug in migraine patients. Now, it was a double blind control trial. It involved about 400 patients, or maybe even 500, so a fairly large number, and you know, as I mentioned, to my mind, you need at least 500, maybe even as many as 1, 000 patients, in order to really show anything in pain management. So in any case, 55 percent response rate in migraine sufferers in the arm that got the drug. What do you think the placebo response rate? It was around 40 to 42%. In other words, the difference between patients who got the drug and patients who got placebo is only about 15%. So the. The response to the medication was actually a placebo response. And then there was another additional 10 to 15 percent which could be attributed directly to the medication. All I am trying to say, given all these results. Problems is that all the things I'm going to talk about have some research to back it up. This may not be the last word and things may change a lot over the next few years and there may never be clarity. Okay, so let's move on to regenerative medicine. So the hope is that it'll help heal, regenerate, turn back time. What are the downsides? First of all, that it's not a no hip covered service. Generally speaking, most regenerative medicine treatments are not covered by any kind of insurance. Whether it's government insurance or a HIP or a private plan. And the reason for that is that most regenerative medicine treatments are not drugs. It's something that often we make out of components of your own body or it's a procedure. It's not a drug. It doesn't have a DIN. Number, second problem is maybe it would have been fine if you had to pay out of pocket if you were guaranteed results. The problem is that in pain management, there is no silver bullet. There isn't any treatment that helps a hundred percent of patients that try it. Majority of treatments, and that includes most surgical treatments, the response rate is anywhere from. 30 to 70 percent. So that means that you could spend a lot of money, try a treatment, and it's not gonna help you at all. What about research? What does research show about some of these regenerative medicine treatments? Well, there are Some animal studies that in fact do show that regenerative medicine treatments stimulate regeneration. Sometimes it's animals, sometimes it's in cultured cells. They also often show that various hormones that stimulate healing or reduce inflammation get released. But the problem is that A lot of things that work in animal studies, a lot of drugs that work in animal studies do not work in humans. If you just look at drug trials, my guess is somewhere around 90 to 95 percent of drugs that work in mice and rats do not get approved for human use. Uh, so what about human trials? Well, human trials do show benefit when it comes to pain reduction and functional improvement. And there's a number of those trials. However, when it comes to actually proving that these procedures cause regeneration, the evidence is much weaker. Again, there are some studies that do show some. Regeneration of cartilage, or perhaps that cartilage doesn't deteriorate as quickly after injection as before the injection. However, for every study that shows that, there's A study that shows that these treatments do not help regeneration at all. Having said all of that, there is at least a possibility that these treatments slow down the aging or reverse aging related processes. Whereas, other forms of treatment do not do that at all. There isn't even a possibility that they do this. In fact, some of the treatments, like cortisone injections, there's evidence that they actually damage cartilage and damage bone. Also, not everybody knows. necessarily cares about anatomical changes. Some patients are just happy to be able to function better, walk better, exercise, work, get back to their work activities. There is some suggestion that these regenerative medicine treatments May, in fact, not so much stimulate regeneration, but perhaps reduce inflammation, reduce pain, and perhaps That's good enough. So let's maybe look at some regenerative medicine treatments available at the clinic and available wider in Ontario. Well the granddaddy of regenerative medicine is actually almost a hundred years old and it's called prolotherapy where you inject a mixture of local anesthetic like, like lidocaine and dextrose. Because it is the treatment that has been around the longest, there was more time to do studies on it. And it actually has probably one of the strongest bodies of evidence to support its use. So what are the pros and cons of prolotherapy? First of all, it's a treatment that, at least in my experience, helps better for tendon sheaths. than for joints. It can certainly be used for joints, but often it's a little bit less effective as some of the other treatments. tend to be more successful for joint pain. So the good thing about prolotherapy is as all regenerative medicine treatments, it's fairly safe. There's no hormones in it. The other good thing about it is it's relatively inexpensive. For a treatment that's not covered by OHIP, if someone is on a budget, generally speaking, prolotherapy. costs anywhere from 150 to 200 per treatment. The downside with prolotherapy is that often it does require multiple visits and multiple treatments, about three to four treatments. For some people it's more, for other people it's less, depends on the response. So, if one ends up getting many protherapy treatments, the cost does start to go up. However, if it, it's the easiest one to try because the cost per treatment is low, and after first couple of treatments, you're going to have a pretty good idea whether it looks promising or not. Then there is another similar treatment called Prolozone, where one is adding ozone, typically in gas form, to prolotherapy mixture. Again, it can be used to treat joints, tendons. muscles, you name it. Also, there is some doctors in Europe who inject discs with ozone or prozone. There's also some doctors who do ozone infusions to treat any number of other conditions. Again, it's a treatment that's much more popular in Europe than here, in Canada. Typically it is slightly more expensive than prolotherapy, but not much more expensive. It usually kicks in faster than prolotherapy. Prolotherapy you need about two to four weeks to see the full effect. So that is why typically the repeat injections are spread apart by two to four weeks. Prolozone, the ozone component at least, kicks in very fast. Now, we can move on to more recent treatment. And by recent I don't mean they were developed in the last six months or a year. By recent I mean these treatments have been around for about 20 years. So long enough that should there be any major problem it should have come up. So the next option is. PRP, platelet rich plasma. Platelet rich plasma was initially used in sports medicine, often athletes quite commonly injure muscles, tendons cartilages because of the intensity of their sport. And then the use was broadened to include more common conditions like osteoarthritis, problems of the spine, problems of the nerves. And it is not, by the way, just limited to pain medicine, PRP has been used for everything from hair regrowth to cosmetics to erectile dysfunction some of the newer applications that I've seen. is for fissures around the rectum, for also polyps in the nose, for fertility, sometimes PRP is injected into ovaries, in other words, sky's the limit. Nevertheless, the majority of use is still in musculoskeletal medicine. The idea with PRP is you take a person's blood, you concentrate platelets, which is a component of the blood responsible for stopping bleeding. They're not exactly cells, they're more like fragments of cells. They contain a lot of proteins. growth factors and other anti inflammatory mediators, and you inject this highly concentrated fluid with a lot of platelets into damaged joints or tendons in hopes of kick starting the healing process. Obviously when you're injecting platelet rich plasma. You're not just injecting a single chemical like you would when you say inject cortisone. You're injecting a soup of chemicals, each one doing something a little bit different. Some chemicals provide formation of new blood vessels. Uh, and of course, if you're going to stimulate healing, any new tissue will need new blood vessels, some components stimulate stem cell division, some components reduce inflammation, and actually some components are pro inflammatory. as well. So, it's a real mix. Also, there's two main types of platelet rich plasma. There's platelet rich plasma that also has a lot of white cells in it. White cells are typically part of your immune system. They protect your body against infections. They're also involved in inflammation. They also contain a lot of growth factors. They also contain a lot of chemicals that are either pro inflammatory and cause additional inflammation, or anti inflammatory and maybe tamp it down. Uh, so there's the PRP with just the platelets. And then there's PRP with white cells and platelets. And there has been a lot of debate as to which one is better. I think there is some general principles that seem to have arisen. One is that, um, for tendon injections, perhaps PRP with white cells is better. However, there is some controversy. thought that perhaps when you inject PRP into joints it's better to have PRP without white cells. There is a problem with that concept, however, and that is there's also Some suggestion that the higher the platelet concentration in the PRP the more likely it is going to work and the more likely it is going to stimulate healing. The thing is that typically PRP preparations that get rid of white cells, they also get rid of a large number of platelets. And so the platelet concentration or the number of platelets that you inject into the joint PRP without white cells is lower than PRP with white cells. So what is the magic number of platelets you want to inject into, let's say, a knee joint in order to optimize chances of response and healing? Again, as everything else, it is controversial. However, there is a number that's being talked about, and the number is 10 billion platelets. So that's actually a very large number. Traditionally, patients would get injections of about a third of that. And for most patients, to be honest, number of platelets seems to work in terms of pain reduction, in terms of improvement in function. Of course, there's no way to know if they work as well in terms of stimulated, stimulating cartilage regeneration and healing. Having said all of that, perhaps if one does get close to 10 billion, maybe you end up with a longer response. It is hard to know. The other issue with getting to 10 billion platelets is That often to get there would, one would have to do injection more than once or collect a very large amount of blood, almost as much as a unit. What is the response rates in PRP? Well, first of all, it varies from joint to joint. In my experience, the best responses are for knee joints. And for other areas, whether it's muscles, hips, spine, the response rate is lower. So, my impression is that knees arthritis response rate is lower. to PRP about 60 to 70 percent of the time. The duration of response varies from months to years. The longest response I've seen in a patient is around five years. How long does it take for PRP to kick in? Again, there's a lot of variability. I sometimes see patients walking away from the clinic feeling better already, whether that's placebo effect or not, I'm not sure. But in general, I usually tell patients two weeks to two months before you see the effect. So it is delayed, perhaps because healing is taking longer. takes longer time than just pain reduction. And sometimes it takes up to six months. to see the full effect, although I would attempt to start thinking about other options if there's zero response at the two month point. PRP, generally speaking, is much more expensive and depending on what type of PRP and how many platelets are there, the range of prices is anywhere from 500. to around a thousand dollars. And again, often for that amount of money, you can treat more than one joint, but chances for response are high if you treat just one. There is some controversy with PRP in terms of whether or not it can be used in patients with malignancy and certainly patients with active malignancy do not get PRP injection. malignancy in the past. It used to be that nobody treated them with PRP, but now it seems to be changing. I'm seeing some papers in the literature where they treated with PRP patients after mastectomy where the wound wasn't healing. The concern, I guess, is that if platelets release a lot of growth factors and there's a tiny bit of cancer sitting in the area that you inject, what if you cause that cancer to grow and divide and, you know, come back? There's also another interesting product on the market, which is sort of like platelet rich plasma. called Enstride. Enstride is actually produced by a huge orthopedic device company, Zimmer Biomat, and it is also a product that you make out of patient's blood, but you process it differently, which causes It's to contain slightly different profile of growth factors. Uh, it's a relatively new product that only came on the market in Canada in 2020. It is also available in England, but as far as I know, not in the U. S. It does contain a lot of platelets, but the thought is that it doesn't just work because it contains a lot of platelets, because actually platelet concentration is a bit lower than with some of the types of PRP. It works because it causes release of certain different growth factors. The short version is It works in some patients, but not others. There are some studies to suggest that perhaps the effect lasts longer than with PRP, and it is a lot more expensive. N stride costs Anywhere from 1, 500 to 2, 000 per injection. The last treatment that's available in Canada with a lot of restrictions is stem cell injections. Uh, there's also many different treatments. types of stem cell injections. Uh, first of all, in terms of availability, availability is very limited. In order to offer stem cell injections, you have to have a Health Canada approved trial. That means that There's a lot less flexibility. At this point, there's only two sites in Canada that offer stem cell injections. One is in British Columbia and one is our clinic in Ontario. There's also limitations in terms of what can be treated. Uh, for our study, for example, we can only treat osteoarthritis and we can only treat a single joint. Also, there are some exclusion criteria, and if patients do not meet those criteria, they're not able to participate. And lastly, out of all the options, it is by far the most expensive. The cost for stem cell injections is 6, 000. There have been some studies comparing stem cell injections to platelet rich plasma injections. and the outcomes are comparable. However, I do not think this is the whole story because what happens in chronic pain in general is that there's subpopulations of patients, some responding better to one approach and some responding better to a different approach. I think it makes all kinds of sense to at least try platelet rich plasma injections before trying stem cells, especially if financial cost is a big consideration. So what happens in stem cell injections? We take stem cells from the patient's fat or from their bone marrow. In some cases, concentrate them. and we inject them back into damaged joints. Initially the thought was that these stem cells actually incorporate themselves into the joint cartilage and change into cartilage and that is how they work. More recent research showed that that's probably not the case. the case. The thinking now is that mesenchymal stem cells, what they do is they release various growth factors that again stimulate healing of the damaged joint and perhaps reduce inflammation. Also, of course, these preparations don't contain just stem cells. Typically they contain any number of other cells. Just like with PRP, the best results seem to be for the knees, although other joints can respond as well. For those patients for whom it works, the benefit can last for a very long time. talking to other physicians who have done these procedures in BC and the US. On average, the response is for about two to three years. I'm talking about patients who actually do respond. I just saw a patient a few months ago We tried bone marrow stem cell injection and it helped him for five years. When he went back and at that point stem cell injections were no longer available in Canada. So he tried PRP this time and PRP did not really help. So that's pretty well all the treatments that are available in Canada. In other countries like Mexico, South America, there's more complicated approaches to stem cell injections because the research is so poor, it's not clear that they're superior to the ones that are available in Canada. They will often contain more growth factors, more stem cells, whether or not it leads to better outcomes and what the risks are. It's still up for debate. So if one goes to places like Mexico what can they offer that you can't get in Canada? Well, what they can do is, again, take the stem cells from bone marrow and fat, let them div divide for a couple of days. In a Petri dish. So you're creating more stem cells and then inject them. Or one can even offer them as an infusion because you have so many, more of them, you are able to infuse them from the, into the blood. And then of course it goes throughout your whole body, which can be a good thing or a bad thing, depending on what type of indication you're trying to use it for. Uh, if you're using it for musculoskeletal pain, there's really no advantage to infusion unless musculoskeletal pain is all over the body. But if you are using it for some condition where it's hard to reach the target, like heart or nervous system, then. infusions make more sense. So there is some debate about whether stem cells that have divided many times, and they do have to divide many times, are as effective as a fresh ones that you just removed from the body and injected right back in. Cells actually age in the same way that people age. And so the more they divide, the older they become. So what is more of them, they may, each cell may not be as effective. And then there's just a general issue of the fact that it's a much more complex procedure. Because these stem cells have to stay in a Petri dish outside of the body for a long period of time. There's always a risk of viruses getting into the culture. or it being contaminated by some bacteria. So the risk of contamination and infection is, of course, higher than if you just remove stem cells from the body and put them right back into the joint. There's also, of course, the issue of cost. Uh, once you start to go to Mexico for some of these procedures the costs start to go up, nevermind the trip and the hotel, there's also cost for the procedure itself, and it tends to go up into tens of thousands of dollars. And then of course, what happens if you have a complication? Then we have Products that are obtained from fetuses, from cord blood, these contain stem cells, and these stem cells are much younger than adult person's stem cells. They do have more growth factors, no question about it. So at least there's a potential that they're going to be more effective than adult stem cells. There's a few additional concerns with those, and those concerns. center around was same growth factors there has been a case in the US where fetal stem cells were used to treat spinal cord injury and the this patient or patients developed benign tumors of the spinal cord. So too much. Growth factors, there's a concern will it increase chances for benign tumors or maybe even cancer. So what about the future? What do I see coming down the pipe? Well, first of all, cell as a drug. is a concept that's actually being embraced already by pharmaceutical companies. Taking the cell, changing its DNA, using CRISPR. There's also all kinds of biological approaches. Will there be a treatment for osteoarthritis. That's a regenerative medicine treatment where it will be absolutely proven that it works and perhaps will be more effective than what we have now. I think it's just a question of time. I think that We will come up with better treatments for osteoarthritis and other chronic pain conditions. The problem is that is the one of cost. Once you start to manipulate cells, the costs Start to grow exponentially. And this is not exactly the same thing, but there are some treatments of outer T cells, which are immune cells for cancer, that is already available, that cost hundreds of thousands of dollars. There's a new genetic treatment for another condition called sickle cell anemia that has come out that costs a million dollars. While I have no doubt that pharmaceutical companies will come out with better regenerative medicine approaches, there's still a question mark of the cost of these approaches and whether or not insurances will choose to cover them or not. To summarize. Regenerative medicine, I think, has a very bright future. We do have some useful tools at present time with a relatively low risk of side effects compared to, say, surgery or even things like cortisone injections. These treatments are not covered by any insurance plans and most likely will not be covered in the foreseeable future. And they're not silver bullet. They're only going to help a certain percentage of people that try them.

Raveena:

Thank you for listening to the fourth episode of Chronic Pain Chronicles with Dr. Karmy, a podcast which explores chronic pain from a physician's point of view. Our episodes will explore some of the most effective and commonly used approaches to managing chronic pain, including ketamine and lidocaine infusions, nerve blocks, and alternative medicine approaches. We will also try to explore the causes of chronic pain and understand where the field is going in the future. I am Raveena Aujla. Till next time. Disclaimer. When it comes to your health, always consult with your own physician or health care provider for personalized advice and guidance. The information provided in this podcast is for educational and informational purposes only and should not be considered medical advice or a substitute for professional medical care.

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Dr. Grigory Karmy

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Raveena Aujla

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