Pain Specialist Dr Pradeep Chopra Feb 2020 Pain Seminar (LDN, low dose naltrexone)

Pain Specialist Dr Pradeep Chopra Feb 2020 (LDN, low dose naltrexone) from LDN Research Trust on Vimeo.

My name is Pradeep Chopra. I'm a pain specialist, and my area of interest is complex pain, pain conditions. So I'm just one of those weird guys who like treating complex pain conditions. Someone has to do that. Right? So I took up that job. No, I don't have any, this is a standard disclaimer. I don't have any conflict of interest. 

We're going to talk about naltrexone, it's the oddest drug you'll ever see. So we'll talk, and we'll talk about naltrexone, and then I'll talk about low dose naltrexone. And Dr Goldstein will talk about very low dose naltrexone. And then he's gonna talk about ultra-low dose naltrexone.

Is there an ultra low dose Not yet. Not yet. Okay. So let's talk about naltrexone for a minute. This was in 1984, it was approved with the FDA for the treatment of alcohol addiction and opioid addiction. And I believe even with heroin addiction, it didn't take off as the drug for detoxification for various reasons, mostly political reasons.

Now they found that in 1982 naltrexone affects cell growth differently depending on which dose you use. So at a low dose, it affects cell growth differently from a high dose. In the mid-1980s, we were hit with the HIV epidemic, and there was no solution to it.
And what happened was. In New York, there was this neuroscientist neurologist by the name of dr Bihari, and he was working at a detox centre, and he saw two kinds of HIV patients. There was a sexually transmitted HIV, and then there were heroin addicts who are sharing needles. So we had two different kinds of HIV.

So the patients who had HIV from addiction were given naltrexone, obviously because he was trying to detox them, but people who had sexually transmitted HIV were not given naltrexone. What he noticed was that the incidence of lymphomas and kaposi sarcomas, like immune conditions, were far less in the, in the patients who had been given naltrexone as compared to those who had not been given naltrexone. So that was one of his observations that he saw. And then later on, of course, different scientists picked it up, and they did some research on it. So what is naltrexone? It's a reversible competitive antagonist at the mu and Kappa receptors so that we know that it's a reversible antagonist. It also works on the Delta receptor to a certain degree, but it's the active metabolite. So when this gets metabolized to six-beta naltrexone it is also working the same as naltrexone to a certain degree. The plasma half-life is six hours.

So for the half-life of the metabolite is about 13 hours. So in general, you know, half-life times four is what is where it takes the full drug to be metabolized. So it takes about 24 hours for it to be metabolized. So remember this fact that this is an important take-home fact. Now commercially available Naltrexone is a 50-milligram pill. And the dose you should have recommended those is 150 milligrams a day. We're not talking about that today at all. Today we're going to talk about 1.75 milligrams to 4.5 milligrams. I'm going to talk about that. A lot of Goldstein is going to talk about some really crazy low doses.

I think you basically sniff naltrexone. Anyway. So the dose we're talking about is four and a half milligrams of low dose naltrexone. That's LDN in short. Now, remember, it gets fully eliminated in 24 hours. So let's talk about LDN.

LDN is, again, it blocks the Mu receptors, but it does it transiently. So it's such a low dose, instead of giving somebody 150 milligrams, you're giving them four and a half milligrams. So it blocks the immune receptors very, very, very transiently.
It's so transient that it’s enough to cause a positive feedback mechanism, to increase the production of endogenous opioids, also known as endorphins. So in these patients, what happens is endorphin levels, and enkephalin levels are increased persistently. So let me go through that again. When you use LDN, you're blocking just a few Mu receptors for a very short time, and so the body in turn, by positive feedback, produces more endorphins and enkephalins. 

So what happens when it produces increased levels of endorphins is it promotes healing, inhibits cell growth, and it reduces inflammation. And I'll go through all of those again. It also works on something called the opioid growth factor, also known as a Met(5)-enkephalin.
The opioid growth factor is a pentapeptide and endogenous pentapeptide produced in the body. Uh. Opioid growth factor activates a specific receptor called the opioid growth factor receptor. So you have OGF opioid growth factor that activates opioid growth factor receptors.

This forms a complex called the growth factor-opioid growth factor receptor complex. There is an increase in the number and density of OGF receptors. So what's happening is because there's so little endorphin, so little. There's so much endorphin being produced that there's an increase in the number of and density of the OGF receptors of this complex. This combination regulates tissue growth, wound repair, it inhibits certain cancers. I'm not going to talk about cancers. I'm a pain guy. I'll talk, talked a little bit about pain stuff, but there's tons of literature on it, working on cancer, especially pancreatic cancer, head and neck, squamous silicones, ovarian cancers, and they must be at least 20 papers on the treatment of skin warts for some reason.
I'm not sure why, but um, they're like at least 20 papers. Let's talk about the cell called the glial cell. Glial means glue. So the nervous system, the brain and the central nervous system are made up of—70 % to 80% of the brain. Our central nervous system is made up of glial cells. And the idea being like, okay, so the rest 20% are neurons and the, and it's packed by cells called glial cells, which were in the old times known as glue.

They didn't know what it was for but now we know that glial cells have a very important role to play. They are part of the immune surveillance under basal conditions. So the glial cells in the central nervous system which actually make up most of the brain, are part of the immune system.

When, when these glial cells get activated they get really angry. They release inflammatory cytokines and chemokines. So you don't want to piss off these glia cells. Neuroinflammatory conditions ……  there's a lot of work being done on Alzheimer's, complex regional pain syndrome, chronic pain conditions where actually the theory being is that these glial cells are the culprit.

These substances, in turn, increase the excitability of the nearby neurons. So in reality, if this is a neuron in the brain, the glial cells are almost right next to it, grabbing onto it. If you ever look at it under a microscope, they're literally next to the neurons. So when these glial cells release inflammatory chemicals, they cause inflammation of the neuron itself.

So let's confuse you a little bit more, I'll bring this all together. Don't worry. So toll-like receptors, toll-like receptors are a class of proteins that play a key role in innate immunity in the immune system. They are usually expressed by macrophages and dendritic cells when there's an infection these microbes are recognized by TLRs. There are about 10 of them which activate the immune system. The one we are interested in as a TLR4, this is predominantly expressed with the microglia. Remember I told you about the glial cells, the different types of glial cells, and one of them is called the microglia.

The expression of toll-like receptors is increased under neuroinflammatory conditions. Now, this is a key thing, remember, opioids caused glial cell activation by acting on the TLR4 receptors. And that causes increased proinflammatory cytokines. Now you must have heard of opioid hyperalgesia and you know this whole thing about why opioids are not good and all that, that's controversial. We'll talk about it later on. But what happens is in patients who are in high, especially high doses of opioids, glial cells get activated. And when these glial cells get activated, they cause inflammatory cytokines to be produced. And that is the basic theory between certain pain conditions that don't respond to treatments is because of this.

And one of the theories behind opioid hyperalgesia is this, is that they're causing glial cell activation. So the idea was that, okay, so if glial cells are getting activated, if I use something to deactivate these glial cells, I'm golden. I can do something, but I can help patients with their dementia or their pain.

So opioid antagonists, like Naloxone or naltrexone block TLR4 signalling, which in turn decreases glial cell activation, which decreases neuroinflammation. This is a very powerful sentence because we don't have any other glial that are de-activators in the market right now. We don't. And this is probably the only drug is a disease-modifying agent. Everything else is not a disease-modifying agent. This is the one that works on the TLR4 signalling, which in turn decreases glial cell activation, which then decreases neuroinflammation. So LDN blocks release of proinflammatory cytokines, including interleukin-6, 12, TNF alpha and NF- k-beta.
It modulates T and B lymphocyte production, which is an immune system, and it also causes a shift in the immune system response from TH2 to TH1. So I'm going to summarize the mechanism of action over here: It is the reversible antagonism of the opiate receptors resulting in increased production of endorphins, which then up-regulates the OGF, the opioid growth factor and opioid growth factor receptor access. So in short, uh, when you give someone LDN, it causes a reversible antagonist on the opioid receptor, which causes OGF or OGFr axis, to increase it blocks TLR signalling, which then decreases glial cell activation, which decreases the production of cytokines and then hence decreases neural inflammation.

LDN also blocks release of proinflammatory cytokines, including interleukin-6, 12, TNF alpha and NF- k-beta. It regulates cell proliferation through p16 and p21 dependent inhibitory kinases. This is more for cancer research. The only part that where I want to just talk about cell proliferation is - there's been some really good data on how it works in patients with diabetic ulcers, it has been shown to improve that. 

So let's talk about pain. Let's say what are the uses of low dose naltrexone, where can you use it? If you look up, if you ever look it up in a textbook, or if you look up online, they're like 30 different conditions. I just picked up the ones that I'm a little more familiar with.
The first one being pain, especially neuropathic pain. So we know pain. There are different kinds of pain. nociceptive pain, which is structural pain, there’s neuropathic pain, which is nerve pain. Most of our pains are a mix of both nociceptive and neuropathic—the differences, which one is more. So, for example, if somebody had back pain, he has both structural pain as well as neuropathic pain.
And so this patient, if you can take away the neuropathic component, you're going to get somewhere with this patient. It works on immune conditions like Crohn's disease, ulcerative colitis, Hashimoto's and cancers, works on autism, Lyme disease, and fibromyalgia. So I'm going to break it down to specific conditions.

In Crohn's disease. This study was done. I'll give you the ref, the citation in a minute, but this was an amazing study on Crohn's disease by Jill Smith.  And what they did was they saw a remission in two-thirds of the patients and 89% of the patients reported improvement to some degree. That's a huge figure in Crohn's disease, and they've been able to actually show colonoscopy pictures of before and after, and you can see how it improves. She did this work with Ian Zagon, who's one of the pioneers of LDN. So these are the two citations if you're interested. (See presentation).

So for IBS, they took 42 patients. It was an open-label study. We gave them low dose naltrexone, just 0.5 milligrams for four weeks. And there was an improvement of 83%. 83% of medicine is huge. I mean, we are looking for a 50% improvement. So they went onto a phase two trial. This was a phase two trial, 50 patients, four weeks. patients reported a hundred, 140% increase in the number of pain-free days. Clinical improvement, bowel urgency, stool consistency, number of stools per day were also reported by week four in both genders, males and females. They've never been able to show a difference. LDN between males and females, if there's any difference in how it works.

LDN and fibromyalgia, actually, there's been another study after this one. This was done in Stanford, by Jared younger. but after that, there'd been a couple of other studies. So, and this was a pilot study, single-blind crossover trials, ten patients with fibromyalgia.
You know, I don't know if you remember those, those things called Palm pilots? Well, half the room remembers. It was like a cell phone without the phone part of it. And so they gave these ten patients Palm pilots, and they said, record your pain all day long. And so they would enter it all day long and then bring them up, and then they would download the data.

So they took ten patients with fibromyalgia, gave them four and a half milligrams daily for eight weeks. It reduced fibromyalgia symptoms, diffuse pain, the sensitivity of mechanical stimulation greater than 30%. Their ESR dropped, indicating a general inflammatory process going on in fibromyalgia, had the greatest reduction of symptoms in response to low dose naltrexone.
I don't want to go into autism today because it's not my field, but this was a book written by Jacqueline McCandless called “Children with starving brains”. And there's some really good information on the use of LD in autism. And I don't think it works in everyone, but it works in more than 50% of the cases.

So I started early and back in 2005 and I was getting a lot of pushback from people like, Oh, this is an addicting drug. People were confusing naltrexone and methadone, I don't know, but I would get pushback from physicians saying, Oh, this is an addictive drug.
So finally, and I didn't have the funds to do whole big research, so I wrote two case reports which we published in 2012. Well, I, you know, I was seeing a lot of complexes or pain syndrome patients, and we really don't have any great tools to treat this condition as one of the most horrible pain conditions known to mankind. We didn't have any tools to treat this.  There were two cases. The first case was a 48-year-old male with CRPS. I know this is one case, but this is what we mean. I've been saying since 2005, and this is what people around the country are now seeing. So it's not just this one case that I'm talking about.

He had CRPS to his foot, which spread to his entire body, developed blisters, dystonic spasms, yet failed everything. This is what he looked like when he came to my office. You had all these scabs, you had these blisters, uh, and you can see the difference in colour over here. Started him on LDN. Two months later, he had improved physical activity, decreased frequency and duration of pain.
I mean, it's a pain didn't go away, but he was much more functional. it didn't change his dystonic spasms. LDN does not work on dystonic spasms as far as I know. This is what he looked. Uh, finally, and you can see a huge difference. This is just LDN. There was nothing else.

This is a 12-year-old girl, she's now much older, had Ehlers-Danlos syndrome, CRPS in the right foot, unstable ankle joint, started around four and a half milligrams once a day. It improved her dystonia, decreased her pain and symptoms of CRPS after two months. This is what she looked like when I first saw her. You can see how red the foot is and how it's dystonic. This was just stuck like this, that you couldn't fix it and we thought it's never going to get better, and this is eventually, this is what happened. 

So let's talk about real life. How do you and your practice use LDN? You start two milligrams in the morning  and I have them take it for four weeks,  I'm sorry, two weeks. I have them take it for two weeks. And I'll explain to you why. One of the things about low dose naltrexone is when you introduce the LDN, it does cause some headaches and causes some insomnia. I don't want to give them four and a half milligrams, and then they'll come back and say, but then I can't, I'm not going to take this drug anymore because it causes headaches or I can't sleep.

So I introduce it slowly. And there are some patients who are very sensitive to drugs. So I like to start at two milligrams, and then I use a compounding pharmacy that has the big scored pills. Um, and then I increase it to four and a half milligrams. They can take it in the morning or at night. Some patients will tell you that makes them sleepy and then some will tell you that it makes them, keeps them awake. So depending on that, you can decide they can take it at night or take it in the morning. In the past, the literature talked a lot about taking it at night at ten apparently at 10:00 PM at night, because then it, your endorphins are the highest at 2:00 PM at 2:00 AM in the morning. But now we don't think it's necessary, all you need to do is take it at once a day.

The usual side effects are headaches, insomnia, and colourful dreams. And I don't tell them about the colourful dreams on the first visit. I'll mention it later on once they've started to improve. So they're more receptive to it. But I do warn them about the headaches and insomnia. Generally, all these side effects go away.

They all go away. Rarely colourful dreams might persist. Um, so all you get is a free movie every night. Now don't be in a rush to see effects. You're not going to see an effect overnight. It takes a while. Um, I usually tell them to expect at least wait four or five weeks to notice a difference.

The common thinking among physicians, in fact, the last conference that was our thinking was I used to do it for three months. I said, give them a trial for three months. But physicians around the country now use it for six months. That's what they feel is the trial. Um, now sometimes you get a patient that'll come back and say, I just couldn't take this drug.
It made me really nauseous because, you know, you're, all of a sudden you're producing a boatload of endorphins in these patients, and so they don't like that effect. Some don't like it. Don't give up. What I do is we, we then back off to 0.5 milligrams a day. And they'll leave it there for a few weeks to a few months, and then maybe go up by another half a milligram to one milligram.
And that might be all that they need. So there are, we do have a bunch of patients who are at say one or two milligrams. On the flip side, if you don't see an effect that four and a half milligrams. There's no harm in going up a little higher. We've had physicians have used six milligrams. I've, I've never had gone higher than six, but I know of physicians have gone up to 12 milligrams, and I've still seen a benefit.

As long as you block the new receptors transiently, you're good. And it should be once a day. You can’t give it, give it to them three times a day or four times a day. You, you have to block it and then all of a sudden the naltrexone goes away, and you're left with a boatload of endorphins. 

It must be ordered from a compounding pharmacy.  It can be a pill, liquid, or cream. The cream, I brought it up because in autistic kids use some, they have a problem. So, but Jacqueline McCandless had mentioned she was using it as a cream in autistic kids. As I said, it doesn't matter what time of the day you take it as long as you take it once a day.

Then, when it's compounded, one of the things, most compounding pharmacies are now aware of how to make LDN, and they know exactly how to make it. They know the whole process.  but one thing to be careful was, is that you don't want an extended-release LDN. And because then that beats the purpose - It should be an immediate release LDN. So there's a, there's a big question about fillers that you should use with LDN. Uh, the one filler you can use is called avicill acidophilus and calcium carbonate, sucrose, lactose are used. Um, some patients are intolerant to certain fillers.

So if you, if you prescribed LDN to somebody, they're like two milligrams or four and a half milligrams, and they start having this bizarre reaction. Think of the filler. Say, if they come back and they say like, I get this flushing or I get this itching, or I feel really, really nauseous is probably not the LDN is probably the filler in that.

So the question that I get a lot is, Oh, the patient has an early, and I'm sorry, we can give this patient opioids, and they really worry about that. What if they need surgery or what if there's an emergency or they need an opioid? When in the beginning when they first, when some of us started using LDN, we were all nervous about this issue, but we've got now about two decades of experience on this thing, and we know that it's fine to take an opioid and.

Personally, I've tried it myself. I took an LDN, and Vicodin together, nothing happened. Uh, it was prescribed to me legally. Okay. But, but what I'm trying to say is that the number of mu receptors that are blocked is so small. I mean. LDN, four and a half milligrams early, and from 150 milligrams of naltrexone, you're blocking so few new receptors that if you gave someone a vitamin or a Percocet, it's really not going to make a difference.  They're not going to have a withdrawal effect. And most emergency room physicians don't even care about it. They'll give them whatever they need, and they're probably gonna get some boatloads of morphine or fentanyl or whichever. So it's okay for them to take it. But if you have a choice. Supposing the patient has an elective surgery coming up and as a question like, okay, what should I do?

Remember I told you his half-life was, um, was four hours, six hours, and then you multiply that by four. Um, so I tell them to stop 24 hours before the surgery and then start their LDN after their last dose of whichever opioid they were given for the, for postoperative pain. You can do that but just being very careful, it doesn't really make a difference. So we've never, I've never read in the literature and talking to multiple physicians. We've never seen withdrawal on patients taking LDN and a low dose of opioid. This is really good web research. You can go to this as an organization called re LDN research trust.

It's a nonprofit organization that, um, you'll find tons of literature on it. In fact, they published a book also. Thank you.

We have time for questions right.
Yes. So, the question was, if patients who have fibromyalgia and are on other drugs, have you been able to get them off that right? Yes. So you don't stop the Lyrica, you don't stop whatever Gabapentin or whatever they are on, don't stop it, but you just add LDN to it.

So the question she asked was, have you ever had patients present with hypomania or bipolar disorder for LDN? No, we haven't seen any issues like that.

I don't really start patients on patients who are already in opioids. I don't start them on low dose naltrexone because it beats the purpose. You're blocking them, your receptors, you're, it's, you're activating the glial cells at the same time as you're trying to deactivate those glial cells by blocking the toll-like receptors. So it kind of beats the purpose 

Diabetic for diabetic neuropathy? Yes. Same dose, approximately four and a half milligrams. So you're killing two birds with one stone. You're helping their tissue. Uh, they have fiber tissues here. You're helping that, and it does work on diabetic neuropathy.