LDN for CRPS: FDA Orphan Drug Designation and Beyond

Dr. Amol Soin earned his medical degree at the University of Akron in Akron, Ohio. He completed his residency in anesthesiology at Rush University in Chicago and his fellowship training in pain management at the Cleveland Clinic. Dr. Soin is triple board-certified in pain management and is also a board-certified anesthesiologist. He is currently a clinical assistant professor of surgery at Wright State University Boonshoft School of Medicine, and is the author of the book “Curing America: A Look Inside America’s Failing Health Care System.”

As the medical director of Ohio Pain Clinic, Dr. Soin offers comprehensive care for managing chronic pain and a variety of spinal disorders, using an integrative approach to identify the causes of pain and other symptoms to improve each patient’s overall health and wellness. He is known for focus on holistic treatments to minimize the use of narcotics in pain management.

LEARNING ABOUT LDN

I’m really interested in LDN, most specifically for people who suffer from Complex Regional Pain Syndrome (CRPS). I have a lot of patients that suffer from that ailment and I’m always looking for options and opportunities to treat them. It’s a very difficult patient population because they really suffer and there are not a lot of great options. I started really thinking about other ways I could help besides the traditional methods, as we are trying to avoid opioids and addictive painkillers for this disease state. I came across low dose naltrexone and tried it with great success, so it really piqued my interest.

When I was doing research on CRPS, I realized that the problem, fundamentally, is an increase in neural inflammation and activation of small nerve cells called the microglia. So I thought, what are some ways that we can attenuate that or treat that, instead of masking the symptoms with a nerve block or a nerve stimulator or a narcotic? What if we could actually treat the pathophysiology?

When you look at the underlying drivers of CRPS and the molecular effects of LDN, they seem to fit

What I learned about LDN is that it actually attenuates (or, for lack of a better term, decreases) the firing (activation) of microglial cells. Those are the same cells that are activated in CRPS. It also inhibits (decreases) some of the pro-inflammatory cytokines such as interleukins and tumor necrosis factor. These circulating chemicals are involved in the cascade of what’s called allodynia, or severe pain, in CRPS. LDN decreases that as well. When you look at the underlying drivers of CRPS and the molecular effects of LDN, they seem to fit. As a result, I’ve been trying it in my practice for quite some time and I keep getting more and more intrigued.

TREATING PATIENTS

The very first patient I tried it on was the 11-year-old described in the case report I published in the journal Pain Medicine Case Reports. He was suffering from CRPS and had failed all the traditional therapies. I tried low dose naltrexone with excellent results. He responded so phenomenally that I decided to expand prescribing of LDN to other patients. I have a lot of patients that suffer from that disease, so I started giving LDN to my patients and they are doing very well with it.

I tried low dose naltrexone with excellent results. He responded so phenomenally that I decided to expand prescribing of LDN to other patients

I probably have 3 dozen patients actively on LDN, which I think is a good number considering it is an awfully rare disease.

What I typically see is a decrease in symptoms first. That sometimes takes time. I would tell you that typically within the first week patients will tell me they’ve noticed something. By the 2nd month of treatment, it’s definitely very significantly noticeable. What do we notice? Well, the first thing we notice is a decrease in pain overall. There are a couple of reasons for that some of which I already mentioned. Another is that low dose naltrexone stimulates the release of endogenous endorphins (your body’s natural pain killer). We do see that effect happen relatively quickly.

I can also tell you every single patient I’ve prescribed LDN has responded, and has responded favorably

Over time, we have noticed what we call remission of the disease in some cases (including the 11 year old that I referenced earlier) in terms of complete resolution of symptoms to the point we were able to stop the drug entirely and the patient was able to get back on their way. Now, I can tell you that doesn’t happen all the time, but it has happened. I can also tell you every single patient I’ve prescribed LDN has responded, and has responded favorably. I think that boils down to adequately and properly diagnosing the disease state, making sure your diagnosis is correct.

When you take someone’s pain away, their life changes dramatically. We’ve noticed an increase in mood, better sleep, and more happiness…in terms of being able to enjoy their life. All of those things tend to happen when we take their pain away.

When it comes to CRPS, I try to see if we can stop the disease from progressing without any pills (pharmaceuticals). What we typically try first, in terms of our algorithmic approach, are things like physical therapy and desensitization-type exercises. If those don’t work, we try a nerve block. If that doesn’t work, and we end up wanting to try oral medications, prior to committing a patient on a lifelong drug like gabapentin or a narcotic, I think LDN belongs early in that paradigm. I do think low dose naltrexone should be first-line.

Aside from some lucid dreams and reduced effectiveness when taking narcotic pain pills, it’s generally well-received. I’m not worried about major side effects. I have not seen any anaphylaxis, or wide swings of blood pressure or heart rate. I have not seen any gastrointestinal problems. I have not seen any nausea or vomiting. I think it’s generally a well-tolerated, safe medication.

My preference would be to avoid taking LDN and opioids at the same time, but in some cases of CRPS, it is not practical and there is utility for opioids, especially with severe flare-ups. I do have experience in prescribing both at the same time. I don’t think it’s a complete contraindication. I do think it’s worthy of a discussion with the patient about what they may notice if they take both at the same time. But if you consider the half-life of both medications, a short-acting opioid and LDN itself, and let’s say you dose the LDN at night, taking the opioid in the morning or even afternoon should have no impact.

That’s the goal. Once their pain starts to go down, we can wean off or scale down their opioids significantly.

I haven’t yet, but in doing the systematic review, I can tell you I learned a lot, especially with neuropathy pain. Diabetic neuropathy, idiopathic neuropathy, chemotherapy-induced neuropathy…LDN seems to be helpful. Also, patients with fibromyalgia or myofascial pain disorders…some of the data seem to indicate that it was helpful, presumably from increasing the endogenous endorphins or potentially decreasing the activation of microglia.

I would think that, in general, you would see some positive impact regarding many pain states from it. I’ve read about people trying it for other disease states, like multiple sclerosis. I don’t have any experience in any of those disease states, as I’ve been using it almost exclusively for CRPS, but I can tell you, in doing the systematic review article, I did learn a lot and it seems to be a lot of practitioners are using it for other things with great success.

If you have a patient that suffers from CRPS that’s been refractory to treatments to date, I would consider trying low dose naltrexone. Or even earlier in the decision pathway. Because when you think about the underlying drivers of CRPS (neural inflammation, allodynia, hypersensitivity to touch, activation of the microglia) and then you think about the mechanism of action of LDN (which attenuates or decreases the microglia, inflammatory cytokines, neural inflammation) it seems to be the perfect drug for that disease state.

It can be difficult from a practitioner standpoint for a couple of reasons. First of all, it isn’t manufactured in lower dosages, so you have to find a compounding pharmacy, which takes a little bit of effort on the side of the practitioner or doctor. A lot of times doctors are busy doing things and there could be hurdles to doing that particular piece. So if you’re a patient and you want to try it, I’d probably suggest you might want to look around for local compounding pharmacies, because it would really help your doctor! There are plenty out there and I’ve found out that it’s actually a very easy process.

Naltrexone in lower dosages, although it’s not covered yet by insurance for this indication (CRPS), is actually very cost effective to get it compounded, so it’s not a huge price burden. In fact, the cost of doing the entire thing is probably less than a co-pay for a branded drug anyway.

RECENT LDN PUBLICATIONS

I realized there wasn’t a really great comprehensive source for physicians on this topic, so I conducted a systematic review of the literature. It was actually a massive undertaking. It took me close to a year to do it, combing through PubMed and Embase, and other directories. I came across 336 different studies and citations around the areas of neuropathy, pain, fibromyalgia, and CRPS. I reviewed those articles and came up with a flow chart for physicians of what the data actually show. That was published recently in the journal Pain Physician which is a high impact pain management journal in our specialty, and it’s searchable on PubMed.

The co-authors are people I’ve worked with for quite some time on a number of different studies. Because the systematic review required a lot of researching, reading, vetting of the articles, we were able to divide up that work amongst multiple people. Some of them are incredibly intelligent individuals, very accomplished, from great institutions. There are people from the faculty of Harvard Medical School that were part of this collaboration. Honestly, it’s great to have intelligent, hard-working people review things to make sure I’m not missing anything. That same team, we collaborated on a couple of different articles in the pain management space.

I think what we really need is a well-designed clinical trial. If we can do that, it would really enhance LDN’s utility from the physician buy-in, general public buy-in, even big-pharma buy-in. One of my longer, overarching goals is to do that.

One of the problems, operationally, with this, is that when it comes to pharmaceuticals, financial situations dictate everything. Because there isn’t a huge financial incentive for a compounded generic medication, it gets challenging to run these studies. Who’s going to pay for it? How’s it all going to work? There is currently an LDN clinical trial for CRPS going on at Stanford University by a very brilliant physician, Dr. Sean Mackey. I believe that it is close to being almost fully enrolled. It takes a while to enroll these patients because it’s a rare orphan disease. So hopefully we’ll have some data there. But I think more studies like this would be a great next step, and I’d really like to try to do that.

FUTURE DIRECTIONS

The overarching goal would be to get something FDA approved-to get an FDA approval for an indication to use it-because that would enhance utility…from insurance payers, from patients, from general physician buy-in. Once it’s approved by the FDA, you know that the science has been vetted. I truly believe that the science is there to support its use. So I started trying to research figuring out how I would do that.

Because naltrexone has been around for so long, there is really no way to get any patents, or intellectual property, which is one method to help get funding for these things. But I discovered there is a way to get some FDA favorable coverage, by getting naltrexone designated as an orphan drug. The FDA had already designated CRPS as an orphan disease, because it has less than 250,000 people, in terms of prevalence, per year. So…believe it or not, I actually applied to get low dose naltrexone an orphan drug designation. Amazingly, two weeks ago, the FDA approved that designation, which is a huge step forward for me because, now, I think I should be able to get funding to run this large trial. If I can do that, we can hopefully get an FDA approval and then I think it’s something we can have patients get access to at a very cheap and economical price, because it’s not expensive to manufacture this medication. This would be a huge leap forward for LDN in our patients.

I actually applied to get low dose naltrexone an orphan drug designation. Amazingly, two weeks ago, the FDA approved that designation, which is a huge step forward for me because, now, I think I should be able to get funding to run this large trial

My next step is to learn more. I want to run a large, blinded, placebo-controlled study using low dose naltrexone. I think that will answer a lot of questions for us and we can learn more and hopefully, eventually, get an FDA approval for the use of LDN for CRPS. The first step for that was for me to get the concept of LDN and the disease state of CRPS designated as an orphan drug for an orphan disease, which we were successfully able to do 2 weeks ago. This is great news. So now we’re on to the next step, which is meeting with the FDA to do something called a pre-IND meeting, which is an Investigational New Drug meeting. I will be filling out an Investigational New Drug application. That’s what I’m working on literally right now, as we speak. I suspect we’ll have our pre-IND meeting within the next 3 months, and we will be able to formally apply for our IND application before the end of the year. Once that’s approved we can start the clinical trial process.

Thinking about timelines- we’re looking at about 12-14 months from today when I can start enrolling patients. I plan to run a study where we watch and follow patients for approximately 3 months, so that we can get the study done quickly and efficiently.

I imagine there would be strong interest. We are all on the same team here, and that’s to find new ways to help patients without addictive painkillers. Low dose naltrexone represents that opportunity for this disease state.