Managing Neuropathy after Transplant

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Managing Neuropathy after Transplant

Thursday, May 5, 2022

Presenter: Danielle Roberts MS, MMSc, PA-C, Bone Marrow and Stem Cell Transplant Program at Winship Cancer Institute of Emory University

Presentation is 40 minutes long with 17 minutes of Q & A.

Summary:  Neuropathy (nerve damage) sometimes occurs after a stem cell transplant. It most often affects hands and feet but can affect other parts of the body as well. This presentation explains what causes neuropathy after transplant and various treatments available to relieve it.

Highlights:

• There are two types of neuropathy: peripheral neuropathy, which usually affects sensation in hands and feet, and autonomic which can interfere with many bodily functions.
• Chemotherapy-induced peripheral neuropathy (CIPN) occurs in 10 to 85% of patients depending on the type of chemotherapy used.
• Peripheral neuropathy can also be a problem for patients who have a scleroderma-like form of skin graft-versus-host disease (GVHD).

Key Points:

(03:36): Peripheral neuropathy is most common in people older than age 55, and those who have diabetes, HIV or received chemotherapy.

(05:50): Symptoms of peripheral neuropathy include tingling, prickling, lack of sensation, coldness, burning sensation, shooting or stabbing pain in the hands or feet.

(09:24): Autonomic neuropathy is a different type of neuropathy that can cause lightheadedness upon standing, dry eyes, dry mouth, feeling full after eating a few bites, loss of bowel control, inability to sweat and/or erectile dysfunction.

(14:12): Reporting symptoms of neuropathy as soon as they occur is crucial and can help prevent permanent disability.

(27:53): First line therapies for peripheral neuropathy include over-the-counter pain medication, capsaicin and soaking feet in cool water

(29:39): Compounded topical agents avoid the GI tract, deliver greater concentration of the drug to the problem area and deliver relief more quickly than a pill.

(32:45): Recent studies have shown Cymbalta (duloxetine) to be superior to gabapentin in controlling neuropathy-related pain.

(33:10): Lyrica (pregabalin) is another good drug for neuropathy, but insurance coverage can be an issue.

(34:38): Anti-epileptic medications, oxycodone and morphine are sometimes used to treat neuropathy but can have serious side effects

(38:17): Physical and occupational therapists can help relieve symptoms of peripheral neuropathy.

Transcript of Presentation:

(00:02): [Susan Stewart] Introduction. Hello, welcome to the workshop Managing Neuropathy after Transplant. My name is Sue Stewart and I will be your moderator for today.

(00:11): I'd like to welcome our speaker, Ms. Danielle Roberts. Danielle is a physician assistant with the Bone Marrow and Stem Cell Transplant Program at Winship Cancer Institute of Emory University. She serves as the Advanced Practice Provider Education Lead and the Co-Director of the Hematology Oncology Advanced Practice Provider Fellowship. Ms. Roberts specializes in managing complex bone marrow transplant patients, such as those with neuropathy and patients with chronic graft-versus-host disease. Please join me in welcoming Danielle Roberts.

(00:52): [Danielle Roberts] Overview of Talk. Thank you, Sue. I want to thank everybody for their time and their attendance for today. Today we're going to talk about managing neuropathy after transplant.

(01:04): Our objectives today are we want to talk a little bit about what exactly is neuropathy. What can be the causes of it? How do we test for it? Then finally, we're going to discuss management for peripheral neuropathy.

(01:19): Peripheral neuropathy is a series of disorders that interrupt the flow of information from the brain and spinal cord to muscles, skin and other parts of the body. What is peripheral neuropathy? Peripheral neuropathy is not just a single disease. It's a general term for a series of disorders that result from damage to the body's peripheral nervous system. This typically occurs when the nerves are damaged or destroyed and can't send messages from the brain and the spinal cord to the muscles, skin and other parts of the body. When this damage occurs, it presents itself as numbness and pain.

(01:43): A simple way for us to talk about how this happens is to think about your nervous system. You have your brain which interprets the signal and then tells us what to do. What happens when that signal is disrupted, the brain can't say, 'Hey, that's hot, pull your hand away'. If you think about back when we used to have TVs with antennas on it, and you used to have to move the antennas in order to correct the signal and to clear the signal up, that's kind of what neuropathy is. Neuropathy is that disruption in this signal. So when you can't feel your fingers, the brain can't say, 'Hey, that's very hot or that's very sharp, you need to move away from it'.

 (02:26): People can experience symptoms of peripheral neuropathy differently.   Also, because of that disruption in the signal, it presents itself differently. Some people may feel a burning sensation. Some people may feel a pain sensation. Some people may not feel anything, or they may say it feels like I have gravel in my toes or in my shoes. That is that kind of disruption in the signal.

(02:49): It can take one to two years to see some improvement in peripheral neuropathy once treatment is started. For some people, the disruption in the signal can heal. How much damage has been done and where the damage [affects] how long this can take to improve. If you think about how long your nerves stretch, if they're starting in your back and they're going to your hands, [it's] a little bit shorter than those really long nerves that have to go all the way down to your toes. When I'm seeing a patient and they're starting to have these symptoms, I usually tell patients that we're going to hope that it's going to improve, but it can take anywhere between a year and two years for us to really start seeing improvement for neuropathy, which is quite frustrating, both for the patient and for us. We would like for everything to be fixed quickly. Unfortunately that's hard to do.

(03:36): Peripheral neuropathy is most common in people older than age 55, and those who have diabetes, HIV or received chemotherapy.  In the general population, about 2.4% of people have neuropathy. The incidence increases to about 8% of people older than the age of 55. Neuropathy is more common in people with diabetes, HIV, and those receiving chemotherapy. The term for that is chemotherapy-induced peripheral neuropathy or CIPN.

(03:56): Neuropathy can be caused by a B vitamin deficiency. Other causes of neuropathy can be due to nutrition, for instance, B12 deficiencies. A lot of times when I'm seeing patients and they're starting to have these symptoms, I'll check for B vitamin deficiencies, I'll check for iron deficiencies. We look at some of those nutritional markers.

(04:11): Factors like kidney disease, increased alcohol use, a history of smoking and whether neuropathy existed before chemotherapy can impact the choice of treatment. You also have to look at what the underlying disease for the transplant was. Was there a big mass on the spine that caused that compression there? So that could be still causing some of the neuropathy, even though that the disease is treated. People who have kidney disease, increased alcohol use, and there are some immune mediated neuropathy, but that's more rare.

(04:38): Predisposing risk factors for neuropathy are age. The older you are the higher risk for neuropathy. The occurrence of neuropathy before the start of chemotherapy. One of the things when I'm seeing new patients that are coming in for chemotherapy, I always assess what their amount of chemotherapy they have before we start treatment. That allows me to do a couple of things. One, it sets up realistic expectations. It also changes how I'm going to start the therapy. I'm a little bit more quick to try to start some of the nutritional support for B vitamins or even doing some topical therapies. Then it also, from an understanding of where they are in treatment, I start asking questions like, is it different than it was before? Those are all things that I do at the start of chemotherapy for patients that I know have neuropathy.

(05:28):A history of smoking, smoking is not good for us. Smoking causes peripheral vascular disease, and with that also causes neuropathy. Unfortunately smoking increases your risk for neuropathy. Patients with impaired renal function with reduced creatinine clearance are also at a higher risk of neuropathy as well.

(05:50): Symptoms of neuropathy include tingling, prickling, lack of sensation, coldness, burning sensation, shooting or stabbing pain in the hands or feet. Let's talk about what the symptoms are. Neuropathy is described as sensory neuropathy. That's that tingling or prickling sensation that you may have in your fingertips or in your toes. It can also lead to kind of that almost dead feeling like where you've sat on your hands or your feet or at night when you kind of slept with your hands underneath your body, and you wake up in the morning, and you can't feel your hands. That deadness symptom is also one of those symptoms of neuropathy.

(06:20): Some patients will say my hands are always cold. Especially those with a history of Raynaud's will really have an increased risk for neuropathy. They'll have more of that cold almost where their fingers turn blue in color. Tightness is a common symptom of sensory neuropathy.

(06:39): Burning is a very, very, very common sensation that I see in my clinics. I had a patient that actually came in yesterday and said, my hands feel like they're burning all the time. He was receiving treatment for myeloma, and one of the drugs can cause that. At that point, we're starting to make changes in his treatment, but he didn't understand why he had that burning sensation. It was a conversation about what is neuropathy, what are the symptoms and how we treat it. We had a long talk about what we were going to do to help him with his symptoms.

(07:12): Shooting, stabbing pains is very common. It can also be where it radiates up. A lot of patients will start having that tingling, prickling sensations in their hands or their toes. Then it can progress where it starts to go up through the palm of the hand or the sole of the foot up into the legs.

(07:30): Some patients with peripheral neuropathy are sensitive when touched or lack feeling in their hands or feet. Sensitivity to contact can be an issue for some patients. It can both be where it is incredibly sensitive, where they don't want anything touching their hands or their feet, or it can be the reverse where they have lack of sensitivity in that area. You see kind of both types of sensation from that standpoint. That's typically what we call sensory neuropathy.

(07:54): Peripheral neuropathy can cause problems walking and decreased grip strength. You can also have weakness where we have feet slapping. This typically comes from where you're having difficulty raising that foot up and moving while you're walking. It can also result in what's called a foot drop where you're dragging the toe. People can have difficulty rising from a toilet or a chair seat. That's because they can't feel their feet on the floor, and they get weakness in their legs, so they have difficulty with that motion.

(08:29): Decreased grip strength is very common as well. When I'm in clinic and I'm talking to patients, I'll commonly ask them, can you open up a water bottle? Can you tie your shoes? Can you button up your clothes? Because that grip strength is part of those fine motor functions that we have. Unfortunately, that becomes diminished with neuropathy and that weakness is part of the side effect or symptom profile that we can see.

I had a patient recently tell me, I have to lift my leg all the way up to walk because she says, I can't feel it, and I'm afraid of falling because she's dragging her toe. I had another patient a while ago, tell me that she looked like a flamingo. It was always one of my favorites. She was like, I lift my foot all the way up like a flamingo does, and then I put it down to ensure that I'm not going to drag my foot when I'm walking because she doesn't want to fall.

(09:24): Autonomic neuropathy is a different type of neuropathy that can cause lightheadedness upon standing, dry eyes, dry mouth, feeling full after eating a few bites, loss of bowel control, inability to sweat and/or erectile dysfunction. We have this sensory kind of motor neuropathy, which is what we just talked about. There's also autonomic neuropathy. This is commonly more difficult to diagnose. It's also the one for most patients which is the most disconcerting. A lot of patients will start telling me they're having this lightheadedness upon standing. They'll go from a sitting position. They'll get up. They'll feel very lightheaded and dizzy.

A lot of us will say, that's just vertigo, but if we have patients who are at a higher risk of neuropathy, either from chemotherapy or because they're off, they have graft-versus-host disease, we have to make sure that this is not actually autonomic neuropathy because this can be detrimental to patients. We can't have anybody falling and hurting themselves. Also, we have to make sure that we're recognizing the symptom and then teaching you how to be sure-footed when you get up. Take your time. Don't rush when you're first getting up out of the chair. Make sure you take a second before moving on.

(10:25): Dry eyes, dry mouth can be that autonomic nervous neuropathy. It also can come from medications. Sometimes it's trying to figure out which is which.

(10:34): Feeling full after a few bites or a small meal.

(10:37): Constipation or diarrhea. I will tell you, I tend to see more diarrhea. Unfortunately, this is kind of that lack of control or the lack of a sensation in which you can feel like you have to have a bowel movement. We tend to see more diarrhea than I do constipation. That's clinically what I see, but in the literature both are reported.

(10:56): You may have some difficulty voiding.

(10:58): Lack of sweating. Again, that goes to that sensory disruption. The body doesn't know that it needs to sweat. Patients will tell me, I know I'm hot, but I'm not sweating. Am I at risk for heat stroke is a common question, especially down in the south where I work, patients get quite worried about that in the summertime.

(11:17): For men, this can unfortunately result in erectile dysfunction.

(11:22): Under that umbrella of neuropathy, we all tend to think of kind of the numbness and tingling as being those primary symptoms, but really, it's this big constellation of symptoms that can affect not only those fine motor movements, but also can result in having some like the lightheadedness and constipation, diarrhea that we see. Lightheadedness is probably the most common that I see clinically.

(11:48): Treatment for autonomic neuropathy is different than the treatment for peripheral neuropathy. The treatments for this can be different between, depending on if we're trying to treat the sensory neuropathy, so the numbness and tingling, we could do topicals for that. We're going to get into that later on. Versus if we have a lot of lightheadedness and dizziness, I'm going to do different treatments for that.

(12:09): When we talk about peripheral neuropathy, the most common way that we tend to describe this is this stocking glove. That's where I was discussing with you, how does this look on your hands? Is it in your fingertips? Does it cover your whole hand, like a glove does? Is it going up into your arms? The same thing on your feet. Is it just on your toes? Is it going up through the balls of your feet and up into your legs?

(12:37): The neuropathy may have different causes and present with similar signs and symptoms, but the most common is this length-dependent or where we call that stocking glove. As we talk about treatments and we talk about grading it clinically, the more area involved, the more symptoms you have, the higher grade this is, and it kind of dictates to us how we're going to do treatments. Especially at the beginning when we start, if lower grades, maybe we do topicals only. If it's progressing up to being more severe, if we're talking about chemotherapies, are we doing dose reductions? Are we going to oral medications at that point?

(13:22): Chemotherapy-induced peripheral neuropathy (CIPN) can occur in 10 to 85% of patients depending on the type of chemotherapy used. CIPN depends on the type of chemotherapy used, with rates between 10 and 85% Chemotherapy-induced peripheral neuropathy is clinically what we see more common in clinic. The prevalence is agent-dependent with reported rates varying from 19% to more than 85%. The most common agents are platinums, your taxanes, thalidomide, and lenalidomide, bortezomib or Velcade, Vincristine and Brentuximab Vedotin.

(13:46): Toxicity can occur with a single dose, but more commonly what we see is after cumulative exposure. When I'm in clinic with patients, I'm asking them every single time I see them, especially when they're on these agents, 'Are you having any neuropathy? Is it present all the time? Is it coming and going? Are there any functional difficulties? 'Because based on what you're telling me and how you're answering those questions, that's going to drive treatment decisions.

(14:12): Reporting symptoms of neuropathy as soon as they occur is crucial and can help prevent permanent disability. I can't stress how important it is to be honest with your providers about how this is going on or how your symptoms are progressing, what's going on with them. Because if we don't take action and we aren't paying attention to those symptoms, unfortunately, you can have permanent disabilities related to the neuropathy.

(14:32): I had a patient that was bound and determine that she was going to get all of her treatment. She didn't want any changes. She went from being able to walk in one day to the next time coming in a wheelchair because she couldn't feel her feet to walk. That's the last thing that we want for you guys. The point of treatment is to get you through and to try the best that we can to preserve your quality of life. We definitely don't want to make it worse, but we're only as good as what we're being told in clinic. Please make sure that as you're seeing these changes in your symptoms, that you're letting your providers know whether it's your physician, the nurse that works in the clinic or the advanced practice provider.

(15:13): Neuropathy can be a manifestation of graft-versus-host disease, particularly in patients with scleroderma-like skin GVHD. This is most commonly seen as chronic graft-versus-host disease. The median time between transplant and the onset of neuropathy is about six months. The neurologic GVHD most often affects the peripheral nervous system. There's a higher prevalence of neuropathy in patients with scleroderma. It's usually associated with long-term immunosuppression and graft-versus-host disease.

(15:40): So for those that are not familiar with scleroderma, scleroderma is a chronic graft-versus-host disease diagnosis that we see. It causes hardening of the tissues that fix into from the outward all the way down and through the layers of the fascia. The downside with scleroderma is it causes reduced range of motion. When it causes that reduced range of motion, we have patients that don't get up and move around as much, but also, you have decreased blood flow to the area. At worst case, we have sometimes where patients will have open sores in those areas. Because of the reduced fluids and the nutrients and everything coming in and out of that area, it's just harder because of the fixation of the tissue, you get neuropathy in those areas.

(16:35): When I start having a patient that comes in that hasn't had any neuropathy and all of a sudden, they're telling me, 'Hey, I'm having some numbness in the balls of my feet', the next thing I'm doing is I'm pulling up the ends of their pants. I'm looking at their legs. I'm taking off their shoes. I'm looking at their feet. I'm making sure I'm not starting to see some of the changes that we see with these scleroderma patients, because I do tend to see it more with those patients.

(17:02): Sometimes, reducing immunosuppressive drugs can improve symptoms of neuropathy.  Long-term immunosuppression. I have had patients that are on Prograf or Sirolimus. As we reduce the immunosuppression, some of neuropathy gets better with that. However, in my experience, I tend to see the neuropathy really in those patients with prolonged graft-versus-host disease that are on lots of steroids and that have that scleroderma diagnosis. For those patients, it's trying our best to treat the underlying cause of the neuropathy whether it be the graft-versus-host disease. If we think it's due to some of the immunosuppression, trying to reduce that appropriately and safely. It is one of those big triggers in my mind when I'm talking to patients that they start telling me that, and they haven't had it before, I'm starting to look and see whether there's other evidence of GVH, especially in a patient that hasn't had much before.

(18:05): We've talked a lot about what peripheral neuropathy is. We've described peripheral neuropathy. We've kind of talked about how it's the disruption of the signal, but how do we really test for, and how do we kind of diagnose it?

(18:19): Neurologists have the most sophisticated tests for peripheral neuropathy. Diagnosing it in my clinic is going to be very different than diagnosing it in a neurologist's clinic. If you're sent to a neurologist, they can do more sophisticated testing, like EMG testing where they actually stimulate the nerves. They're able to tell where the deficits are and how severe the deficit is. For me, I refer a lot to neurology for that patient that I can see they're starting to have new onset neuropathy. I've started these treatments. If I'm not getting anywhere with treatment, and I'm not seeing any improvement, then a lot of times I'm referring them out to neurology to have that more sophisticated testing.

(19:03): Light touch testing and vibration testing are initial tests for neuropathy. In my own clinic, when I'm starting to see neuropathy, or I'm worried about a patient's symptoms, and they're starting to tell me that they may have some neuropathy, then I'll usually start with what we call a light touch testing. This is a little piece of plastic. I have the patients take off their shoes and sit on the bench or the chair. I have them close their eyes. Then I'll touch their toes or the soles of their feet. I'll ask them, can they feel it? Usually they can tell me they feel the light touch or if they're already telling me they can't feel it, then this is when we're starting to grade the neuropathy. What they should be able to say is right big toe or left hand, and I'll go back and forth to different areas. I start usually at the toes, and I work my way up through to the area they either tell me they can't feel it anymore, or I've gotten all the way up past the ankle, and we're not having any sensory difficulties.

(20:07): The other way to test this is using the vibration testing. You do this with the tuning fork. What you do is you hit the tuning fork, you place it on the joint space, and you have patients tell you if they can feel it. You ask them to tell them when they stop feeling it, and that can be a way to see how the sensory is in those individual areas. I will do it on the bone at the big toe. I'll do it on the ankle, and then you can do it on the shin as well as the knee. Again, I always start at the toes and then I work my way through the ball of the foot and then up the leg, because you want to test each individual area to see where the sensory loss is and where it's most, and where they pick up the sensation again.

(20:56): Accurate testing for peripheral neuropathy helps determine how advanced the neuropathy is and dictates appropriate treatment. This is important for multiple reasons. One, it helps us grade clinically how advanced the neuropathy is, but it also allows us, as we start on therapies. And for patients that are telling me they're getting better; we can do the testing. If we are starting to see areas of sensation that they didn't have before, then we've got a response to therapy. That's a great outward sign, both for the clinicians and for the patients, that we're doing the right thing for them. It's always nice to be able to say, 'Hey, look, you're getting better. You used to not be able to feel this on your heel, and today you tell me that you can feel this'. Those are the two kind of testing from a light touch and then vibration.

(21:38): Pin prick tests can help diagnose loss of sensation. The third testing that I do in clinic is a kind of testing for pinprick. This is that kind of sharp touch. It's using a little kind of end of a little needle or sometimes I'll break a toothpick in half and use the end of it just as a little bit of a sharp touch. Again, I do it the same way. Can you feel it on your toes? Can you feel it on the balls of your feet and working the way up the leg so that we can see where the level of sensory loss is? The patients who can't feel the light touch are usually not going to be able to fill the pinprick, but I still do all the same things.

(22:25): Some people have reverse sensation; they can't feel anything like light touch. They can feel lots of things with pinprick or the opposite, they can't fill pinprick, but they feel things with light touch. In my clinic, if I'm going to do the testing on the patient, I'm doing all of it. I'm going to measure for the light touch. I'm going to measure for the vibration. Then I'm also going to measure for the pinprick.

(22:48): Other tests for peripheral neuropathy measures strength, muscle performance, and reflexes. Other testing should include what is your strength? I'll examine the legs. I'll examine the arms. I usually will have patients try to test their strength. I always tell them to punch me in the stomach, which everybody always loves. Then I tell them, I'm not going to really let you hurt me, but I'm holding onto their hand. I'm having them punch me hard so I can tell 'can they knock me off their feet'? Can they pull me off of their toes? Can they lift their legs up against me putting pressure down onto the thighs?

(23:19): The muscle examination is important, especially for that autonomic neuropathy. The autonomic neuropathy, they may have not had any problems with sensation, but yet their muscle strength may be weak. Again, this tells us more of the overall global picture of what's going on with the patients and allows me to either appropriately treat them or get them to the right person to treat them.

(23:45): You want to test the reflexes. Again, this tells us where the level of sensory deficit is.

(23:51): Evaluating the gait or walking can indicate if a person may have peripheral neuropathy. One of the most important things is to evaluate the gait or the walking. I always tell patients at the end of the clinic, I'm going to watch you walk out of the clinic, because I want to see how they're moving. In the rooms, we have a very small space. I have some patients that in a short amount of time, they won't drag their toes at all. If they're just walking a short distance, say from the chair to the exam table, they'll be fine. Some of that is because of muscle weakness. The longer they walk, the more weakness that they have, the more tired those muscles get, and the more likely they are to drag that toe or to start really kind of changing the way they lift that foot up.

(24:38): I walk them out of the room and watch them walk down the hallway so that I really get a good measure of what their gait is like. Are they walking wide-based because they're worried they're going to fall because they're dizzy? Are they picking up their foot like a flamingo because they're afraid of dragging their toe or are they just full on dragging that toe because they don't know what's going on yet? So that's another great way for us to evaluate the overall picture for what's going on from a neuropathy standpoint.

(25:16): For my patients who need to see neurology, again, it's a referral onto them. Our neurology partners are great. They can do the EMG testing. From there, they can talk about appropriate treatments or physical therapy. It's a great working relationship between us and the neurologist, to effectively evaluate tests and appropriately treat.

(25:43): Now onto the part you're probably all waiting for. How do we treat it and what do we do with this? Treatment options. There are lots and lots of things that are out there. Unfortunately, what works for some people doesn't work for all. A lot of times this is, we've tried this, okay, this didn't work, so we're going to try something else.

(26:05): Treatment options for peripheral neuropathy include topicals, like lidocaine patches, anti-inflammatory creams, capsaicin and oral medications. I like topicals. I like topicals for lots of reasons. We're going to get into that in just a moment. There are patches like lidocaine patches. There's anti-inflammatory creams that you can put on there, like Diclofenac. Then there's holistic treatments like capsaicin.

(26:20): There are oral medications that we can use. Currently, duloxetine or Cymbalta is the only agent endorsed by ASCO or the ESMO for treatment of chemotherapy-induced peripheral neuropathy. I'm sure everybody's heard of Gabapentin. That's been the mainstay for years for neuropathy. Lyrica is another drug similar to duloxetine. It's actually FDA approved for diabetic neuropathy. Antidepressants can work well. Looking at those nutritional deficiencies and using supplements or vitamins when appropriate.

(26:57): Treatments for peripheral neuropathy that don’t include drugs include acupuncture, massage, and TENS units. Now there's lots of other mechanical treatments, acupuncture, massage TENs units. We're going to talk more about that. Over the last year to two years, there's actually been some great improvement with neuropathy and looking at alternative therapies that are not always medication in order to treat.

(27:17): When I gave this lecture about three years ago, a lot of what we're going to talk about in a minute didn't actually exist. It makes me happy to see that there are other options for our patients. There's a lot of patients that just have fatigue from the amount of medications that we're giving them. There's a lot of people, and appropriately so, that are like,' I just can't take another pill or I don't want to take any more narcotics, what else can we do?' There's been a lot of movement in that direction. I'm really happy for you guys that we are able to offer new supportive treatments that are not always a medication.

(27:53): First line therapies for peripheral neuropathy include over-the-counter pain medication, capsaicin and soaking feet in cool water.  What are some first line therapies? Soaking the feet in cool water. You have to test the water. We want to make sure that it's not too hot, because we don't want to get you burnt.

(28:02): There's over the counter pain medicine like Tylenol or ibuprofen, topical agents. I like Capsaicin a lot. It's my go-to for first line therapy for my patients. Capsaicin is the active ingredient in chili peppers. It's thought to be very anti-inflammatory. Putting that on the soles of the feet seems to work well for patients. There's actually been several studies recently that have looked at this, and its actually what patients are reporting with using Capsaicin, they're actually seeing improvement. I think it's a good first line agent for patients to use.

(28:38): There are lidocaine patches. Over the counter it's a 4% patch that you can get. Those are those salon-size patches. Prescription strength is 5%. I will tell you right now, I cannot get insurance to typically cover the 5% patch because the 4% is available over the counter. That's usually what I tell patients to do. You can use a maximum of three patches daily for about 12 to 18 hours. I usually tell patients to trial this for about three weeks. If it doesn't work or offer improvement in that amount a time, it's typically not going to. The great thing about doing that is, as long as you don't have any open wounds or any breakdown on the bottom of the feet, there's really not a lot of significant adverse effects. From that standpoint, it's great to use.

(29:25): There are combination gels creams that can be made that are great to use. The problem with this is sometimes they're time consuming and not all insurances will cover for this.

(29:39): Topical compounded agents avoid the GI tract, deliver greater concentration of the drug to the problem area, and deliver relief more quickly than a pill. I like the compounded agents, so I tend to try to go to this for our patients. There are multiple reasons. One, it avoids the GI tract. Most of our patients are on a lot of medications, so anything I can do to try to avoid the GI tract, that's not going to cause any nausea or diarrhea, I try to do so. You also get greater concentration of the drug when it's delivered directly to the area where it's applied. Whereas if you're taking it orally, it has to go through breakdown through our liver or our kidneys. You actually get less of the drug making it to the area that it's needed. Applying it directly to it is higher concentration. It's also not dependent on the blood flow for the delivery to the site, so higher effectiveness in a shorter amount of time.

(30:21): The average drug, as it goes through all the things that it needs to do to get broken down in your body, can take 20 to 30 minutes for you to even see any improvement. Some of the other medications, you have to build up to steady state in your system, so it can take up to a week or more for you to see improvement. But if you put it directly on the area, you can see almost immediate improvement. It also has decreased toxicity because it's not being systemically absorbed. You don't have to worry about interactions with other medications.

(30:49): I see improved compliance, because again, a lot of patients just don't want to take any more pills, but as you massage it and rub it onto your feet, tend to be a little bit higher compliance. You can do multiple ingredients. For patients who may have renal dysfunction, they can't take a lot of anti-inflammatory drugs, you can still apply them onto the top of the skin. You're able to use some drugs and accommodations that you may not be able to orally, but you can if we're using them topically. Then there's flexible dosing with it. You can go up on some drugs on the dose and maybe decrease on other drugs.

(31:24): If this is available to you, I encourage you to talk to your physicians or your advanced practice providers about this. Again, it can sometimes be difficult to get because they do have to go to compounding pharmacies for this.

(31:37): The other problem that I run into with some of my patients is just cost because not all insurances will cover it, but typically if you start talking to the insurances, they will tell you, okay, we'll cover this particular combination. Sometimes it's just kind of getting to what they actually are willing to pay for, which is a hassle sometimes in all of us, but it's so worthwhile if it offers relief.

(32:02): Second line treatments include oral medications like antidepressants. Second line treatments would be oral medications. The mainstay of this are antidepressants. They change the brain's chemistry and communication to help relieve those pain sensations. Again, Cymbalta (duloxetine) is the one that at this point now, is kind of the go-to medication for chemotherapy-induced peripheral neuropathy. Venlafaxine or Effexor can also be effective for patients. Tricyclic antidepressants, amitriptyline, nortriptyline. However, they have a higher side effect profile. You have to worry about interactions with other medications. I tend not to use them as much. I do like amitriptyline. My go to though is the duloxetine right now.

(32:45): Recent studies have shown Cymbalta (duloxetine) to be superior to gabapentin in controlling neuropathy-related pain. Gabapentin (Neurontin) has been a mainstay for neuropathy for years it seems like. The recent studies have shown duloxetine to be superior to gabapentin in controlling those pain sensations or the symptoms associated with chemotherapy-induced neuropathy. That's why we're seeing a change in practice because of those recent studies.

(33:10): Lyrica (pregabalin) is another good drug for neuropathy, but insurance coverage can be an issue. The difficulty from a prescriber standpoint for that particular medication is that it's FDA approved for the treatment of diabetic neuropathy. When we're trying to use it for either graft-versus-host disease-induced neuropathy or that chemotherapy-induced neuropathy, there can be a payment issue. A lot of times they'll require us to use Gabapentin or Duloxetine first. Basically say that you have not responded to either one of those before pregabalin will be paid for by the insurance companies.

(33:48): Pregabalin is a good medication. I like it. I tend to use it in the setting where people have failed Gabapentin because I do think there's efficacy in that situation for using that particular medication. I also like Lyrica because of the dosing with it. It comes in a couple of different dosing levels, and you can change the amounts in terms for using it. Same thing with Gabapentin. Gabapentin has several different dosing levels.

(34:17): Cymbalta for pain control or duloxetine for pain control, the dose is around 60 milligrams a day is what's been found to be effective dosing. Some people take 120, but the studies most recently have shown that 60 milligrams a day is the optimal dose for pain control.

(34:38): Anti-epileptic medications, oxycodone and morphine are sometimes used to treat neuropathy but can have serious side effects. Other medications can be anti-epileptic medications. These are used less often because of the side effect and interactions that they have, but they are an option. Especially if we've gone through other medications and you're not responding, pain medication tends to be a mainstay for treatment. A lot of times we're using Oxycodone or morphine, both the long acting and the immediate release to control pain.

(35:07): What we are finding in the literature now is that for pain control or at least for what it seems to be, as we're doing more and more studies on this, that the side effects with oxycodone and morphine, both long-acting and short-acting, the benefit for using it for neuropathy doesn't outweigh the side effects. You're starting to see a lot of us that are going away from the narcotics, especially at the beginning, trying to use the other medications. If that's not working then moving to the narcotic pain medication as that kind of second line, third line therapy.

(35:49): Medical marijuana helps some patients with peripheral neuropathy. One of the most common questions that I get in clinic is about medical marijuana. Depending on the state that you live in, it is easier for patients to be able to use this or be able to easily get this. I like medical marijuana for neuropathy. I think this works great for patients, especially for those patients who have failed two to three lines of prior therapy. You can have medical marijuana as CBD, which is the cannabis or the THC, which is the active ingredient. It also comes with synthetic. This is Nabilone and Dronabinol. I'm sorry, I always have difficulty saying that. Marinol is the trade name for that. There are side effects with this. What we initially saw using especially Marinol is that you wouldn't get psychosis or euphoria with it; however, we're starting to see that more and more with patients, especially at higher doses. With prolonged use, you do not want to stop without a taper due to withdrawal symptoms.

(36:51): Cognitive behavioral therapy and neurofeedback can help with symptoms of neuropathy. There are nonpharmacologic treatments for this. We have cognitive behavioral therapy. This can be self-guided or with group therapy. There is neurofeedback now, which involves auditory or visual stimuli or rewards. This actually has resulted in significantly improved neuropathy-related pain, quality of life and fatigue for patients.

(37:14): Cryotherapy, in clinical trials, is being used to treat chemotherapy-induced peripheral neuropathy. There's cryotherapy, we're seeing this more and more. It's in clinical trials. It's been used for both the prevention of, with prophylactic chemotherapy, and it's also been used once you have the chemotherapy-induced neuropathy. We are seeing that used. It's often combined with compression therapy to improve the symptoms.

(37:37): Scrambler therapy is the newest treatment for peripheral neuropathy. Scrambler therapy is the newest in treatment that's come for chemotherapy-induced neuropathy. It involves the use of a device that delivers a stimulation to the skin. Basically what it does is it's replacing those pain signals. The data's been mixed and less promising. They need additional studies, but it's out there and it is an option.

(38:03): There are sensorimotor training or whole-body vibration training. Patients and intervention groups reported subjective improvements, so that's an option that didn't exist when I did this talk a couple of years ago.

(38:17): Physical and occupational therapists can help relieve symptoms of peripheral neuropathy. For all of my patients with neuropathy, especially the ones that have foot drop or they're having muscle weakness, I move immediately to physical therapy and massage for those patients, as well, because that seems to help. Most physical therapists now are able to do dry needleing, which is a form of acupuncture. We're seeing a lot of improvement with that. There's some good data to support the use of acupuncture. The nice thing about acupuncture is that it's being covered by your insurance, and so is massage, especially if you can get your providers to write you a prescription.

(39:03): If you can’t feel your feet, daily inspection of your feet and foot care is important. I never want to discount the general foot care. You want to make sure that if you can't feel your feet, that you're inspecting your feet because any type of wound can lead to a serious infection or sores. Make sure you're wearing sturdy shoes. Make sure you do not apply direct heat to your feet or your legs.

(39:22): You should always test the temperature of the water with your hands or some part of your body that you can feel like your elbow. You want to wash your feet daily with lukewarm water, apply moisturizer. You want to use a mild or fragrance-free soap. You want to dry by blotting or padding. You won't want to use too much friction because again, that can exacerbate symptoms.

(39:46): Don't go barefoot. You don't want to step on anything that may hurt your feet. Choose good footwear, closed toe, lightweight, low heel. No stiletto heels for my ladies out there.

 (39:59): I went ahead and included some different studies and new treatments out there for the treatment of neuropathic pain in case you guys were interested. I believe that we need to go to questions now. I just want to thank you all for your time today and for your participation in this. It is an honor to care for my patients with neuropathy and with graft-versus-host disease. If there's anything that I can do or questions that I can answer for you, we're going to turn it over to that now.

Question and Answer Session

(40:34): [Susan Stewart] Thank you so much, Danielle. That was an excellent presentation and there are indeed a lot of questions. We will try to get through all of them. First question is can compression socks that are used for neuropathy cause the skin to break down on the legs. This woman wears 15-20s, about 12 hours a day.

(40:56): [Danielle Roberts] The answer is yes. I do encourage the use of compression socks because I think it helps with the flow of the blood and helping maintain that and can actually help with improving of the sensations. However, if you've got a lot of swelling in your legs, that's where we can see the breakdown, 15 to 20 is typically a lighter compression. It's usually what I recommend as well. If you're finding that you're having some breakdown of the skin with them, I would limit the amount of time. Also, I tend to tell patients not to sleep in them at night because you're more apt to scratch or rub at night that you won't know, and that can increase the risk of having some breakdown of the skin as well.

(41:39): [Susan Stewart] All right, thank you. Next question, are leg cramps like the ones I get frequently at night considered a form of neuropathy? I've been plagued by leg cramps at night for 15 years since being on Revlimid about seven years after my transplant 15 years ago. I'm not on any myeloma treatment presently.

(42:04): [Danielle Roberts] That's a great question, and it has a complicated answer. In the graft-versus-host disease land, when I have a patient that all of a sudden develops leg cramps, typically, yes, that is their form of neuropathy. That's when I'm starting to look for those scleroderma-type changes.

(42:22): For my patients that are on Revlimid, it can be a form of the neuropathy. It also can be a side effect of the medication, too. It's hard sometimes to decipher what is related to the medication, what is related to neuropathy. Leg cramps are horrible for patients. It's horrible for anybody. There's nothing worse than waking up in the middle of the night with that Charlie horse and that contraction of that big calf muscle. The only thing that you can do is kind of massage or walk it out. I wish I had a better answer for you. I think the easy answer is to say it should definitely be in the consideration. I would further talk with your physician about that.

(43:06): [Susan Stewart] All right, good answer. Next question is you mentioned difficulty urinating with neuropathy. Do you ever see increased urinary frequency, feeling the need to urinate, not urgency with peripheral neuropathy?

(43:20): [Danielle Roberts] Yes, I do see that. We see kind of both sides, and so that increased need to urinate can sometimes again, kind of how I describe the diarrhea, it's that lack of being able to control. You feel like you have to urinate all the time and that's more of that autonomic neuropathy. For women, when I see that symptom, I always want to do the additional workup as well. I want to make sure we don't have urinary tract infections. Want to make sure that if it's not related to some type of infection process, then it's actually doing pelvic floor physical therapy. Physical therapy has come a long way. I love my rehab medicine colleagues and my physical therapy colleagues. For women, they actually have pelvic floor rehab that can be done that can help strengthen those pelvic floor muscles that can decrease that sensation so that you don't feel like you're having to go to the restroom all the time. It also can help with leakage if that's an issue as well, too.

(44:23): [Susan Stewart] All right, next question. I've been taking alpha-lipoic acid since my transplant and my feet have gotten better, but after resuming Velcade, the neuropathy got worse. How long is it safe to take alpha-lipoic acid?

(44:41): [Danielle Roberts] To the best of my knowledge, there's not a timeframe in which we have to stop it. I have lots of people that take it for a long period of time. There is a recent study that came out that actually... Years ago, we all put everybody on alpha-lipoic acid because people were seeing relief with it. There's a newer study that recently came out, and they're not seeing as much improvement with using that particular drug. There's always the question of do things just stop working after a period of time, and that may be what's happening at this point. If I've had a patient on a particular medication or supplement for quite some time, and they're not getting better with it, then I usually have them stop it. Then I try something else to see if that will help improvement.

(45:29): [Susan Stewart] All right, this gentleman wants to know whether Voltaren is a compounded topical agent.

(45:36): [Danielle Roberts] It is not compounded. It is a topical agent. It is a great topical agent, and most APPs and physicians can prescribe it and it's easily attainable at most local pharmacies.

(45:51): [Susan Stewart] All right, next question is neuropathy a progressive condition or will it stabilize with the underlying disease?

(46:00): [Danielle Roberts] It can be progressive if we do not recognize it, especially if it's caused by an offending agent, and we either stop or decrease the dose of the offending agent. From a chemotherapy-induced neuropathy standpoint, it can be progressive if we're not recognizing the signs and symptoms, and we're not making the appropriate adjustments for medications. From a graft-versus-host disease standpoint, I do see progressive neuropathy and that's usually telling me the body's trying to tell me, 'Hey, there's something going on, pay attention, we need to look at other things'. Typically, once it's recognized, what we should hopefully see, and as we've removed the offending agents, is we should see it at least stabilize. What we're hoping is to actually see it improve over time.

(46:50): [Susan Stewart] Okay, this gentleman wants to know when he should stop using compression stockings.

(46:58): [Danielle Roberts] I love compression stockings. I tell patients to use them all the time. If the symptoms completely go away, and you're not having any swelling anymore, then it's okay to stop using the compression socks, unless you have other types of needs for it like peripheral vascular disease. All depending on your reasoning for using them would dictate how and when you should stop them. If it's solely being used for swelling and for neuropathy, and those symptoms are going away, I think it would be safe to stop them. However, again, I live in the south, it's hot in the summertime. Nobody wants to wear compression hose in the summertime, but we tend to swell more in the summertime. I just told somebody the other day, 'I need you to wear your compression hose with your socks at work'. He didn't like that, but I'm hoping he's going to do it anyways.

(47:46): [Susan Stewart] Okay. This person has neuropathy in their feet and wants to know if this causes swelling of a foot and ankle.

(47:57): [Danielle Roberts] It can at the beginning. As we treat it, we should hopefully start to see that improve. Also, swelling can be causative for neuropathy. I'll have some patients that will notice when they're more swollen the neuropathy is worse. As the swelling improves, the neuropathy will improve as well.

(48:16): [Susan Stewart] All right, this gentleman wants to know what vitamins you would suggest for neuropathy.

(48:24): [Danielle Roberts] I usually recommend a good B complex vitamin because it's not just the B12 deficiencies that can cause neuropathy. You can also see it in B6 B1. I generally recommend a good complex B vitamin. I like magnesium, as long as it's not giving any diarrhea. Believe it or not, vitamin D. If patients are vitamin D deficient, and unfortunately in the United States, because we spend so much time indoors, most of us are vitamin D deficient, giving vitamin D, a little bit of magnesium, and some B vitamins back can be a great cocktail for improvement in neuropathy.

(49:03): [Susan Stewart] All right. The next person wants to know, have you ever seen acrocyanosis of the feet with neuropathic pain and toenail changes at the time of diagnosis before treatment?

(49:17): [Danielle Roberts] Unfortunately, I have not.

(49:22): [Susan Stewart] All right. This person wants to know he has numbness in his big toes only after chemo. Is this considered neuropathy. If so, what can be done? He doesn't have any pain only numbness.

(49:37): [Danielle Roberts] It can be that this is your presenting sign for neuropathy. I would encourage you to talk to either your advanced practitioner you're seeing or your physician that you're seeing. Typically at this point is when I'm starting either some topicals, like topical capsaicin, because it is one of my go-tos. And I'm usually starting the B complex vitamins, my go-tos in that setting. I personally, and not knowing what chemo you're on and not knowing kind of what the intent is, it's hard to say about making treatment adjustments, and that's where you need to discuss it with your physician or your advanced practice provider, but I definitely would have that conversation with them.

(50:18): [Susan Stewart] All right, this woman has scleroderma, diabetes and GVHD. She was recently diagnosed with neuropathy through EMG after months of hip pain and falls from drop feet. She's wondering what type of doctor could help. What does she look for?

(50:36): [Danielle Roberts] Oh, that's an excellent question. I love this. At our institution, I use our rehabilitation medicine doctor. He does a lot of physical therapy, acupuncture, or at least plugs you into the right system for that. He also helps encourage exercise. Then if there is specific areas of pain, he does injections to control those symptoms. I like the rehabilitation medicine because of the physical therapy component of it. I think physical therapy is so important for neuropathy, especially for patients who have foot drop, so I use that.

(51:17): The other group that I tend to use a lot is our supportive oncology group. In our team, we have the oncology group that treats, if they're undergoing active therapy or in the GVHD clinic, we're taking care of those things. I like the combination of both groups to be able to help manage the pain symptoms, be able to get you to the right physical therapy, and really tell the physical therapy what areas to work on. That tends to be my recipe for success in trying to help manage our patients.

(52:17): [Susan Stewart] All right, next question can stage three kidney disease cause neuropathy?

(52:23): [Danielle Roberts] It can. We tend to see higher rates of neuropathy in our patients with kidney disease.

(52:32): [Susan Stewart] All right, this is another alpha-lipoic acid question. I'm using alpha-lipoic acid and L-carnitine with good effects. Should I consider going to Gabapentin?

2:43): [Danielle Roberts ] Honestly, if it's working well for you and you're not having a lot of side effects, if I was seeing you in clinic, I probably wouldn't make any changes because nothing we do is without its fair share of side effects. Certainly if you felt that it was not helping or you weren't having a good response to that, that would be when I would tell you to discuss it with your clinicians about changing to a medication like Gabapentin or looking at Cymbalta.

(53:13): [Susan Stewart] All right, this woman would like to know what the treatments are for autonomic neuropathy that you talked about.

(53:19): [Danielle Roberts] Yes. For autonomic neuropathy, I tend not to use as much of the oral medications as I do physical therapy and rehabilitation medicine. Much of autonomic neuropathy is the lightheadedness and dizziness, the foot drops, things like that. I find that doing rehabilitation medicine with physical therapy, I get better results.

(53:39): For patients who have a lot of lightheaded and dizziness, and they have what we call orthostatic hypotension, which is where, when you stand up, your blood pressure drops down, there can be specific medications that look at making sure that doesn't happen from a blood pressure standpoint. I do that. I often am prescribing a lot of foot braces, physical therapy, acupuncture for my patients with that autonomic neuropathy, or pelvic floor exercises, things like that because it seems to be that improving the muscle strength and going from that standpoint does better for autonomic versus doing a lot of medications, which can increase some of those side effects.

(54:23): [Susan Stewart] Okay. I think we may have covered this. I'm not sure whether she's referring here to compression socks or something different perhaps you know. She says, do you think the socks advertised for neuropathy work?

(54:38): [Danielle Roberts] I think it's very patient dependent. I have patients, some that say they do, and some say they don't. I will tell you that personally, my grandmother loves them. She says it makes her neuropathy feel much better. Again, that is a very personal, personal choice. I think it's definitely an easy thing and worth trying. Again, it's something that you're not having to take medications for.

(55:08): [Susan Stewart] All right. Next one is kind of a compound question. Can GVHD cause neuropathy in the autonomic parasympathetic vagus nerve and the central nervous system, as well as where we feel it in the peripheral system? Then second question, can GVHD damage the myelin sheaths of the nerves causing a demyelating process as well as damaging the neuron cells themselves?

(55:36): [Danielle Roberts] That's a hard question to fully answer. There's a GVHD diagnosis, myasthenia gravis, that can have some of those type symptoms. As far as the other question, it's hard. The last time, because I had a patient that presenting with those similar symptoms and I did kind of deep dive into the literature about that. It's hard to find a lot of literature for that. We are actually making sure that you're looking at other sources of it and making sure that there's not another reason to have those type symptoms. I'm sorry. I don't a good answer for you. I think it's a really complex question and that I would definitely, if you're having those symptoms, would definitely want to get you back to your oncologist and making sure that we're working you up appropriately.

(56:37): [Susan Stewart] All right. The next question is, does your definition of peripheral neuropathy include a burning sensation without perceptible sensory loss on exam?

6:48): [Danielle Roberts ] Yes. I had a patient that I saw this week that only has a burning sensation, and he has no sensory loss on exam. He has no difficult with any functional difficulties, but it's persistent. He said that it went from only being in his fingertips and the burning sensation is now all the way through the palms of his hands. I did make adjustments to his medications because of that.

(57:10): [Susan Stewart] Closing. Okay. With that question, I think we need to wrap up. Time has gone fast and thank you so much for that presentation, Ms. Roberts, and thank you very much to the audience. Some excellent questions, very thought provoking.

 (57:26): If you have any other questions or any other issues that you would like to address about this topic or anything else, please feel free to visit BMTInfonet.org or email us at help@bmtinfonet.org, or give us a call toll-free at (888) 597-7674. It's been a privilege having you here today. Have a wonderful rest of the afternoon.