Neuromodulation for Neuropathic Pain Syndromes With Dr. Prasad Shirvalkar

For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life.

In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Prasad Shirvalkar, MD, PhD, author of the article “Neuromodulation for Neuropathic Pain Syndromes,” in the Continuum® October 2024 Pain Management in Neurology issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of neurology at the University of California San Francisco in the Department of Neurology and a neurohospitalist, general neurologist, and clinician educator at the San Francisco VA Medical Center at the San Francisco General Hospital in San Francisco, California.

Dr. Shirvalkar is an associate professor in the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology at Weill Institute for Neurosciences at the University of California, San Francisco in San Francisco, California.

Additional Resources

Read the article: Neuromodulation for Neuropathic Pain Syndromes

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Host: @AaronLBerkowitz

Guest: @PrasadShirvalka

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor in Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Prasad Shirvalkar about his article on neuromodulation for painful neuropathic diseases, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and if you wouldn't mind, please introducing yourself to our listeners. 

Dr Shirvalkar: Thanks, Aaron. Yes, of course. So, my name is Prasad Shirvalkar. I'm an associate professor in anesthesiology, neurology and neurological surgery at UCSF. I am one of those rare neurologists that's actually a pain physician. 

Dr Berkowitz: Fantastic. And we're excited to have you here and talk to you more about being a neurologist in in the field of pain. So, you wrote a fascinating article here about current and emerging neuromodulation devices and techniques being used to treat chronic pain. And in our interview today, I'm hoping to learn and for our listeners to learn about these devices and techniques and how to determine which patients may benefit from them. But before we get into some of the clinical aspects here, can you first just give our listeners an overview of the basic principles of how neuromodulation of various regions of the nervous system is thought to reduce pain?

Dr Shirvalkar: Yeah, I would love to try. But I will promise you that I will not succeed because I think to a large extent, we don't understand how neuromodulation works to treat pain, to describe or to define neuromodulation. Neuromodulation is often described as using electrical stimuli or a chemical stimuli to alter nervous system activity to really influence local activity, but also kind of distant network activity that might be producing pain. On one level, we don't fully understand how pain arises, specifically how chronic pain arises in the nervous system. It's a huge focus of study from the NIH Heal Initiative and many labs around the world. But acute pain, which is kind of when you stub your toe or you burn your finger, is thought to be quite different from the changes over time and the kind of plasticity that produces emotional, cognitive and sensory dimensions. Really what I think is its own disease, chronic pain, of which there are multiple syndromes when we use neuromodulation, either peripheral nerve stimulation or electrical spinal cord stimulation. One common or predominant theory actually comes from a paper in science from 1967 and people still use it, foundational theory and it's called the gate control theory. Two authors, Melzack and Wall, postulated that at the spinal level, there are, there's a local inhibitory circuit or, you know, there's a local circuit where if you provide input to either peripheral nerves or either spinal cord ascending fibers that to kind of summarize it, there's only so much bandwidth, you know, that nerves can carry. And so that if you literally pass through artificial signals electrically, that you will help gate out or block natural pathological but natural pain signals that might be arising from the periphery or spinal cord. So, you know, one idea is that you are kind of interfering with activity that's arising for chemical neuromodulation. The most common is something known as intrathecal drug infusion drug delivery ITTD for that we quite literally put a catheter in the spinal fluid, you know, at the level of the dorsal horn neurons that we think are responsible for perpetuating or creating the pain.

Where's the pain generator? And you really, you can infuse local anesthetic, you can infuse opioids. And what's nice is you avoid a lot of systemic side effects and toxicity because it goes right to the spinal cord, you know, by infusing in the fluid. So there's a couple of modalities, but I will say just, like maybe all of our living experience, pain is in the brain. And so, we don't really understand, I would say, what neuromodulation is doing to the higher spinal or brain levels.

Dr Berkowitz: Fascinating topic. And yeah, very interesting to hear both what our current understanding is that some of our current understanding is based on data that's 60 years old and that we're actually probably learning about pain by using these modulation techniques, even though we don't really understand how they might be working. So interesting feedback loop there as well as in as in the as in this land. So, your article very nicely organizes the neuromodulation techniques from peripheral to central. So, encourage our listeners to check out your article. And first before we get into some of the clinical applications, just to give the listeners the lay of the land, can you sort of lay out the devices and techniques available for treating pain at each level of the neuroaxis? We'll get into some of the indications in patient selection in a moment, but just sort of to lay out the landscape. What's available that you and your colleagues can use or implant at different levels when we're thinking of referring patients too?

Dr Shirvalkar: Absolutely. So, starting from the least invasive or you know, over the counter patients can purchase themselves a TENS machine. Many folks listening to this have probably tried a TENS machine in the past. And the idea is that you put a couple of pads, at least two. So you have like a dipole or you have a positive and a negative lead and you basically inject some current. So, the pads are attached to a battery and you can put these pads over muscle. If you have areas where myofascial pain or sore muscles, you can put them, frankly, over nerves as well and stimulate nerves that are deeper. Most TENS machines kind of use electrical pulses that occur at different rates. You change the rates, you can change the amplitude and patient can kind of have control for what works best. Then getting slightly more invasive, we can often stimulate electrically peripheral nerves. To do this we implant through a needle, a small wire that consists of anywhere from one electrical contact to four or even eight electrical contact. What I think is particularly cool, like TENS, which is transcutaneous electrical nerve stimulation that goes through the skin. Peripheral nerve stimulation aims to stimulate nerves, but you don't have to be right up against the nerve. So, yeah. We typically do this under an ultrasound and you can visualize a nerve like the sciatic nerve, peroneal nerve, or you know, even if someone has an ulnar or a neuropathy, you know, that's the compression. There's a role obviously for surgery and release, but if they have predominantly pain, it's not related to a mechanical problem per se, you could prevent a wire from a peripheral nerve stimulator as far as one centimeter from a nerve and it'll actually stimulate that that modulated and then, you know, kind of progressing even more deeply. The spinal cord stimulation, SCS, it's probably the most ubiquitous or popular form of neuromodulation for pain. People use it for all kinds of diseases. But what it roughly involves is a trial period, which is a placement of either two cylindrical wires, not directly over the spinal cord, but actually in the epidural space, right? So, it's kind of like when you get an epidural injection or doing labor and delivery, when women get epidural catheters, placing spinal cord stimulator leads in that same potential space outside the dura, and you're stimulating through the dura to actually target the ascending dorsal column fibers. And so, you do a trial period or a test drive where the patients get these wires put in. They're coming out of the skin, they're connected to a battery, and they walk around at home for about a week, take careful notes, check in with them, and they keep a diary or a log about how much it helps. Separately. I will say it's hard to distinguish this, the placebo effect often, but you know, sometimes we want to use the placebo effect in clinical practice, but it is a concern, you know, with such invasive things. But you know, if the trial works well, right, you basically can either keep the leads where they are and place a battery internally. And it's for neurologists. You're familiar with deep brain stimulation. These devices are very similar to DVS devices, but they're specifically made for spinal cord stimulation. And there's now like seven companies that offer manufacturers that offer it, each with their own proprietary algorithm or workflow. But going yet more invasive, there is intrathecal drug delivery, which I mentioned, which involves placement of the spinal catheter and infusion of drug into spinal fluid. You could do a trial for that as well.

Keep a patient in the hospital for a few days. You've all probably had experience with lumbar drains. It's something real similar. It just goes the other way. You know, you're infusing drugs, and it could also target peripheral nerves or nerve roots with catheters, and that's often done.

And last but not least, there's brain stimulation. Right now, it's all experimental except for some forms of TMS or transcranial magnetic stimulation, which is FDA approved for migraine with aura. There are tens machine type devices, cutaneous like stimulators where you can wear on your head like a crown or with stickers for various sorts of migraines. I don't really talk about them too much in in the article, but if there's a fast field out there for adjunctive therapy as well, 

Dr Berkowitz: Fantastic. That's a phenomenal overview. Just so we have the lay on the land of these devices. So, from peripheral essentially have peripheral nerve stimulators, spinal cord stimulators, intrathecal drug delivery devices and then techniques we use in other areas of neurology emerging for pain DBS deep brain stimulation and TMS transcranial magnetic stimulation. OK let's get into some clinical applications now. Let's start with spinal cord stimulators, which - correct me if I'm wrong - seem to be probably the most commonly seen in practice. Which patients can benefit from spinal cord stimulators? When should we think about referring a patient to you and your colleagues for consideration of implantation of one of these spinal cord stimulator devices? 

Dr Shirvalkar: So, you know, it's a great question. I would say it's interesting how to define which patients or diagnosis might be appropriate. Technically, spinal cord stimulators are approved for the treatment of most recently diabetic peripheral neuropathy. And so, I think that's a really great category if you have patients who have been failed by more conservative treatments, physical therapy, etcetera, but more commonly even going back, neuropathic low back pain and neuropathic leg pain. And so, you think about it and it's like, how do you define neuropathic pain. Neuropathic pain is kind of broadly defined as any pain that's caused by injury or some kind of lesion in the somatosensory nervous system. We now broaden that to be more than just somatosensory nervous system, but still, what if you can't find a lesion, but the pain still feels or seems neuropathic. Clinically, if something is neuropathic, we often use certain qualitative descriptors to describe that type of pain burning, stabbing, electric light, shooting radiates. There's often hyperpathia, like it lingers and spreads in space and time as opposed to, you know, arthritis, throbbing dull pain or as opposed to muscle pain might be myofascial pain, but sometimes it's hard to tell. So, there aren't great decision tools, I would say to help decide. One of the most common syndromes that we use spinal cord stimulation for is what used to be called failed back surgery syndrome. We never like to, we now try to shy away from explicitly saying something is someone has failed in their clinical treatment. So, the euphemism is now, you know, post-laminectomy syndrome. But in any case, if someone has had back surgery and they still have a nervy or neuropathic type pain, either shooting down their legs and often there's no evidence on MRI or even EMG that that something is wrong, they might be a good candidate, especially if they're relying on long term medications that have side effects or things like full agonist opioids, you know that that might have side effects or contraindication. So, I would say one, it's not a first line treatment. It's usually after you've gone through physical therapy for sure. So, you've gone through tried some medications. Basically, if chronic pain is still impacting your life and your function in a meaningful way that's restricting the things you want to do, then it it's totally appropriate, I think, to think about spinal cord stimulation. And importantly, I will add a huge predictor of final court stimulation success is psychological composition, you know, making sure the person doesn't have any untreated psychological illness and, and actually making sure their expectations going in are realistic. You're not going to cure anyone's pain. You may and that's, you know, a win, but it's very unlikely. And so, give folks the expectation that we hope to reduce your pain by 50% or we want you to list personally, I like functional goals where you say what is your pain preventing you from doing? We want to see if you can do X,Y, and Z during the trial period. Pharmacostimulation right now. Yeah. Biggest indication low back leg pain, Diabetic peripheral neuropathy. There is also an indication for CRPS, complex regional pain syndrome, a lesser, I'd say less common but also very debilitating pain condition. For better or worse. Tertiary quaternary care centers. You often will see spinal cord stem used off label for neuropathic type pain syndromes that are not explicitly better. That may be for example, like a nerve injury that's peripheral, you know, it's not responding. A lot of this off label use is highly variable and, you know, on the whole at a population level not very successful. And so, I think there's been a lot of mixed evidence. So, it's something to be aware about. 

Dr Berkowitz: That's a very helpful framework. So, thinking about referring patients to who have most commonly probably the patients with chronic low back pain have undergone surgery, have undergone physical therapy, are on medications, have undergone treatment for any potential psychological psychiatric comorbidities, and yet remain disabled by this pain and have a reasonable expectation and goals that you think would make them a good candidate for the procedure. Are those similar principles to peripheral nerve stimulation I wasn't familiar with that technique, I'm reading your article, so are the principles similar and if so, which particular conditions would potentially benefit from referral for a trial peripheral nerve stimulation as opposed to spinal cord stimulation? 

Dr Shirvalkar: Yeah, the principles are similar overall. The peripheral nerve stimulation, you know, neuropathic pain with all the characteristics you listed. Interestingly enough, just like spinal cord stim, most insurances require a psychological evaluation for peripheral nerve stim as well. And we want to make sure again that their expectations are reside, they have good social support and they understand the kind of risks of an invasive device. But also, for peripheral nerve stem, specifically, if someone has a traumatic injury of an individual peripheral nerve, often we will consider it seeing kind of super scapular stimulation. Often with folks who've had shoulder injuries or even sciatic nerve stimulation. I have done a few peroneal nerve stimulations as well as occipital nerve stimulation from migraine, so oxygen nerve stimulation has been studied a lot. So, it's still somewhat controversial, but in the right patient it can actually be really helpful.

Dr Berkowitz: Very helpful. So, these are patients who have neuropathic pain, but limited to one peripheral nerve distribution as opposed to the more widespread back associated pains, spine associated pains.

Dr Shirvalkar: Yeah, Yeah, that's right. And maybe there's one exception actually to this, which is brachial plexopathy. So, you know, folks who've had something like a brachial plexus avulsion or some kind of traumatic injury to their plexus, there is I think good Class 2 evidence that peripheral nerve stem can work. It falls under the indication. No one is as far as to my knowledge, No one's done an explicit trial, you know PNS randomized controlled trial. Yeah, that's, you know, another area one area where PNS or peripheral nerve stems emerging is actually, believe it or not in myofascial low back pain to actually provide muscle stimulation. There are some, there's a company or two out there that seeks to alter the physiology of the multifidus muscle, one of your spinal stabilizer muscles to really see if that can help low back pain. And they've had some interesting results. 

Dr Berkowitz: Very interesting. You mentioned TENS units earlier, transcutaneous electrical nerve stimulation as something a patient could get over the counter. When would you encourage a patient to try TENS and when would you consider TENS inadequate and really be thinking about a peripheral nerve stimulator? 

Dr Shirvalkar: Yeah, you know TENS we think of as really appropriate for myofascial pain. Folks who have muscular pain, have clear trigger points or taught muscle bands can often get relief from TENS If you turn a TENS machine up too high, you'll actually see muscle infection. So, there's an optimal level where you actually can turn it up to induce, like, a gentle vibration.

And so folks will feel paresthesia and vibrations, and that's kind of the sweet spot. However, I would say if folks have pain that's limited or temporary in time or after a particular activity, TENS can be really helpful. The unfortunate reality is TENS often has very time-limited benefits - just while you're wearing it, you know? So, it's often not enduring. And so that's one of the limitations.

Dr Berkowitz: That's helpful to understand. We've talked about the present landscape in your article, also talk a little bit about the future and you alluded to this earlier. Tell us a little bit about some off label emerging techniques that we may see in future use. Who, which types of patients, which conditions might we be referring to you and your colleagues for deep brain stimulation or transcranial magnetic stimulation or motor cortex stimulation? What's coming down the pipeline here? 

Dr Shirvalkar: That's a great question. You know, one of my favorite topics is deep brain stimulation. I run the laboratory that studies intracranial signals trying to understand how pain is processed in the brain. But, believe it or not, chronic pain is probably the oldest indication for which DBS has been studied. the first paper came out in 1960, I believe, in France. And you know, the, the original pivotal trials occurred even before the Parkinson's trial and so fell out of favor because in my opinion, I think it was just too hard or too difficult or a problem or too heterogeneous. You know, many things, but there are many central pain syndromes, you know, poststroke pains, there's often pains associated with Parkinson's disease, epilepsy, or other brain disorders for which we just don't have good circuit understanding or good targets.

So, I think what's coming down the pipeline is a better personalized target identification, understanding where can we stimulate to actually alleviate pain. The other big trend I think in neuromodulation is using closed loop stimulation which means in contrast to traditional electrical stimulation which is on all the time, you know it's 24/7, set it and forget it. Actually, having stimulation respond or adapt to ongoing physiological signals. So that's something that we're seeing in spinal cord stem, but also trying to develop in deep brain stimulation and noninvasive stimulation. TMS is interestingly approved for neuropathic pain in Europe, but not approved by the FDA in the US. And so I think we may see that coming out of pipeline broader indication. And finally, MR guided focused ultrasound is, is a kind of a brand new technique now. You know, focused ultrasound lesions are being used for essential tremor without even making an incision in the skull or drilling in skull. But there are ways to modulate the brain without lesioning. And, you know, I think a lot of research will be emerging on that in the next five years for, for pain and many other neuronal disorders.

Dr Berkowitz: That's fascinating. I didn't know that history that DBS was first studied for pain and now we think of it mostly for Parkinson's and other movement disorders. And now the cycle is coming back around to look at it for pain again. What are some of the targets that are being studied that are thought to have benefit or are being shown by your work and that of others to have benefit as far as DBS targets for, for chronic pain?

Dr Shirvalkar: You know, that's a great question. And so, the hard part is finding one target that works for all patients. So, it may actually require personalization and actually understanding what brain circuit phenotypes do you have with regards to your chronic pain and then based on that, what target might we use? But I will say the older targets. Classical targets were periaqueductal gray, which is kind of the opioid center in your brain. You know, it's thought to just release large amounts of endogenous opioids when you stimulate there and then the ventral pusher thalamus, right. So, the sensory ascending system may be through gait control theory interferes with pain, but newer targets the answer singlet there's some interest in in stimulating there again, it doesn't work for everybody. We found some interesting findings with the medial thalamus as well as aspects of the caudate and other basal ganglion nuclei that we hopefully will be publishing soon in a data science paper. 

Dr Berkowitz: Fantastic. That's exciting to hear and encourage all of our listeners to check out your article. That goes into a lot more depth than we had time to do in this short interview, both about the science and about the clinical indications, pros and cons, risks and benefits of some of these techniques. So again, today I've been interviewing Dr Prasad Shirvalkar, whose article on neuromodulation for painful neuropathic diseases appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you again to our listeners for joining today. 

Dr Shirvalkar: Thank you for having me. It was an honor.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.