In part 2 of our feature on the The Lancet Neurology publication “Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain,” Neurology Advisor interviews lead author Nagy Mekhail, MD, PhD, to discuss the importance of neuromodulation in managing chronic pain. For further background and context we encourage you to start with part 1.
In their study published in The Lancet Neurology, authors concluded that this trial provided “evidence for the safety and significantly superior clinical efficacy of a novel, closed loop system compared with a fixed-output, open-loop spinal cord stimulation for pain relief in patients with chronic intractable back and leg pain.”
For further discussion on the potential for neuromodulation, and significance of these findings, Neurology Advisor spoke with Nagy Mekhail, MD, PhD, Professor at the Cleveland Clinic Lerner College of Medicine, Director of Evidence-Based Pain Medicine Research and Education in the Department of Pain Management at the Cleveland Clinic, and lead author of the study.
The following is a transcript of the interview; some questions have been edited for brevity and clarity.
Neurology Advisor: Can you share your thoughts on the importance of recognizing chronic pain as a disease state and how its approach and management differs from acute pain?
Dr Mekhail: The concept that chronic pain is a disease is a concept that I would love neurologists to embrace. It is important to note that acute pain is a symptom of an underlying problem, whereas chronic pain is actually a disease by itself. Chronic pain may be related to an injury or a disease or a process, which with time, becomes a self-perpetuating mechanism of the disease.
As a chronic disease, we don’t aim to eliminate chronic pain; because at this point we can’t. Much like we can’t eliminate hypertension, or diabetes, we also cannot eliminate chronic pain; but, we can manage chronic pain. So far, the management of chronic pain has been with medication, the most important of which being opioids. As we know, opioids don’t really treat the pain – they mask it. We also have to take into account the extensive profile of side effects of opioids, as well as the potential for abuse and misuse. Other medications have been used as an intervention for chronic pain, but have demonstrated minimal success.
Neurology Advisor: Can you describe the clinical basis for neuromodulation and its potential for managing chronic pain?
Dr Mekhail: The idea of neuromodulation, or SCS [spinal cord stimulation], is that an electric stimulation of a specific target on the spinal cord can actually mask the pain or block the pain sensation. The first SCS was done 1967, since then the development has been exponential.
The advancement of technology, including the type of lead, shape of lead, type of wave form we deliver, the frequency and several modalities all have one thing in common: physicians decide the dose to which the spinal cord will be exposed. Call it frequency, call it amplitude, ultimately, it is an eclectic stimulation dose that is sent to the spinal cord. Unfortunately, we have never been able to say how much of this dose reaches the target of the spinal cord. Also, before now, we had no idea how the target of the spinal cord was responding to the electrical stimulation.
In the last 60-plus years, we have been giving controlled doses and hoping that they will help in managing the pain. The advantage of this new technology, and results outlined in the paper, is that for the first time we are able to record how much stimulation is reaching the target of the spinal cord. Through objective neurophysiologic measurements we are able identify the right target of the spinal cord fibers and monitor the spinal cord activity and its response to the stimulation.
Neurology Advisor: In other words, you are listening to the spinal cord and not just administering therapy, with no idea of what happened at the target level?
Dr Mekhail: Absolutely. That is the beauty of this closed-looped ECAP [evoked compound action potentials] system. We put the spinal cord lead in the appropriate spot and start stimulation; the sensor in the lead will monitor the ECAP and send the data to the generator to make sure the next dose of stimulation will produce the same action potential. This process occurs in real time.
This is a unique phenomenon that allows us to communicate with the spinal cord and produce effective treatment and maintain this treatment within the therapeutic window for the majority of the time.
Neurology Advisor: One of the key findings of your study was that those receiving closed-loop stimulation were within the therapeutic window approximately 95% of the time. What are the clinical implications of better maintaining this therapeutic window?
Dr Mekhail: Those patients that remain within the therapeutic window were shown to have better pain relief, better quality of life; they are more active, less disability, and are less dependent on opioids.
I would also highlight that one of the cardinal features of chronic pain is that it interferes with sleep. Participants in the closed-loop stimulation group, on average, got 1 to 2 hours of sleep better than the control participants. More importantly, their activity levels the following day were much more improved than participants in the control group receiving open-loop SCS.
The effect on disability is also worth noting. We were able to move patients from the morbid state of disability to a milder state of disability, which is phenomenal. This takes it a step further than just managing their pain; we are able to help these patients be more functional.
It is also worth noting that for many years the neuromodulation field’s endpoint was 50% pain relief in 50% of patients. Whenever I lecture about this I use this example: if a surgeon was removing half of the appendix in half of patients with appendicitis, it would be laughable. With this closed-loop technology, we are able to substantially improve that endpoint to reach a new bar: ≥80% pain relief in approximately 50% of the patients.
Also importantly, approximately 55% of patients in the closed-loop group of our study were able to cut back or eliminate narcotic use. That is significant, from quality of life perspective for the patient and also from a societal perspective. This also has a huge potential for addressing the abuse, addiction, and associated complications of narcotic medications.
Neurology Advisor: Can you speak to the efficacy of a closed loop SCS system compared with an open loop fixed dose system?
Dr Mekhail: With the control group, or fixed dose stimulation, we noticed that there may be a good response, initially. But as time goes on, these patients drive themselves out of the therapeutic window, because they are not getting effective stimulation or they are overstimulated and don’t like it and turn down their stimulation on the remote. The result is the efficacy of the stimulation goes down over time.
Given this reduction in efficacy, several studies have looked at the explant rate of SCS devices. On average, we lose 7 to 10% of these patients annually, likely because they are not getting the relief they were hoping for or because the relief was not sustained.
If we monitor spinal cord activation and keep these patients in the therapeutic window, where the stimulation is most effective for them individually, using the closed-loop ECAP monitoring system, we’ve found that people stay in the therapeutic window over time. At 3 months, closed-loop maintained spinal cord activation within the therapeutic window 91.1% of the time, compared to 59.5% of the time with open-loop. At 12 months, time within the therapeutic window improved to 95.2% of the time, compared to 47.9% of the time with open-loop. This shows that the response with closed-loop is at least sustained, if not getting better over time.
Neurology Advisor: This is, of course, the ultimate goal in medicine. To be able to fine-tune treatments, such that it maximizes the therapeutic index while providing optimal results for patients.
Dr Mekhail: Absolutely. This system can also have a positive effect on health care utilization. Patients will need to visit their physician less often, use less medication, require less emergency care – the gains are exponential.
Neurology Advisor: What you’ve highlighted are important positive findings of this treatment modality. But, no treatment is without its potential for adverse effects. Can you highlight such effects associated with this form of neuromodulation?
Dr Mekhail: We had some adverse events, but they were not related to the closed-loop technology. They were related to the nature of implanting the device in the spinal cord. There was a 1 to 2% risk for infection and a 1 to 2% risk for lead migration. These risks are inherent in these type of procedures.
In 134 patients that were studied and followed-up for over a year, I am not aware of any complications related to the closed-loop technology. There is no technology that is perfect from day 1, but I’m sure in the future there will be newer generations that will continue to improve upon it.
Neurology Advisor: Are there any known contraindications for a patient to receive this type of treatment?
Dr Mekhail: It is the same contraindication as neurostimulation: a patient who has issues related to systemic infection or system anticoagulation problems would be contraindicated for this procedure. Another contraindication would be if a patient’s anatomy does not allow for the device to be placed in the correct location.
The most important thing is to choose the right patient for the right technology. While this technology is great, it is not for everybody. It is not for all forms of chronic pain. It is mainly for patients who have chronic back and leg pain related to surgery or to degenerative spinal disorders or those with spinal stenosis or arthritis of the spine.
Neurology Advisor: How soon do you foresee this treatment modality being made available to the patient populations you highlighted?
Dr Mekhail: Currently, it is available in Europe. In the United States, the study is currently under FDA review.
Neurology Advisor: What are some future research directions that you hope for in the field as it pertains to spinal cord stimulation?
Dr Mekhail: Based on these results, we have a number of ideas for second generation research. One focus that is of strong interest to me is cost effectiveness. We need to be smart about choosing the right patient at the right time. So, we are planning on cost effectiveness studies to look at patients who have been implanted and focus on their healthcare utilization before and after the implant and try to put a figure on cost-saving potential for successful therapy with spinal cord stimulation. That will be a huge learning curve to our specialty.
I would also like to study the potential for neuromodulation in other areas of pain. One of them is headache or migraine. Right now, we don’t have many options to offer patients with chronic daily headache or migraine. Neurostimulation of the occipital nerves could be a huge potential to treat these patients. The main reasons many people miss work are the flu, back pain and headache. So this has a great potential to treat a huge number of patients and decrease cost of care by simply modulating how the nervous system works to relieve chronic headache. The importance of addressing this is understood by neurologists more than anyone else.
The third focus I would like to take is on how the patients who have had back surgery compare with those who did not. And if we can find out if those with chronic back pain can be treated with neuromodulation and avoid back surgery that would be a significant advancement in our field. In the US, we perform 5-fold more back surgeries per capita than Sweden. If we are able to identify the characteristics of patients who didn’t have back surgery, but had chronic pain and responded well to neuromodulation, we can save patients from both the cost and subsequent comorbidities associated with back surgery.
Neurology Advisor: Are there any final thoughts you’d like to share with our readers?
Dr Mekhail: I think this is only the start. I think the technology will only improve and the patient selection will continue to improve. Hopefully, one day we will be able to serve the patients that we are currently not able to serve. I’m really excited about the potential of this closed-loop SCS technology and how it can impact patient’s lives.
Disclosure: This clinical trial was supported by Saluda Medical. Please see the original reference for a full list of authors’ disclosures.
Mekhail N, Levy RM, Deer TR, et al. Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): a double-blind, randomised, controlled trial [published online ahead of print, 2019 Dec 20]. Lancet Neurol. 2019;S1474-4422(19)30414-4. doi:10.1016/S1474-4422(19)30414-4
In case you missed it, click here to read part 1 of this feature.