Abstract
Objective
Strokes involving sensory pathways can result in contralesional pain syndromes often refractory to pharmacologic interventions. Scrambler therapy (ST) is a noninvasive electroanalgesia device used to treat pain caused by peripheral neuropathy; however, data are scarce regarding its use in conditions secondary to central nervous system pathology. We evaluate the efficacy of ST to treat poststroke pain.
Methods
Twenty patients with a history of prior stroke resulting in contralesional pain were randomized to receive ST or Sham as an adjunct to their stable medication regimen. Participants underwent 5 consecutive daily 40‐min sessions. The study was blinded to patient and assessor. Pain scores (0–10) were recorded at baseline, pre‐ and postsession, and 4 weeks after final treatment. Student's t‐tests compared differences in the mean change in pain score between groups immediately post‐treatment #5, and at 4‐weeks. The chi‐squared analysis compared the proportion of patients in each group with >50% pain reduction.
Results
Participants randomized to ST had a mean change in pain score of −3.73 (SD 2.85) postintervention and −2.57 (SD 2.07) at 4 weeks, while the Sham group had a mean change in score of −0.94 (SD 1.36) and −0.25 (SD 0.84) (p between groups = 0.012, 0.004, respectively). Significantly more participants treated with ST reported a >50% reduction in pain immediately postintervention compared to Sham (70% vs. 10%, p = 0.006), but not at follow‐up (30% vs. 10%, p = ns).
Interpretation
ST may effectively decrease poststroke pain compared to Sham. Larger studies are needed to evaluate confounders such as stroke location, time from stroke, and concomitant treatment with medications.
Introduction
Language and motor impairments are often considered the most disabling deficits caused by stroke. Fortunately, acute treatments for ischemic stroke such as alteplase and mechanical thrombectomy have significantly improved outcomes, resulting in smaller infarcts and improved function. However, even small strokes involving areas such as the sensory cortex or the thalamus can result in significant contralesional pain syndromes due to a disruption of sensory circuits. Of the approximately 795,000 strokes per year in the United States, 1 roughly 10% (~80,000) lead to development of severe pain most commonly referred to as poststroke pain, central pain, or thalamic pain syndromes. 2 This discomfort can prevent patients from returning to work and lead to a poor quality of life.
For some patients experiencing poststroke pain, medications that traditionally treat other pain syndromes such as peripheral neuropathy and migraine are prescribed, including serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and anticonvulsants, and are used with variable efficacy. 3 , 4 Finding the correct medication regimen that works for an individual can be difficult and the side effects of these therapies can lead to noncompliance, even in cases when they are at least partially effective in controlling discomfort. Finding a consistently effective long‐term treatment would provide a huge potential for patients to experience recovery, the ability to return to work, and a better quality of life.
Scrambler therapy (ST) is a noninvasive electroanalgesia device that is FDA‐approved for the treatment of chronic intractable pain, acute pain, and postoperative pain. Prior studies indicate it can be highly successful in treating patients experiencing neuropathic pain originating in the peripheral system such as postoperative pain, postherpetic neuralgia, and cancer pain and is well‐tolerated. 3 While irritation at the site of stimulation can occur, other side effects are rare. 4 Although much of the work shows evidence for pain relief involving the peripheral nervous system, case studies have also shown effective treatment of a central thalamic pain syndrome using ST may be possible. 4 To date, there has been no clinical trial exploring the use of ST in the central nervous system, and more specifically, to treat poststroke pain. In this pilot study, we examine the efficacy of ST at reducing central nervous system pain and maintaining pain reduction in patients following a stroke compared to a Sham placebo group. The results from this study have the potential to introduce a new intervention for poststroke pain and offer a more effective therapy, free of medication toxicity and without significant long‐lasting side effects.
Methods
Participant population
We conducted a randomized, single‐blind, Sham‐controlled study with 20 participants who reported stable contralesional pain following a prior stroke. Approval for use of the ST device was obtained by the Institutional Review Board prior to beginning the study. Men and women over 18 years of age with prior ischemic or hemorrhagic stroke seen on neuroimaging and a positive finding of pain in the area(s) affected by their stroke were included. Participants with transient ischemic attack and no evidence of stroke on MRI were excluded, along with those with contraindications to ST including implantable devices such as pacemakers, defibrillators, and spinal cord stimulators; history of myocardial infarction in the past 6 months; uncontrolled epilepsy; and symptomatic brain metastases. All patients were informed of the study procedures during recruitment, and informed consent was obtained for each participant.
Participants currently prescribed medications to treat poststroke pain (e.g., TCAs, SNRIs, and antiepileptics) were asked to continue their treatment regimen as prescribed; however, no additional dose adjustments were made over the course of the study period. Gabapentin doses were held 4 h prior to treatment in order not to worsen pain for those receiving benefit, but to avoid its potential interference with the central nervous system's processing of stimulation. Doses scheduled after the daily treatment session were permitted.
Treatment protocol
Randomization of treatment groups occurred using a random number generator. Both patients and study team members performing the pain assessment were blinded to the treatment arm, though the study team member performing stimulation was aware of the assigned treatment arm. Pain scores were obtained and recorded at baseline prior to any neurostimulation using a dermatomal map and Numerical Rating Scale (0–10) that also included descriptions of the pain at each value and faces expressing the corresponding level of discomfort. Assessments were repeated prior to and after each treatment session, and again 4 weeks following the intervention to determine longer‐term efficacy (Fig. 1).
Figure 1.
Study timeline.
Electrode placement was dependent on a participant's area of pain. (Fig. 2). A maximum of 5 sets of electrodes were placed inside the dermatomes affected by pain. Placement for each patient was kept largely the same for the duration of the study and was only changed when irritation from the electrodes was described or when pain levels in the dermatome were reduced to 0. Current was turned on and adjusted until the stimulation could be felt strongly but was not perceived as uncomfortable. Participants in the ST group received a full 40‐min cycle of treatment with ST during each session, using a consistent level of current intensity. Participants in the Sham group felt an initial increase in channel intensity; however, then the channels were turned off for the duration of the session. Both groups experienced an alert indicating that treatment had ended after 40 min. All patients received a total of 5 consecutive daily treatments, or until a total pain level of 0 was reported on 2 consecutive assessments which occurred for only one participant after 3 sessions.
Figure 2.
Scrambler device. (A) The Scrambler device. (B) Electrode placement was individualized based on the reported area of pain.
Statistical analysis
Analysis was performed using Stata version 14 to evaluate both the acute and longer‐term efficacy of ST for reducing discomfort in individuals with poststroke pain. To evaluate the acute efficacy, Student's t‐test was conducted to compare the mean change in pain scores from before the participant received any treatment to their score following completion of the fifth session. The study was designed so that with a sample size of 20 (n = 10 per group) we would have 80% power to detect a difference in mean change in score of 1.3 points or greater between groups. Paired t‐tests evaluated the significance of change in score within each group. In addition, a chi squared analysis was used to compare the percentage of patients experiencing: (1) any benefit, and (2) a >50% reduction in pain between groups. To evaluate longer‐term efficacy, a similar set of analyses were performed at the 4‐week follow‐up time point.
Results
A total of 20 patients completed their assigned intervention and follow‐up assessment.
Ten were randomized to receive ST while the remaining 10 were randomized to Sham therapy. The average age of participants in the ST group was 60.0 years while the average age of participants in the Sham group was 56.9 years. The average time from stroke for participants in the ST group was 35.0 months (range: 1–131 months) and 29.5 months (range: 8–133 months) for those in the Sham group. The ST group was 30% female and 30% Black while the Sham group was 70% female and 60% Black. Full demographics and stroke characteristics of the population can be seen in Table 1. (Table 1).
Table 1.
Between group comparisons of demographics, stroke characteristics, and baseline pain scores.
| Variable | Scrambler (ST) | Sham | p‐value |
|---|---|---|---|
| Age, years mean (SD) | 60.0 (8.3) | 56.9 (15.4) | 0.581 |
| Time from stroke, months mean (SD) | 35.0 (39.2) | 29.5 (37.6) | 0.753 |
| Female, n (%) | 3 (30%) | 7 (70%) | 0.074 |
| Black, n (%) | 3 (30%) | 7 (70%) | 0.074 |
| Stroke size, cc mean (SD) | 32.4 (29.7) | 13.4 (22.3) | 0.180 |
| Stoke location | |||
| Medulla, n (%) | 1 (10%) | 1 (10%) | |
| Thalamus, n (%) | 4 (40%) | 5 (50%) | |
| Other, n (%) | 5 (50%) | 4 (40%) | |
| NIHSS on admission, # mean (SD) | 8.6 (8.0) | 3.7 (3.5) | 0.158 |
| Residual stroke deficits | |||
| Weakness, n (%) | 4 (40%) | 5 (50%) | |
| Aphasia, n (%) | 2 (20%) | 1 (10%) | |
| Cognitive impairment, n (%) | 1 (10%) | 0 (0%) | |
| None, n (%) | 5 (50%) | 5 (50%) | |
| Prior medications | |||
| Gabapentin/pregabalin, n (%) | 6 (60%) | 5 (50%) | |
| TCA, n (%) | 3 (30%) | 1 (10%) | |
| SNRI, n (%) | 2 (20%) | 2 (20%) | |
| Baclofen, n (%) | 2 (20%) | 1 (10%) | |
| Pretreatment pain score, mean (SD) | 6.68 (1.95) | 5.73 (1.75) | 0.267 |
Acute efficacy
Participants randomized to ST had a mean pain score of 6.68 ± 1.95 at baseline while the Sham group had a mean score of 5.73 ± 1.75. (Table 2) With each treatment, the mean pain score improved for the ST group while remaining relatively constant for those undergoing Sham (Fig. 3). Following their five assigned treatment sessions, the ST group had a mean change from initial score of −3.73 ± 2.85, a 56% reduction in pain, while the Sham group had a mean change in score of −0.94 ± 1.36 (a 16% reduction in pain). Notably, 9 of 10 patients treated with ST saw some improvement in their pain score over the 5 treatment sessions, while 7 of 10 in the Sham group reported some benefit (p = 0.264) (Fig. 4). However, 7 of 10 (70%) of the patients treated with ST reported a decrease of greater than 50% in their pain score, while this was the case for only 1 (10%) of the patients undergoing Sham (p = 0.006) (Fig. 4). Paired t‐tests also demonstrated a significant change in score following treatment for patients undergoing ST (p = 0.003), but not for Sham therapy (p = 0.057) between the baseline and postsession #5 visit.
Table 2.
Acute and chronic efficacy of scrambler therapy versus Sham.
| Post treatment (acute) | Initial pain score mean (SD) | End of treatment mean (SD) | Paired t‐test p‐value | Mean change mean (SD) | Percent change |
|---|---|---|---|---|---|
| Scrambler | 6.68 (1.95) | 2.95 (2.97) | 0.0025 | −3.73 (2.85) | −55.8% |
| Sham | 5.73 (1.75) | 4.79 (2.51) | 0.057 | −0.94 (1.36) | −16.4% |
| Between group comparison p‐value | 0.012 |
| Post follow‐up (chronic) | Initial pain score mean (SD) | End of follow‐up mean (SD) | Paired t‐test p‐value | Mean change mean (SD) | Percent change |
|---|---|---|---|---|---|
| Scrambler | 6.68 (1.95) | 4.12 (2.98) | 0.0035 | −2.57 (2.07) | −38.5% |
| Sham | 5.73 (1.74) | 5.48 (2.14) | 0.369 | −0.25 (0.84) | −4.4% |
| Between group comparison p‐value | 0.0041 |
Figure 3.
Changes in mean group pain scores over treatment duration. The mean pain score of each group at baseline, after each treatment, and at follow‐up. Participants undergoing ST saw consistent decreases in pain scores following each treatment.
Figure 4.
Percent pain reduction of participants. Percentages of participants experiencing “any” and >50% reduction in pain immediately post‐treatment and at follow‐up. Those undergoing ST were significantly more likely to experience >50% reduction in pain immediately post‐treatment.
Longer‐term efficacy
Pain relief continued for the ST group through the 4‐week follow‐up assessment. The ST group reported a mean change in pain score of −2.57 ± 2.07 from baseline, a 38% reduction in pain. (Table 2‐ Results) The Sham group demonstrated a mean change of only −0.25 ± 0.84 (a 4% reduction). Paired t‐tests performed within each group again yielded a significant p‐value of 0.004 for the ST group and an insignificant p‐value of 0.369 for the Sham group. Longer‐term, 8 of 10 patients treated with ST continued to endorse any improvement in their pain (Fig. 3) while only 4 in the Sham group reported improvement (p = 0.068) (Fig. 3). Three patients in the ST group continued to report a >50% decrease in pain compared to only 1 treated with Sham (p = 0.264) (Fig. 3).
Discussion
Our results indicate that individuals treated with ST see significantly greater improvement in their contralesional poststroke pain compared to patients treated with Sham, even for those currently taking or who have tried and failed traditional pain medications. Patients treated with ST saw an average reduction in their pain after 5 sessions of almost 4 points on the numeric rating scale, with 90% experiencing at least some pain reduction and 70% experiencing greater than 50% relief. Individuals in the Sham group often reported some effect with treatment, however, had a much lower mean change, and were far less likely to endorse >50% pain control. Effects persisted up to the 4‐week assessment, when for many pain began to return. Though there remained a significant difference between groups in change in score from baseline to follow‐up, results were muted, and there was no longer a difference in those experiencing >50% pain relief. This strongly suggests that ST may be an effective, nonpharmacologic intervention, even for those with difficult to treat pain already prescribed medications, but that recurrent treatments may be required for long‐term pain relief.
Poststroke pain is a debilitating condition that can result in exceptionally poor quality of life. It is unfortunately common, impacting roughly 10% of all stroke patients. 2 However, the prevalence is dramatically higher when considering strokes that result in damage to the somatosensory pathways, increasing to nearly 50% when involving areas such as the thalamus and medulla. 2 Current treatments for management of pain symptoms are largely ineffective. Traditionally, SNRIs, TCAs, and anticonvulsants have been used to treat poststroke pain given their history in treating other pain disorders 5 , 6 , 7 ; however, their effectiveness is variable, and they are often ineffective at providing significant relief. In addition, toxicity and medication side effects can lead to noncompliance even in cases where they have effectively reduced discomfort. The inability to achieve adequate pain control leaves patients demoralized, defeated, and often disabled. This has a huge impact on their ability to return to work and engage with family and friends, leading to isolation and disability. Effective treatments such as ST have significant potential to improve function and quality of life.
One of the reasons that ST may be effective in treating poststroke pain is its proposed unique mechanism of action. The current is intended to mimic a neuronal action potential by synthesizing 16 unique waveforms and combining them into 256 dynamic strings. These “information packets,” are continuously changed using the device software algorithm and carried to C‐fibers, where instead of blocking nociceptive signals, they modulate them into sensations that are interpreted as both “nonpainful” and endogenous by the central nervous system, creating long‐lasting pain relief. 3 This is in contrast to a transcutaneous electrical nerve stimulation (TENS) device, which exerts its effect utilizing the gate‐control theory, inhibiting pain impulse transmission by stimulating A‐beta fibers. 3 TENS devices are designed to generate a repetitive square‐shaped waveform which stimulates non‐noxious afferent A‐beta fibers. Through the activation of these A‐beta fibers, TENS inhibits nociception transmission as a secondary effect while the device is on. However, once a TENS device is removed and A‐beta fiber stimulation ceases the pain generally returns. 3 Both devices work in differently than current medications, which typically reduce pain perception by lowering the overall excitability within the pain pathway. As an example, anticonvulsants such as gabapentin modulate the release of neurotransmitters by binding to voltage‐gated calcium channels and activate the descending pain inhibitory pathway through increasing the release of noradrenaline. 8 While this can effectively control pain in some circumstances, there can be other widespread effects that lead to unwanted symptoms.
Though this study compared ST only to Sham in patients already on stable medication regimens, it is important to consider the magnitude of pain reduction compared to trials involving currently used pharmaceuticals. A prior study examining the efficacy of gabapentin in the treatment of neuropathic pain showed a 1.5 point decrease (21%) at the 8‐week time point compared to a 1.0 point decrease with placebo. 5 Similar results were seen in studies evaluating the efficacy of the TCA amitriptyline to treat central poststroke pain and individuals taking pregabalin, compared to placebo. 6 , 7 In comparison, treatment with ST demonstrated a consistent decrease in pain following each session and an average reduction in pain of greater than 50% following just 5 treatments. It is unknown whether providing more than 5 treatments would result in a longer period of pain‐freedom, or if subsequent treatments after a 4‐week break may result in an even greater pain reduction, though it seems likely this may be the case based on work in the peripheral nervous system. 3 Extended treatment protocols and optimization of combined ST‐medication regimens may further enhance long‐term pain relief, but require further study.
ST has been successfully used to treat disorders of the peripheral nervous system including neuropathies due to diabetes, surgery, and chemotherapy. 7 More recently, the effectiveness of neurostimulation in the central nervous system to treat conditions such as neuromyelitis optica has been explored. 9 In one of the largest reported cohorts of patients to date who were randomized to a 10 day treatment cycle, a 3.5 point reduction (70%) in average pain score was observed for patients undergoing ST compared to a 1.0 point reduction (20%) in the Sham group. Differences in pain between the two groups persisted when reassessed at 30, but not 60 days. 10 Case reports of ST's success in providing significant and long‐lasting pain relief in a patient with thalamic injury (Dejerine–Roussy Syndrome) have also been reported 4 , 10 and are consistent with our results, suggesting the ability of ST to successfully treat pain originating in both the peripheral and central nervous systems. It is believed that ST is capable of treating poststroke pain by reducing the activity of a hyperactive pain pathway that causes the increased perception of pain. By increasing top‐down inhibition 11 and reducing excitatory activity through resetting central sensitization, 12 ST is thought to work on this pain pathway in two different ways that both aim to reduce the activity of it. 13 Despite these thoughts and the results of our study, further studies are needed in order to determine the exact mechanisms ST may use to reduce pain specifically in patients following stroke.
This study is not without limitations. The cohort included a relatively small number of participants, all treated at a single center. This limited our ability to fully explore factors such as stroke size and location, time from infarct, and concurrent use of pain‐reducing medications. However, despite these limitations, our pilot data indicate that ST appears more effective than Sham at reducing the average pain score immediately following 5 treatments and that effects remain for many individuals at the 4‐week time point, though will likely eventually require booster sessions for long‐term pain control. A clear and consistent pattern was observed for each participant, with those treated with ST demonstrating a decrease in pain perception following each treatment.
Overall, results suggest that ST may be an effective acute and potentially longer‐term treatment of poststroke pain and may be a suitable alternative to pharmacologic treatment. The ability of ST to reduce pain to a greater extent than previously studied medication regimens, without significant toxicity or side effects, could improve care by reducing burden of disease and enhancing quality of life for stroke survivors. A larger study is needed to determine whether adding treatment sessions during the initial treatment protocol or in the extended window, pairing ST with traditional pain‐relieving medications, or determining the effect of factors such as size and location of lesion or time from stroke may allow for further optimization of treatment protocols. Nonetheless, our data indicate that ST used alone for as little as 5 sessions may have significant benefit and should be considered for those with poststroke pain.
Author Contributions
R.S.‐C., D.M., E.L., and E.B.M. contributed to the conception and design of the study; R.S.‐C., D.M., E.L., and E.B.M. contributed to the acquisition and analysis of data; R.S.‐C. and E.B.M contributed to drafting the text or preparing the figures and tables.
Conflict of Interest
There are no relationships involved in this study that could lead to perceived conflict of interest.
Acknowledgments
This study was made possible due to a generous philanthropic donation from a grateful patient and we are thankful to them and their family.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.