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12 Articles in Volume 17, Issue #1
A Brief History of the FDA’s Role in the Ongoing Effort to Ensure Safe Opioid Use
Distinguishing Neuropathic, Non-Neuropathic, and Mixed Pain
How Can Healthcare Providers Better Advocate for Patients With CRPS?
Ketamine for the Treatment of CRPS?
Letters to the Editor: Opioid Calculator; Metformin
Living With CDC Opioid Guidelines
Neurohormones in Pain and Headache Management: New and Emerging Concepts
Optimizing Neuropathic Pain Relief With Scrambler Therapy
Pain Management and the Elderly
Spinal Cord Stimulation: What Clinicians Need to Know
The Association Between Depressive Disorder and Chronic Pain
Updates in Management of Complex Regional Pain Syndrome

Optimizing Neuropathic Pain Relief With Scrambler Therapy

A review and retrospective study on the effectiveness of scrambler (stimulation) therapy to reduce noncancer-related neuropathic pain syndromes, with apparent, maximal pain relief achieved at 1 to 2 weeks.

Minimizing the incidence of medication dependence in patients with chronic neuropathic pain (NP) poses significant difficulty for treating physicians. A recent increase in accidental deaths related to prescription opioid use has boosted the investigation of novel techniques for the treatment of chronic pain.1 In addition to the risk of opioid dependence, chronic pain patients suffer from a wide range of secondary medical conditions, including mental health difficulties and physical disabilities.2 Given the need for simultaneous treatment for chronic pain and associated comorbid conditions, pharmacological interventions alone are often inadequate when managing complex chronic NP syndromes.3

Scrambler therapy alleviates chronic pain relief with a novel, noninvasive stimulation. Scrambler therapy alleviates chronic pain relief with a novel, noninvasive stimulation. Photo credit: Edmond Boese, MD, Eagle, ID

Efforts to minimize risk of harm to chronic NP patients and their families prompted the development of noninvasive and nonpharmacological interventions.4 This trend toward more comprehensive and personalized standards of care will likely aid in appropriately relieving pain in patients suffering from NP syndromes, and will allow physicians to more directly address any associated medical conditions.

Among the novel alternative treatments for chronic NP syndromes is a patient-specific neurostimulative technique called scrambler therapy (ST). Scrambler therapy uses a noninvasive transcutaneous electrostimulation device that has shown promise for providers and patients seeking alternatives to traditional pharmacological pain relief techniques. Scrambler therapy works by introducing a pleasant sensation that acts as a distraction by sending a new message to nerve fibers that were used to receiving pain signals.

This retrospective review aims to shed light on the nature and extent of pain relief experienced during and across stimulation visits. The authors hypothesize that ST will reduce pain ratings for patients with a variety of chronic NP syndromes across and within stimulation visits.

Scrambler Therapy Promises Sustained Relief From Chronic Pain

Scrambler therapy was designed primarily as a method for treatingcancer-related pain syndromes like chronic chemotherapy-induced peripheral neuropathy (CIPN).5 Researchers explored the application of ST as a way of alleviating pain in cancer patients when metastases in the epidural space prevented use of nerve blocks and opioids from offering sufficient relief, and when adverse side effects prohibited achievement of adequate pain relief.

A preliminary case series reported findings of effective pain relief for 3 patients who were affected by severe cancer pain.6 In a separate pilot study of patients with CIPN, ST reduced pain scores by 53%, tingling by 44%, and numbness by 37%.7 This same study indicated that pain-relieving benefits of ST were sustained through 10 weeks of follow-up care. In another study, Coyne and colleagues measured changes in pain level on the Numerical Pain Rating Scale (NPRS)—a pain rating scale with 0 corresponding to “no pain” and 10 corresponding to “worst pain imaginable.” They found that when cancer patients were allowed to mark decimal points, pain ratings decreased from 6.6 before treatment to 4.6 over 3 months.8

Initial success in alleviating cancer-related NP syndromes allowed ST to emerge as a potentially successful treatment for a broader category of NP syndromes, including postherpetic neuralgia, low back pain, polyneuropathy, and peripheral neuropathy.4 Marineo et al aimed to directly compare ST to guideline-based drug therapy for patients grouped into a larger category of poly- or mono-radiculopathy.4 This randomized pilot study provided preliminary evidence that the neurostimulative technique may successfully alleviate pain better than pharmacology, reporting a mean rate of pain reduction of 91% in the first month of ST.4 As personalized noninvasive treatments develop, growing evidence has been presented in favor of these devices to successfully alleviate chronic pain over time.7,9

In a recent examination of ST, this method produced a reduction in chronic pain from a pretreatment score of 7.41 to 1.60 pain score (based on NPRS) following 10 sessions of treatment.9 This comprehensive study also divided patients into several broad categories of chronic pain, ultimately suggesting that the ST’s efficacy may be dependent on pain type. While promising, these pain rates and time frames for pain relief in patients with general chronic pain syndromes differed from those reported in the studies examining ST in a population of CIPN patients.7,8

Reports of inconsistent rates and time spans for achieving pain reduction reflected an urgent need for further research concerning the mechanism and efficacy of ST. Of particular interest to researchers was identifying the length of time necessary for ST to achieve consistent, maximal benefit. Additional considerations in pursuing this research included whether specific types of NP syndromes, pain locations, and severity levels were better suited to favorable treatment response with ST.

This retrospective review was conceived to bolster the current evidence basis by examining the efficacy of repeated ST treatments over time through a lens of specific NP conditions.

Pain Relief From ST Assessed Across Multiple Conditions

A retrospective chart review was conducted among 25 patients who received ST as administered by a neurologist between 2014 and 2015 at an outpatient pain management clinic in Hopewell, New Jersey.10 Basic demographic factors, including age and sex, were gathered. Pain-related data was also collected for pain diagnosis or classification, areas of pain, and descriptive characteristics of reported pain. Concomitant medications and pre- and post-stimulation blood pressure were noted.

Stimulation treatment details were gathered, including side effects, frequency (volume) of stimulation, location of treatment, dates of treatment, and number of treatments. Institutional review board approval was obtained for this chart review,10 which met compliance standards and ethical guidelines set by the participating institution.

Assessment and Collection of Pain Experiences

During patient visits, baseline diagnoses of pain were ascertained through physician consultation and completion of a Diagnosing Neuropathic Pain Questionnaire (DN4). The DN4 used pain characteristics such as burning, painful cold, electrical shock, tingling, pins and needles, numbness, itching, touch hypoesthesia, and pinprick hypoesthesia. The pain assessment revealed characteristics of pain from which pain types were categorized for each patient. Concomitant medications were also noted prior to treatment. Each patient sat in a recliner chair while a technician examined the skin for excoriations or lesions. Then, stimulation was delivered by the FDA-approved MC5-A Calmare Device (Fairfield, Connecticut).11 Stimulation sessions to deliver pain relief typically lasted 45 minutes per patient. The number of stimulation sessions and location of surface electrodes varied based on the individual course of treatment. Visits 1-10 were attended by 16, 16, 14, 10, 9, 7, 6, 6, 6, and 4 patients, respectively.

Like the conventional transcutaneous electrical nerve stimulation (TENS) devices, the average scrambler stimulation will deliver a charge of 38.8 C.11,12 ST has been found effective and safe for treatment of CIPN and a variety of neuropathic pain conditions, but it is contraindicated in patients with implanted pacemakers or automatic defibrillators, aneurysm clips, vena cava clips, skull plates, the presence of hardware (eg, cage and rods), intrathecal pumps, and spinal cord stimulators, as well as patients with a diagnosed psychosis or other severe uncontrolled mental illness.10,12 Upon initiation of the stimulation, patients reported experiencing a reduction in pain and felt a sensation of pressure or rippling instead.11,13 The procedure was intended to introduce a painless message, rather than introduce an exogenous process.13 In other words, through changes in brain plasticity, the process was expected to create a new pain sensation that prompted the brain to anticipate a non-pain signal, preferring it to the prior pain. The outcome of this procedure was intended to have the patient arrive at an improved state of homeostasis.13 To reach a new level of plasticity, the treatment regimen usually required 10 30-minute to 1-hour sessions.

Patients’ pain scores were recorded at 3 intervals: prior to receiving stimulation; 15 to 20 minutes into the procedure; and post-stimulation, using the NPRS. Patients were instructed to complete pain diaries, keeping track of both NPRS pain rating and narrative comments in between treatment periods. Patients who experienced varying degrees of pain severity were treated with the Calmare device regardless of their comorbidities or intensity of pain. Descriptive statistics and independent samples t-tests were used when appropriate.

Charts from 25 patients were reviewed to gather results of pain response to ST. This retrospective review included data from 9 men and 16 women, 28 to 83 years old. The range of diagnoses included idiopathic peripheral neuropathy (upper and lower extremities), complex regional pain syndrome (CRPS), radiculopathy of the back, trigeminal neuralgia, neuropathic groin pain, and postherpetic neuralgia (Figure 1). Of the patients, 68% were concomitantly taking medications, including pregabalin, gabapentin, topiramate, alprazolam, clonazepam, carbamazepene, primidone, lorazepam, and diazepam. Pain diaries revealed that no adverse events occurred as pertained to the ST.10

Across all patients and visits, the mean pain ratings were 3.6 ± 1.4 for pre-treatment response, 2.0 ± 0.9 at mid-therapy, and 1.9 ± 0.8 at the end of treatment.10 Overall, pain decreased across individual (P < 0.03) and multiple treatment visits (P < 0.02) (Figure 2).

While no significant interaction was found between reduction in pain over the course of single and multiple visits, the data offered the possibility for an interaction (P ≤ 0.1). Of the 16 patients who attended more than 1treatment visit, significant decreases in pain ratings were found in comparing the pre- and mid-treatment ratings for visits 1, 2, 3, 4, 5, and 7 (P < 0.05). Similarly, significant decreases in pain ratings were found between pre- and post-treatment ratings for visits 1, 2, 3, 4, 5, and 7 (P < 0.05).

The number of patients attending visits decreased over the course of treatment, with a noticeable drop-off after the first visit. The first visit was free of charge and gave patients an opportunity to assess the potential benefit of the treatment. Continuation of treatment presented a significant financial burden and may explain the reason many patients decided not to continue treatment. Another possible explanation for the patient drop-offs in treatment was the extended time commitment, in both lost work or child-care hours, and need for transportation for 10 sessions. For those patients who continued treatments, this may be a reflection that they felt the treatment worked effectively; they stopped when they felt they did not need further stimulation.

Fifteen patients were also treated for secondary pain that was musculoskeletal in nature. In most cases, baseline pain was lower than that reported for the primary pain site. For secondary areas of pain that were not related to musculoskeletal pain, no significant pain reduction was observed across visits (P = 0.1) or stimulation time frame (P = 0.4).10 confirming prior observations by others.7

Patient Pain Response Following Stimulation Therapy

There is mounting evidence for the efficacy of ST stimulation in decreasing chronic pain across several pain types.7,9,14 However, reliability in the observed rate of pain reduction has remained variable.4,7,8 The variability of pain reduction may have occurred as a result of differing study parameters, the many different types of pain, locations of pain, or starting pain severity.15 Difficulties in identifying the mechanism or root of pain also may have contributed to difficulties in diagnosing and distinguishing between different types of pain.16,17 Given the challenges in measuring changes in pain experiences, ST may need to be examined through the lens of specific NP syndromes in order to provide satisfactory evidence of reduced pain in patients with NP.18

The types of chronic pain discussed in prior studies included postherpetic neuralgia, chronic low back pain, polyneuropathy, peripheral neuropathy, and CIPN.7,9 A few studies examined the therapy with respect to 1 specific type of pain. One study reported pain reduction as a result of ST in patients with cancer-related pain induced by bone and visceral metastases.11 Patients with postherpetic neuralgia have also been examined separately to determine whether pain relief is experienced with stimulation.14 In addition to cancer-related pain syndromes and postherpetic neuralgia, low back pain has been examined with regard to efficacy of ST.19 Preliminary findings of this sham-controlled study suggested that low back pain can be decreased significantly with 10 sessions of stimulation; however, Starkweather et al called attention to significant differences in pain sensitivity and differential mRNA expression of 17 pain genes as well.20 Positing that mRNA expression and pain sensitivity are altered as a result of ST may serve as a first step toward identifying the mechanism of cutaneous electrostimulation.

The change in mRNA expression may indicate that ST can have long-lasting or sustained therapeutic qualities, especially if the stimulation affects an individual’s pain sensitivity. This finding further complicates an understanding of pain outcomes given the involvement of various locations and types of pain, which may have responded differently. These findings in conjunction with the timing of pain reduction identified by the small retrospective study may aid in elucidating the timeline for efficacy of ST in the subcategory of NP syndromes.

Our retrospective study21 reflects the general trend in research, suggesting that ST may be an effective treatment for reducing pain intensity in patients with various types of NP syndromes. The chart review of patients with NP syndromes shows an overall decrease in pain across individual and multiple ST treatment visits. This general finding supports the few existing studies concerning the therapy’s efficacy, but does so in a population affected more specifically by noncancer-induced neuropathic conditions: idiopathic peripheral neuropathy, CRPS, radiculopathy, trigeminal neuralgia, neuropathic groin pain, and postherpetic neuralgia. These conditions include some neuropathies not previously studied for efficacy of treatment with ST.

In addition to the overall pain reduction observed, our findings show significant decreases in pain from pre- to post-treatment ratings within each visit. Visits with significant decreases in pain from prestimulation to during, and from pre- to poststimulation include 1, 2, 3, 4, 5 and 7. As sample size was reduced with patients dropping out, the statistical power became too small to see significant differences in pain relief from visits 6 and 8 through 10. These data provide preliminary insight into how many treatment visits may be necessary for optimal pain relief in the short term. There is currently very little quantitative data that speaks to the longevity of the therapy’s efficacy. Subsequently, a prospective study may aid in determining the number of treatment visits, the length of stimulation, and stimulation parameters necessary to achieve the best pain relief over the longest period of time.

Alternatively, this study only displayed a significant decrease in pain when primary areas of pain were being treated with ST. This suggests that the severity of pain, in addition to the location of pain, plays a role in ST’s ability to alleviate symptoms. These findings are consistent with the notion that ST is better suited for those patients with neuropathies as opposed to musculoskeletal pain.9 Thus, more research regarding how severity and location of pain influences ST’s efficacy are warranted.

This retrospective study has significant limitations inherent to the methodology. Patients with a variety of pain syndromes, pain intensity, comorbidities, and medications were included in the study. The small sample prevents a meaningful posthoc analysis that would elucidate the effect of ST on function and either synergistic or negative effect of concomitant medications. Future prospective studies should consider the use of standardized outcome measures to glean the efficacy with regard to improvement of daily function. Despite the limitations of sample size and retrospective nature, this study supports ST as a pain relief device. Additionally, the findings prompt more comparison of the length of treatment, the number of areas being treated, the severity of pain in areas being treated, and specific classification and/or type of pain diagnosis.


This small retrospective study highlights the possible role of ST in alleviating pain in a number of NP syndromes. Although 1 treatment may alleviate pain and is a predictor for responsiveness to treatment, the current recommendation is to treat until the pain has resolved, with a maximum of 10 treatments. Findings from this retrospective study support the use of ST as a potential method for reducing chronic pain for a variety of neuropathic conditions, particularly CRPS.10 In conjunction with the growing body of literature, this study offers support to clinicians who are looking to recommend a noninvasive stimulation technique as an alternative or supplement to pharmacology or invasive pain reduction strategies.

Larger controlled studies are necessary to validate these findings and provide more definitive evidence for the efficacy of ST for the relief of NP.

Last updated on: February 14, 2017
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Neurohormones in Pain and Headache Management: New and Emerging Concepts

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