Scrambler Therapy in Acute and Chronic Pain: A Review

*James A. Tolley*

#### **Abstract**

Scrambler therapy utilizes a device and technique that delivers a non-invasive electro-analgesic treatment regimen to patients in pain, both acute and chronic. It has been used in many patients suffering from neuropathic pain and other causes of pain that have been resistant to other treatment modalities, including oral analgesics, opioids, and nerve blocks. It operates using a specific protocol that requires training and experience but can be quite effective and lead to prolonged pain relief when administered appropriately. This chapter will review the relevant theory and mechanism of scrambler therapy and discuss the studies that have been conducted to evaluate its efficacy in a variety of pain disorders.

**Keywords:** scrambler therapy, chronic pain, acute pain, electroanalgesia, Calmare, neuropathic pain, neuropathy, non-invasive

#### **1. Introduction**

Chronic pain (CP) among adults is a common problem occurring in approximately 20% of the population in the United States and Canada [1, 2]. The prevalence of CP can increase with age with a recent survey of the elderly demonstrating a rate of 78% among respondents [3], many of whom had a neuropathic component to their pain. A total of 24% were taking opioids as part of their pain management regimen. Concerns with the use of opioids have led to the search for non-opioid alternatives of which gabapentin is one such option. However, the number needed to treat (NNT) neuropathic pain with gabapentin is relatively high at 6.6 [4]. Duloxetine has also been used to treat chronic back pain with a NNT of 10 [5]. As a group, serotonin-noradrenaline reuptake inhibitors have a NNT of 6.4 in a meta-analysis of pharmacologic therapy for neuropathic pain in adults [6]. Scrambler therapy has been touted as another alternative to treat neuropathic and other chronic pains with minimal side effects. This chapter will review scrambler therapy and its use to treat various chronic and acute pains.

#### **2. Scrambler therapy history/mechanisms/theory**

Scrambler therapy (ST) was developed in the early 1990s by Guiseppe Marineo in Italy [7]. It has been erroneously compared to transcutaneous electrical nerve stimulation (TENS), and although it is non-invasive and uses electrical stimulation, that is where the similarities end. TENS achieves its effects through several potential mechanisms, one of which involves the gate control theory of pain [8] as proposed by Melzack and Wall [9]. It is postulated that the peripheral stimulation of larger myelinated A-beta and A-delta fibers by the TENS device results in conduction blockade of the smaller pain transmitting C-fibers in the dorsal horn [8]. ST, alternatively, stimulates C-fibers directly and operates under the principles of information theory [10].

According to Claude E. Shannon's Information Theory [11], a communication system consists of five parts which are analogous to the components of the human nervous system, the purpose of which is to convey information about the environment to an individual. The information source produces the message, which in the case of pain, is the adverse stimulus that could cause potential harm to the organism. The transmitter alters the message and prepares it for transmission along the channel, which is what the nociceptor does in converting the stimulus into chemical information and then an electric action potential to transmit along the unmyelinated C-fiber. The receiver then restores the original message as intended for the ultimate destination which would be analogous to the somatosensory cortex and human consciousness, respectively [12].

Chronic pain is therefore a perturbation of an information system which ST seeks to correct. Guiseppe Marineo developed a device that acts as an artificial neuron to stimulate C-fiber receptors with "non-pain" information that the nervous system recognizes as "self" [10, 13, 14]. The commercially available version of the device contains five artificial neurons allowing for treatment of up to five areas of pain simultaneously [15]. Each artificial neuron can create 16 different synthetic action potentials which are then algorithmically combined into a total of 256 strings of "painless" information along with the "noise" that is necessarily present in information systems [10].

Testing to verify the safety and efficacy of the artificial neuron technology was performed at the University of Rome Tor Vergata for seven years from 1999 to 2006 on almost 2300 patients with severe neuropathic pain that had been refractory to other methods of treatment. Successful treatment was defined as more than 50% pain relief, and at 2-month follow-up, nearly 80% of patients had achieved this rate of success with essentially no side effects [10]. This data along with a few other clinical trials was used to obtain marketing approval in both Europe and ultimately from the United States Food and Drug Administration in 2009 [10, 16].

The inventor of the device has provided several recommendations and observations to improve outcomes of ST both in his own writings [10] and in response [17] to a multi-center study with a much lower rate of overall success at 38.1% [18] compared to the initial data with success rates near 80%.


stimulation of the C-fibers [10]. Stimulation should occur in an area adjacent to the pain, ideally in a dermatomal distribution and should not be painful.

• Pharmacology: Drugs that interfere with action potentials, such as anticonvulsants and local anesthetics will decrease the effectiveness of ST. Ketamine can have a similar effect, while muscle relaxants may increase the incidence of side effects such as muscle weakness or hypotension [10].

Considering the proposed role of information theory in the mechanism of ST, these recommendations would make sense. Neuropathic pain can be thought of as a disturbance in the normal homeostatic processes of the C-fibers and their receptors leading to chronic, neuropathic pain. Yet C-fibers also transmit pleasant tactile sensations [21] suggesting the lack of pain necessary during ST treatment for maximal efficacy has a biologic basis as does the interference found with certain drugs. During treatment, the changes that led to chronic, neuropathic pain are in effect being reversed, leading to a normalization of C-fiber activity that can persist over time.

However, one should note that the inventor does hold the patent to the device [22] and has had financial arrangements in place to benefit from its sale [23]. This is not to say that the device does not work precisely as described nor with the proposed efficacy, but one should evaluate the available information critically. The remainder of the chapter will review several of the available studies and case reports based upon indication and will allow the reader to come to their own conclusions.

#### **3. Scrambler therapy for chemotherapy-induced peripheral neuropathy (CIPN)**

As noted, ST was developed for use in patients with cancer pain or neuropathic pain [17], so it is not surprising that there are several studies looking at its use in patients who develop CIPN. In one of the first studies following FDA approval in 2009, Smith et al. [24] published, in 2010, a pilot trial reporting results on 16 patients with CIPN of three months to eight years duration with an average age of 58.6 years. The average reduction in pain at the completion of 10 days of 60-minute treatments was 59%. There was no difference in opioid usage and no adverse effects were noted.

At the 2013 meeting of the American Society for Clinical Oncology, Campbell et al. [25] presented an abstract comparing ST to an active sham device that delivered a barely perceptible electric sensation designed to be nontherapeutic. There were seven patients with painful CIPN that started in each arm of 10 daily sessions of 50 minutes. The authors state that there were no differences in the primary endpoint of pain reduction between groups but conclude that a sham is feasible and could be used for future controlled studies.

In 2013, Coyne and colleagues evaluated the effects of ST on 39 patients with cancer-related pain, 33 of which had CIPN [26]. The mean age of the patients was 56.5. ST treatments were 45 minutes in duration and performed for 10 daily sessions over a two-week period. Outcomes for pain and several quality-of-life measures were compared at baseline and days 14, 30, 60 and 90. Pain was significantly improved at all points following the conclusion of ST as were items on the Brief Pain Inventory (BPI) related to mood, sleep and relationships. Opioid usage did not change, however. There were no side effects noted. The authors felt that ST was effective in relieving CIPN and suggested that ST should be further investigated for other forms of pain also.

In 2015, Lee and colleagues published a pilot study on 20 patients with cancerrelated neuropathic pain (CNP) of whom six had CIPN [27]. Patients had received conservative therapy for at least six months prior to enrollment in the study. The principal investigator had received training on the device from the inventor in Italy and in turn provided training to the others who would administer the ST treatments. Treatment consisted of ten daily 40-minute sessions with the possibility of skipping two days for weekends. The median age of these patients was 57.0. The endpoints were assessed at 2 weeks following conclusion of the ST compared to baseline. The decrease in pain score was statistically significant, but only six of the 20 patients reported more than 50% pain relief at the 2-week follow-up. Half the patients were satisfied with the treatment. Regular opioid usage did not decrease but rescue usage just achieved statistical significance at P = 0.05. None of the patients reported any significant adverse events. The authors mention in the discussion that their pain relief was decreased compared to other studies. They mention the heterogenicity of pain characteristics in their patients but do not state if the patients were continued on anticonvulsants which may have impacted the results.

Also in 2015, a study of 37 patients with CIPN was reported by Pachman et al. [20]. Patients had to have CIPN for greater than or equal to one month with a pain score of 4/10 or more. Patients were treated with up to 10 daily sessions of 30 minutes using ST. The average age was 58 with a range of 33 to 79 years. Patients were followed for 10 weeks. The study noted an average reduction in pain score of 53% following 10 days of treatment which seemed to persist throughout the follow-up period. However, the authors also note that later patients seemed to do better than earlier patients presumably as the study team gained more experience with the device and treatment protocol. Again, no adverse events were reported. The authors felt that this preliminary data showed ST may be effective for CIPN and called for additional studies.

In 2018, Tomasello et al. reported the results using ST for treating CIPN in 9 adolescents aged 12 to 17 [28]. The teens received 45-minute treatments over 10 consecutive days. At the end of the 10-day period, pain was significantly improved from an average of 9.22 to 2.33. Quality of life was improved in such metrics as generalized activity, walking, mood, sleep and relationships. Patients were on a variety of analgesic drugs which were tapered before or during ST. ST was tailored to each patient's needs with some requiring 14 days of treatment and one needing 21 days. In all but one patient, the pain score was 0 at the end of ST, and all patients were able to stop or decrease their analgesic drugs. Seven of the patients remained pain free at six months of follow-up. There were no reported adverse effects. The authors called for further studies with larger sample size but felt that ST could represent a good "first-line treatment" for CIPN given its efficacy and safety as well as the lasting effects.

In 2019, the results of a randomized phase II pilot study were published by Loprinzi et al. [29]. A total of 50 patients were randomized to receive either ST or TENS as a control group. The median ages were 61.5 for ST and 61.0 for TENS. ST sessions were for 30 minutes on 10 consecutive weekdays and TENS sessions were for 30 minutes per day for 14 days. Following the 2-week study period, patients were followed weekly for the next 8 weeks. A 50% or greater reduction in pain scores was seen in 40% of the ST patients and 20% of the TENS patients. At the end of the 8-week follow-up period, ST patients still had a 33% reduction in pain scores compared to baseline. One patient receiving ST noted minor ecchymosis at electrode placement sites and one noted contact dermatitis. Patients had to be willing to wean off gabapentin or pregabalin to participate in the study. The authors did not report other analgesic drugs that were being used nor the impact of the therapies on usage

during the follow-up period. Patients receiving ST were more likely to recommend that treatment to others compared to the TENS group. There was an opportunity for the patients to crossover to the other treatment group following the 8-week follow-up period which is reported below in a separate publication by Childs et al. [30].

Of the 24 patients that had completed ST, 12 chose to crossover to the TENS group. Of the 22 patients completing the TENS arm in the first portion of the study, 10 chose to crossover and try ST. Again, treatments occurred over a 2-week period followed by 8 weeks of follow-up. The primary outcome of a 50% reduction in primary symptom score was achieved by 6 of the 10 patients undergoing ST and only 3 of the 12 patients treated with TENS (P = 0.11). Although not statistically significant, the trend was similar to the results of the initial phase and led the authors to conclude that larger studies on the efficacy of ST in treating CIPN are warranted [30].

In 2020, the results of a randomized trial of ST versus treatment with "sham" placement of electrodes was reported by Smith et al. [31]. A total of 35 patients were randomized with 17 in the ST group and 18 in the "sham" treatment arm. All patients were weaned off anticonvulsant medications. Treatments were for 30 minutes on 10 consecutive working days. Outcomes were recorded at baseline, day 10, and days 28, 60, and 90. The authors found no significant differences between the groups at any time point. Only 25% of patients in the ST group achieved a 33% reduction in pain at the 10-day mark compared to 17.6% in the "sham" group. Differences between the groups were not statistically significant. In the discussion, the authors offer several reasons as to why the results were not consistent with previous studies including placement of the electrodes such that the "nonpain" signal was ineffectively transmitted.

More recent publications have been systematic reviews of the literature looking at the treatment of CIPN with either pharmacologic or nonpharmacologic means and included ST. In a review of randomized controlled trials (RCTs) of both pharmacologic and nonpharmacologic management, Jones et al. [32] included three of the more recent studies mentioned above [29–31]. They point out the lack of statistical significance in these three RCTs and feel that ST for treatment of CIPN is not supported [32]. In another review, also published in 2022, Wang et al. [33] included the three RCTs [29–31] as well as four single arm studies [20, 24, 26, 27] concluding that ST was of limited or no efficacy in the treatment of CIPN and that the inconsistency between RCTs and the other studies suggested a placebo effect.

Finally in early 2023, Klafke et al. [34] published clinical recommendations for nonpharmacologic treatment of CIPN using a systematic review and an expert consensus process. Interestingly, the only studies included for ST were those by Coyne et al. [26] and Loprinzi et al. [29]. There were no specific conclusions nor recommendations for ST [34]. The authors felt that complimentary therapies should be considered in each individual case.

#### **4. Scrambler therapy for cancer pain**

The first reports of the use of ST involved patients with cancer pain and were published by the inventor of the technology. In 2003, Guiseppe Marineo reported on the use of ST in 11 terminal abdominal cancer patients [35], including pancreatic, gastric, and colon cancer. Nine of the 11 patients were able to stop oral analgesics in the midst of the ST sessions, and the other 2 were able to reduce dosages. The same year, Marineo et al. [13] published the results of an additional 33 terminal cancer patients treated with ST for their pain. All patients responded to the ST and 72% of them were

able to stop oral analgesics completely while the rest were able to reduce the dosage considerably.

In 2013, Park et al. [36] reported a case series on three patients treated with ST that were not well managed with other modalities. All three patients were suffering from bony metastases and despite regional analgesic techniques in two of the patients and opioid usage in all three, pain scores ranged from 6 to 8 and severely impacted quality of life. The patients underwent 10 sessions of ST with a meaningful reduction in pain scores to 2–3.5/10 which lasted for two months. Two of the patients did have a worsening of pain at the two-month mark and underwent a second round of 10 ST sessions.

Two years later, a pilot study of ST for treating pain from bony and visceral metastases as well as primary tumors refractory to other therapies was published [37]. The study was a retrospective case series of 25 consecutive patients treated with ST who had failed standard treatments at the time. The average age of the patients was 62.0. All patients received at least 50% reduction in pain scores which lasted from 4 to 24 weeks. The average pain score was reduced from 8.4 at baseline to 2.9 following ST. Patients reported an increase in the average number of sleeping hours from 4.4 to 7.5. The authors state that patients reported a decrease in the usage of breakthrough opioids but do not quantify this information. They reported no adverse effects from ST.

In 2017, a series of three women with difficult to manage chronic post-mastectomy pain (cPMP) treated with ST was reported by Smith et al. [38]. ST sessions were 45 minutes in duration, but none of the patients required 10 consecutive treatments to obtain marked relief of over 75%. Quality of life improved for all three patients. One patient was able to wean off chronic opioids and another returned to work. Pain relief lasted for several months and treatments were repeated as necessary. There were no adverse effects noted.

The following year, another positive case report using ST for the treatment of pain due to breast cancer-related lymphedema was published [39]. The patient was 39 years old and had undergone a right mastectomy. Four years later, she underwent ST for a total of 10 sessions of 45 minutes each for treatment of pain. Her pain score was reduced from 8/10 to 2/10. No mention is made of other prior therapies for her pain nor is there any period of follow-up reported.

In 2020, a randomized controlled trial on the use of ST in pain due to head, neck and thoracic cancer was published by Kashyap et al. [40]. The study was specifically designed to determine the impact of ST on opioid usage in patients experiencing cancer pain. A total of 80 patients were enrolled into 2 arms, a control group and an intervention group receiving ST, which consisted of 40-minute treatment sessions over 10 consecutive weekdays, in addition to the usual analgesic therapy. One patient in the ST arm was lost to follow-up after the ninth day of ST because his pain had completely resolved and found further treatment unnecessary. Mean pain scores were similar at baseline between the two groups (6.57 for control and 6.65 for ST) and decreased during the trial period in both arms. However, the reduction in pain was greater in the ST group, and this difference was statistically significant from the third treatment onward. The total reduction in pain scores over the 10 days of treatment was 3.42 in the control arm and 5.91 for the ST group. There was no difference in the usage of tramadol, but a statistically significant reduction in the usage of morphine by the end of ST treatments. The authors suggested that being the "stronger" of the two opioids, morphine was reduced preferentially. There were no adverse effects reported with ST. The authors concluded that the use of ST for refractory head, neck and thoracic cancer pain is recommended.

#### *Scrambler Therapy in Acute and Chronic Pain: A Review DOI: http://dx.doi.org/10.5772/intechopen.111898*

This same group published the results of their quality of life (QOL) comparisons in a separate paper [41]. QOL assessments were conducted at baseline, at the end of the 10 days of ST, and at one week after the last ST session. Baseline QOL were similar between the two groups. Overall QOL worsened in the control group during the study, while it improved significantly for the ST intervention group. The authors felt that if QOL had been impacted solely by pain, there might be some improvement in the control group since there was pain reduction in both groups. It should be noted that morphine consumption did increase slightly in the control group which seemed to correspond with the changes in QOL. The authors felt that the benefits of ST could be explained by improved pain as well as decreased morphine intake and its related side effects.

Another case report on the use of ST for pain from bone metastases in a single patient was published in 2021 [42]. The 69-year-old patient with metastatic non-small cell lung cancer was severely limited in the ability to use his right arm due to scapular and humeral head involvement and the resultant pain. He had undergone radiation several months prior and cryoablation to the scapular mass one month prior to ST without benefit. He remained on his oral analgesic regimen but after six 30-minute sessions over 10 days, he was pain free and able to use his right arm to eat. He remained pain free for several weeks until his death.

Finally in 2020, Kashyap and Bhatnagar [43] published a systematic review on the use of ST for cancer pain. Their review included several of the studies mentioned in this section on cancer pain and the section on CIPN as well as some studies on chronic pain that contained mixed patient populations some of whom had noncancer pain. The reader is referred to the paper as it is a good source of references related to the topic of ST and cancer pain over the past 2 decades. They conclude that large RCTs are still needed but that ST may be an option for cancer pain unresponsive to other modalities.

The next section of this chapter will look at the available evidence for the use of scrambler therapy (ST) in other types of neuropathic pain unrelated to cancer or chemotherapy.

#### **5. Scrambler therapy for peripheral neuropathic pain**

Neuropathic pain occurs due to a disorder that affects the somatosensory nervous system and can have multiple etiologies affecting the peripheral or central nervous systems [44]. There is often a combination of loss of sensation and pain which can be spontaneous or evoked in the affected area. Examples would include post-herpetic neuralgia (PHN), diabetic neuropathy (DN), and central post-stroke pain to name a few. There is an excellent treatise on neuropathic pain published in 2021 by Finnerup et al. to which the reader is referred [44]. This section will discuss peripheral neuropathic pain while the next will discuss central neuropathic pain.

In 2012, the inventor of the ST technology along with several other authors [45] published a small RCT in which 52 patients were randomized to receive either standardized guideline-based drug management with amitriptyline, clonazepam, and oxycodone versus the same drug treatment with the addition of ST for 10 treatment sessions of 45 minutes each. There were 26 patients in each group with either PHN, post-surgical neuralgia, or spinal cord stenosis. Baseline pain scores were reduced from 8.1 to 5.8 in the control group and from 8.0 to 0.7 in the group receiving ST at one month and continued to be significantly reduced at three months. Furthermore, there was a significant reduction in the usage of pain medications in the ST group

with more than half of those taking opioids and anticonvulsants able to eliminate them entirely. There were no adverse effects from the ST.

A series of 3 patients with PHN treated with ST was published in 2013 [46]. All 3 patients were elderly women who had failed other methods of treatment and despite daily analgesics suffered from pain scores ranging from 6 or 7 out of 10. Each underwent 10 ST sessions of 50 minutes each. By the end of the treatments, all patients had a pain score of 2 which only increased slightly to 3 or 4 at one month follow-up. There were no adverse effects reported.

Another case report of a 54-year-old woman was reported four years later [47]. There was no mention of prior or current analgesics. The patient underwent 10 ST sessions of 40 minutes. By the end of therapy, her pain score had decreased from 7 at baseline to 1, and QOL scores had increased. There were no reported adverse effects. There was no reported follow-up period, so it is unclear how long the effects lasted.

A more extensive case series of 10 patients with PHN was reported by Smith and Marineo in 2018 [48]. The patients consistently had pain scores greater than 5/10 and were part of a subgroup of two other studies, one of which was previously reported [45], that was analyzed separately. Patients were treated for 30 to 45 minutes with 10 weekday sessions of ST [48]. The average pain score decreased from an average of 7.64 at baseline to 0.42 at one month follow-up with continued marked improvement at three months. Five of the 10 patients had complete resolution of pain, and most were able to reduce or cease the use of oral analgesics. There were no adverse effects reported.

A prospective study of 45 patients with neuropathic pain of various etiologies treated with ST was published in 2018 [49]. Etiologies included lumbar radiculopathy, PHN, and trigeminal neuralgia to name a few. The primary endpoint was a decrease in the number of signs and symptoms of neuropathic pain according to the Neuropathic Pain Diagnostic Questionnaire (DN4) [50]. Patients underwent 45-minute sessions of ST on 10 consecutive weekdays [49]. Sessions were discontinued if the pain resolved or continued if the patient was continuing to receive benefit. Four of the patients had complete resolution of pain prior to completing 10 sessions. The median number of sessions was 10.5 with a range of 5–20. Of the 45 patients, 62.2% had a decrease in the DN4 score and 88.8% had a greater than 50% reduction in pain intensity.

Also in 2018, a case report on the treatment of DN using ST was published [51]. The patient was 45 years old and had been treated with insulin for five years. She developed bilateral plantar foot pain with subsequent electromyogram demonstrating peripheral polyneuropathy. Her pain score was 6/10. She did not respond to oral analgesics nor regional analgesia with injections of bilateral posterior tibial nerves and lumbar sympathetic ganglion blocks. She underwent 45-minute ST treatment sessions once per week for 10 weeks placing the electrodes around the ankles. Her pain score decreased to 2/10 by the end of treatment and one week later. It was decided that the patient would return when she felt it necessary and had not returned for six months.

Another case report using ST for the treatment of DN was published in 2021 [52]. An 80-year-old woman with longstanding severe DN in the hands and feet was treated with 3 sessions of ST of 40 minutes. She had no adverse effects attributed to ST but did develop recurrent atrial fibrillation which prevented further treatments. However, her pain score had been reduced from 8/10 to 0/10 which persisted at fourand 11-months post treatment.

In 2021, a prospective study analyzed subgroups of neuropathic pain phenotypes to determine if there was a differential response to ST based upon phenotype rather than etiology of the pain [53]. Twenty-five patients completed the study which consisted of a total of 10 ST treatments of 30 minutes each. The investigators divided

#### *Scrambler Therapy in Acute and Chronic Pain: A Review DOI: http://dx.doi.org/10.5772/intechopen.111898*

the 25 patients into three clusters based upon responses to the Neuropathic Pain Symptom Inventory [54]. They found that patients with paroxysmal pain had more favorable outcomes than persistent pain [53]. The overall reduction in pain across the 25 patients was only 22%. The authors acknowledged that the ST operator's experience was limited and that 93% of the patients were taking anticonvulsants both of which have been suggested could have an impact upon outcomes [10]. The authors did feel that the more favorable response in paroxysmal pain could be due to damaged Aβ fibers [53], and since ST is felt to utilize C-fibers for transmission of the "non-pain" signals, the response to ST is preserved.

A narrative review of the four main neuromodulation modalities was published in 2022 [55], and evaluated spinal cord stimulation (SCS), peripheral nerve stimulation, TENS, and ST. Most of the literature that the authors were able to find related to SCS and TENS. They were only able to find the two case reports on ST treating DN noted in the above paragraphs. The authors concluded that SCS had the most data for efficacy, while data for TENS was mixed. There was simply not enough data available for ST and more studies are needed in treating DN.

In 2021, Abdi et al. published a focused review summarizing the history of ST, its mechanism of action, and the evidence at that time regarding the clinical effectiveness of ST in treating noncancer neuropathic pain [7]. Several of the studies have been mentioned in this section, but others have either mixed etiologies or include patients with cancer and noncancer pain that will be discussed in subsequent sections. The authors call for more clinical trials to confirm the positive findings reported thus far.

#### **6. Scrambler therapy for central neuropathic pain**

In 2018, D'Amato presented a case report in which a 52-year-old woman developed central neuropathic pain following resection and radiation of a brainstem medullary cavernoma [56]. She had suffered from a burning pain to her left leg for 12 years prior to ST. Oral analgesics including antidepressants, anticonvulsants, and opioids were of limited effectiveness, and her pain was 6/10 which would increase to 10/10 with activity. Pregabalin was discontinued prior to 10 ST sessions of 45 minutes each. By the completion of ST, her pain was 0–0.5/10 for almost two months when the pain returned. She underwent an additional 5 sessions of ST which reduced her pain to 2/10 for the next three months. She remained on duloxetine and only took occasional tramadol while enjoying improved physical functioning.

In 2019, there was case report using ST for the treatment of persistent central neuropathic pain following transverse myelitis [57]. The 65-year-old woman had tried multiple oral medications, including opioids, as well as meditation and acupuncture over the course of more than three years prior to ST which was administered in 45-minute sessions over 10 consecutive weekdays. Her pain was rated at 5/10 on the morning of her first session. Pain was in both lower extremities, her torso, and right arm. By the end of the 10 treatment sessions, her pain had essentially resolved and remained at low levels for 90 days. Her sleep and activity tolerance improved.

A year later, the same primary author published the results of a randomized single-blind, sham-controlled trial in patients with neuromyelitis optica spectrum disorder [58]. A total of 11 patients were assigned to the ST group and 11 to the sham group. Both ST and sham sessions were conducted for 10 consecutive weekdays for 35 minutes each. Baseline measures of pain severity, pain interference, sleep disturbance, anxiety and depression were obtained. These were reassessed at the end

of treatment and at 30- and 60-day follow-up. The ST arm saw median pain scores decline from 5.0 at baseline to 1.5 which was statistically significant, whereas the sham group experienced a small, insignificant decline from 5.0 to 4.0. A reduction in depression was seen in the ST group, but scores related to anxiety, sleep and pain interference failed to reach statistical significance. Pain scores remained significantly decreased at 30 days (p = 0.0195) but not at 60 days (p = 0.0518). There were no serious adverse effects reported.

Also in 2020, a case report of a 56-year-old man with centralized post-stroke thalamic pain, or Dejerine-Roussy syndrome, treated with ST was published [59]. After six years of disabling pain, multiple daily 40-minute ST treatments followed by monthly booster treatments were able to nearly eradicate his pain allowing resumption of normal activity and cessation of all pain medications without any side effects.

In 2021, a case report treating centralized neuropathic pain associated with Parkinson's disease was published by Wang et al. [60]. A 63-year-old man suffered from constant shocking and burning pain in the lower extremities with severe nighttime pain flares in a "coat-hanger" distribution. The patient received a 35-minute ST treatment for his legs and the area of his nighttime flares during which his baseline pain of 5/10 decreased to 0/10 which lasted for three days. He was able to sleep through the night without any lower body or upper body pain or spasms. His second 35-minute treatment resulted in no pain for seven days. He then had a third and fourth treatment 24 hours apart with the result that his pain remained at 0/10 for six weeks. He reported markedly improved sleep and quality of life and wished to undergo booster treatments as necessary.

#### **7. Other studies and case reports using scrambler therapy**

This next section will discuss other uses for scrambler therapy. While some of the studies could have been included in the previous four sections on cancer-related pain and non-cancer neuropathies, they are included here either because they are larger studies including patients with both cancer and non-cancer pain, or they are somewhat unique, and it was felt that they should be included in their own section. This would include use of ST for treating pruritus in burn patients and the use of ST in acute pain or pediatric patients.

#### **7.1 Larger studies with mixed groups of patients**

In 2012, Sparadeo et al. [61] reported the results of 173 patients treated for chronic neuropathic pain. There were four groups including isolated spine pain, neuralgia, complex regional pain syndrome (CRPS), and multi-site pain patients. Patients underwent 10 treatment sessions of ST. The baseline pain score across all patients was 7.24 which had significantly decreased to 1 immediately following the final treatment. A total of 91 of the patients agreed to a 3–6-month follow-up survey with a mean follow-up period of 4.2 months. All seven variables of the Brief Pain Inventory (BPI) Score [62] were significantly reduced at follow-up. The authors concluded that ST is an effective treatment for chronic neuropathic pain [61].

In 2011, Ricci and colleagues [63] published the results of a prospective study of 73 patients with chronic pain, 41 of which had pain related to cancer and 32 with non-cancer pain. The etiologies and characteristics of the pain were quite varied with some having nociceptive pain, others with neuropathic pain, and others with

mixed characteristics. The length of time the pain was present was variable as well as whether the pain was continuous or intermittent. ST treatments were for 30 minutes on 10 consecutive weekdays. The authors did report results for patients with and without cancer pain. The patients with cancer pain saw pain scores decrease from 5.4 to 1.4 and those with non-cancer pain from 7.0 to 1.8 by the end of treatment. At the 2-week follow-up period, pain scores remained significantly reduced at 2.6 and 3.4 respectively. At the end of the 4-week study, the authors reported that 81% of the overall group had achieved a response. There were no adverse events reported. The authors felt that further research might lead to possible explanations for the 20% of patients that exhibit no response to ST treatment.

Eight years later, Ricci et al. [64] published the results of an additional 219 patients using the same methodology as their 2011 study above. In this study, 83 patients had cancer pain, and 136 had non-cancer pain. Again, they analyzed the results of each individual group (cancer and non-cancer) as well as all patients together. As in the first study, pain etiologies were quite varied. The cancer patients saw pain scores decrease from 6.25 to 2.90 following ST treatment and 2.97 two weeks later. The non-cancer patients had a reduction of pain scores from 6.55 at baseline to 3.42 at the end of ST. These reductions were statistically significant. There were no adverse events reported. The authors do not provide the percentage of responders versus nonresponders but do state that overall, 10.5% of the patients were pain free at the 2-week follow-up after completion of ST. There were 44 patients that repeated ST following successful treatment due to pain recurrence. The majority repeated treatment at two to five months following the first round of ST. Repeat treatments were able to reduce pain significantly from 6.27 at baseline to 2.94 at 4 weeks.

In 2015, there was a large multicenter retrospective analysis published on behalf of the Scrambler Therapy Group out of Italy [65]. There were 201 patients treated in one year with a variety of reasons for chronic pain, including PHN, low back pain, peripheral neuropathy, polyneuropathy, and other causes of chronic pain. The baseline pain score was 7.41 prior to the typical 10-day treatment course with 45-minute sessions. Following treatment, the mean pain score was 1.60. The success rate, defined as greater than 50% reduction in pain score, ranged from 82 to 93% when the four major types of chronic pain were analyzed separately. The authors note medication reductions among several oral analgesics and total elimination of opioids in 55 out of 77 patients. Three-month follow-up showed improvements in pain, sleep, and other quality of life metrics.

There was a prospective, double-blinded, randomized, sham controlled trial of military veterans suffering from chronic pain due to combat injury or repetitive use trauma published in 2020 [66]. The data from 47 patients were analyzed with 28 in the active ST group and 29 in the sham group. Pain scores were evaluated at baseline, at the conclusion of ten 30-minute sessions of treatment (ST or sham), and four weeks following the conclusion of the intervention. Most of the patients (97%) suffered from low back pain with radicular symptoms. Overall, 90% of patients responded to treatment regardless of the group assigned, and the authors found no difference in the reduction of pain, use of analgesics, and quality of life.

The inventor of the technology penned a letter to the editor [67] regarding the above study [66] stating that the protocol did not appear to comply with the methods of use presented to the FDA. He further states that because the proper use of ST requires operator and patient interaction for proper placement of the electrodes, it is essentially impossible to perform a true double-blinded study. He had submitted another letter [68] nearly a decade earlier in 2011 noting the same issues with

the methodology of another study [63] and referenced many other methodological problems that existed [68]. As a result, a three-day training course on theory of ST and practical applications had been developed.

#### **7.2 Burns**

In 2016, there was a pilot study published on the use of ST in the management of burn scar pruritus [69]. Sixteen patients were treated with 10 weekday sessions of 40 minutes. The electrodes were placed on the skin surrounding the burn. If pruritus was not reduced at the beginning of treatment, electrodes were repositioned. The degree of pruritus was rated from 0 to 10, analogous to a pain scale. The degree of interference with daily activities was measured using the Leuven Itch Scale (LIS) [70]. Scores were recorded at baseline, following five treatments, and at the end of 10 treatments [69]. The degree of pruritus decreased significantly at both 5 and 10 days. Scores were 6.75 at baseline, 5.06 at day 5, and 4.13 at day 10. LIS scores also showed significant improvement. The authors concluded that ST was a feasible alternative for treatment of burn scar pruritus and further study was warranted.

In 2022, several of the same authors were part of a group that published the results from a prospective, double-blind RCT using a sham control [71]. Ten consecutive weekdays were used for treatment sessions of 45 minutes. The ST group received a stimulus that was the maximal amount tolerated without pain, whereas the sham group received a very low level of stimulus throughout the session. Measures of pain, depression and function were assessed at baseline and at the end of treatment. Furthermore, MRIs of the brain were obtained, and cerebral blood flow (CBV) was mapped at both time points. There was a total of 43 patients with 20 in the ST group and 23 in the sham group. Six of the 20 ST patients' pain improved such that they did not complete the two weeks of the study protocol and only data from 14 were included in the analysis. Both groups had a reduction in pain from baseline to the completion of treatment. The ST group median pain score decreased from 6 to 3, while the sham group decreased from 7 to 6. The publication stated that both changes were significant and that the p value for the sham decrease of 7 to 6 was actually more significant (p = 0.001) than the ST group (p = 0.004). There were also significant differences in CBV between the two groups, and the reader is referred to the study for a more detailed discussion [71].

#### **7.3 Chronic post surgical pain**

In 2019, Yarchoan et al. published a case report on two patients who received ST to treat post-surgical scar pain [72]. One of the patients was a 57-year-old woman with thoracotomy pain following surgery and chemoradiation for lung adenocarcinoma. Her pain was 9/10 which was reduced to zero 20 minutes into a 30-minute session. This relief lasted nearly six months. The other patient was 70 years old and underwent partial hepatectomy for cancer. Her pain prevented her from wearing a seat belt and a bra. It was constantly present and worsened significantly with movement. She underwent a 40-minute treatment session which eliminated her allodynia and pain, but the pain returned so on the eighth day, she underwent another treatment. At three months, her pain had remained at 2/10 or less.

In 2020, an additional two cases were published in a report by Kashyap et al. [73]. A 40-year-old male presented six months following adrenalectomy for cancer with 6/10 pain in the left lower back and iliac region. Oral analgesics escalated over the

next six months to include 10 mg of morphine every 4 hours to maintain 6/10 pain. He underwent 10 sessions of ST of 35 minutes each after which his pain score had decreased to 1/10 and the morphine was no longer needed. The second patient was a 56-year-old male with carcinoma of the right buccal mucosa at the time of disease recurrence and reoperation. Subsequent pain of 6/10 on the right side of the face and chest despite tramadol prompted the use of ST as an alternative. Following 10 sessions of 35 minutes each, the patient's pain score was 0/10.

#### **7.4 Other isolated case reports**

Scrambler therapy has been used for several other chronic pain disorders for which isolated case reports are available including low back pain in which pain and depression was improved [74], arthritis of the knee with resulting improvement in pain and quality of life [75], and for paraneoplastic neuropathy and pruritus in which two patients were treated with very positive results [76].

One of the more impressive case reports involves the use of ST for treating HIVrelated peripheral neuropathy [77]. In 2017, Smith et al. reported on a 52-year-old man suffering from neuropathy since 1998 who had been on long-acting morphine and oxycodone since 2012. In just four treatments of 45 minutes, his pain had decreased from an average of 8/10 to 1–2/10 on the right foot and 4/10 on the left. He was able to stop his opioids. Six months later, pain had returned in the toes such that he underwent only two treatments with one additional treatment four months later.

There are two case reports using ST to treat neuropathic pain associated with amyloidosis. In the first [78], a 58-year-old man with lower extremity neuropathy for a few years was diagnosed with amyloidosis and underwent chemotherapy. His pain spread to involve the trunk and upper extremities. The patient required methadone and oxycodone as part of his oral analgesic regimen. ST was effective in reducing his upper extremity pain by 40–50% but it only lasted for three weeks. He eventually underwent placement of an intrathecal drug delivery system. The second case report [79] describes a 70-year-old woman with 13 years of peripheral neuropathy from amyloidosis that was worsened by chemotherapy. She underwent four daily 40-minute treatments of ST for her upper extremities which declined to zero and lasted eight months. She did have worsening of lower extremity neuropathy and requested ST for that pain as well.

The first known case of ST used to treat pain from schwannomatosis was reported in 2022 [80]. A 48-year-old woman underwent five treatments to her right groin and anterior thigh during which her pain was reduced from 6/10 to 0/10 which had persisted for a minimum of three weeks.

Scrambler therapy has been used successfully in the treatment of radial and femoral nerve injuries following extracorporeal membrane oxygenation [81]. It is a brief report, but the pain score was reduced from 8/10 to 0.5/10 for two months following two days of treatment. In a letter to the editor [82], the use of ST to treat phantom limb pain is described. Following 10 weekday sessions of 30 minutes each, the patient remained pain free at two-month follow-up from a starting pain of 7/10.

Finally, there is a case report on the use of ST for pain and joint range of motion following arthroscopic rotator cuff repair [83]. It is unclear from the report how soon following surgery that ST was used for this patient and whether this was as part of the acute recovery process or as a result of chronic pain following surgery. The pain score was reduced from 8 to 1 following 10 sessions of ST and presumably physical therapy. Range of motion was likewise increased, but it is difficult to know how this would compare to ordinary post-operative progress.

#### **7.5 Low back pain**

In 2011, a small prospective study of eight patients with chronic low back pain was reported by Ghatak et al. [84]. Eight patients, half of whom were female, underwent six treatment sessions of 45 minutes each with pain scores and the Oswestry Disability Index (ODI) [85] compared at baseline and following the sixth treatment. Mean pain scores decreased from 8.1 to 3.6 and the ODI showed a significant improvement in functional status with the reduction from 49.9 to 18.4 being statistically significant.

An abstract on the use of ST for failed back surgery syndrome presented at the 2011 Annual Meeting of the American Society of Interventional Pain Physicians reported on 10 patients following 10 sessions of 60 minutes [86]. They reported a 28% reduction in pain without side effects.

In one of the more interesting studies published in 2015, Starkweather et al. [87] conducted a double-blind RCT dividing 30 patients into an active ST group and a sham group. Not only did the investigators compare pain scores and pain interference, but they also conducted quantitative sensory testing (QST) and drew blood to look at the mRNA expression of 84 genes involved in the pain pathway, i.e., transduction, maintenance, and modulation. The sham treatment was conducted with the same device at what was felt to be a subtherapeutic threshold for ten 30-minute sessions while the active group received ST. Each group was assessed at one and three weeks following the conclusion of treatment. The ST group showed a significant decrease in both pain and interference, whereas the sham group did not. There were differences between the groups on QST testing with the ST group experiencing less sensitivity to pain. There were 10 genes identified with differential expression in the ST group compared to the sham group at the three-week follow-up period when compared to baseline. In the discussion, the authors note that the levels of nerve growth factor and glial-derived growth factor were significantly lower in the ST group compared to the sham group at three weeks post treatment. Elevated levels of these proteins have been implicated in the process of peripheral sensitization [88], although it is unclear what role they might play in chronic low back pain.

#### **8. Scrambler therapy for complex regional pain syndrome**

There is one publication of four cases of adults with complex regional pain syndrome (CRPS) who have been treated with ST [89], although the report by Sparadeo et al. [61] mentioned previously did include 20 patients with CRPS. In the case report [89], the adults ranged from 41 to 70 years of age with a duration of CRPS symptoms from 4 to 38 months. The ST treatments were 45 minutes in duration and the required number to obtain complete pain relief ranged from 7 to 12 sessions. Baseline pain scores were 7/10 or above, and the pain free duration was 6 to 21 months without the need for medications. The authors felt that ST could be an effective treatment modality for patients with CRPS.

#### **9. Scrambler therapy in pediatric patients**

In addition to the nine adolescents who received ST for the treatment of CIPN reported by Tomasello et al. [28], there is a single case report of ST used to treat neuropathic pain related to leukemia in an 11-year-old [90] and one case report

#### *Scrambler Therapy in Acute and Chronic Pain: A Review DOI: http://dx.doi.org/10.5772/intechopen.111898*

using ST to treat an episode of acute pain [91]. The patient with leukemia [90] was suffering from left groin and thigh pain. Lesions were discovered on pelvic MRI that were thought to involve the obturator nerve. Because the patient and caregiver were fearful of injections, rather than obturator nerve block, the patient underwent 45-minute ST sessions over three days during which pain was reduced from 8/10 to zero. Medications, including fentanyl patch, were weaned and discontinued. One month later, the patient remained pain free. In the other case report [91], a 12-yearold girl with a history of congenital myopathy and removal of osteoblastoma of the foot treated with surgery six years prior, developed acute right scapular pain without occurrence of trauma or any specific etiology. She continued to have 5/10 pain even after ketorolac and diazepam. She underwent four days of ST treatments of 45 minutes each after which she was pain free. She remained pain free for at least eight weeks following treatment.

#### **10. Author's commentary**

As a pediatric anesthesiologist and chronic pain physician, my interest in Scrambler Therapy began in 2013 when I had first learned about it while treating a pediatric patient with recalcitrant CRPS. The patient went to Dr. D'Amato in Rhode Island to undergo ST (aka Calmare). Although it did not change her pain, and she eventually required implantation of a spinal stimulator [92], I was intrigued by the concept. Since that initial exposure, I have sent several patients to New Jersey for ST, many of whom have had quite impressive results. Anecdotally, I felt that there was an "art" to the treatments and that experience played a role in outcomes. After the research for this chapter, I can see that my impressions were correct. CRPS has been called the "suicide disease" due to the unrelenting pain that patients experience and feel that suicide is the only means by which they can achieve relief. Almost half (49.3%) of adult patients with CRPS have contemplated ending their lives, and 15.1% have attempted suicide with average attempts of 2.1 [93]. It would be difficult to imagine the prospect of lifelong agony as a child or adolescent with CRPS. It is therefore my hope that more research into the effectiveness of ST for the treatment of pediatric CRPS can occur to add an additional modality in treating this disabling and excruciatingly painful disorder.

#### **11. Conclusion**

Scrambler therapy has been in use for more than 20 years and has been used to treat a wide variety of painful conditions especially those that are neuropathic in nature. It operates using a unique mechanism that is designed to recalibrate the nervous system and reverse changes that can theoretically occur with chronic pain. Although there are many studies and case reports that have examined its efficacy and have demonstrated the ability of scrambler therapy to decrease the use of opioids and other analgesics, it is still misunderstood and has yet to be widely adopted in the treatment of chronic and acute pain.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

James A. Tolley Clinical Anesthesiology, Indiana University School of Medicine, Indianapolis, IN, USA

\*Address all correspondence to: jtolley@iuhealth.org

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Scrambler Therapy in Acute and Chronic Pain: A Review DOI: http://dx.doi.org/10.5772/intechopen.111898*

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