Scrambler therapy is a pain management approach that uses a machine to block the transmission of pain signals by providing non-pain information to nerve fibers that have been receiving pain messages.

The first study on scrambler therapy was published in 2003 by a team of researchers led by Giuseppe Marineo, professor in delta research and development at University of Rome Tor Vergata in Italy. He and colleagues reported that scrambler therapy was effective at reducing pain symptoms in patients with severe, drug-resistant pain from terminal cancer.

Charles L. Loprinzi

The Calmare scrambler therapy device has since received FDA clearance in the United States for use in patients experiencing pain from cancer and chemotherapy, pain as a result of chronic diseases such as diabetes, multiple sclerosis and arthritis, back and neck pain, failed back surgery syndrome, and phantom limb pain among others.

HemOnc Today asked Charles L. Loprinzi, MD, Regis professor of breast cancer research at Mayo Clinic in Rochester, Minnesota, about the safety and efficacy of scrambler therapy, as well as his ongoing research efforts.

Question: Can you describe scrambler therapy and how it came about?

Answer: Scrambler therapy is an electro-cutaneous treatment. Although people may think of it as being similar to transcutaneous electrical nerve stimulation (TENS) therapy, scrambler therapy is felt to work through a different mechanism. TENS is thought to work through the gateway theory of pain relief, whereby normal touch sensations blocks pain sensations. Scrambler therapy, on the other hand, is proposed to provide normal-self, non-pain electrical information via nerves that have been transmitting chronic pain information. Through a process termed plasticity, this is able to retrain the brain so that it does not ascribe pain to the chronic pain area. Scrambler therapy consists of a machine, which looks somewhat like an electrocardiogram machine. Leads are placed on patients, around the areas of chronic pain. Scrambled electrical signals are then sent to the brain that perceives them as normal, non-pain signals. Via this process, the brain is retrained to think that there really is not pain in the area that is being treated.

Q: How and when did you become involved with this treatment approach?

A: I was introduced to scrambler therapy in 2010 by Thomas J. Smith, MD, now at Johns Hopkins University, who had heard about scrambler therapy and decided to try it in patients with chemotherapy-induced peripheral neuropathy (CIPN). He subsequently published a pilot trial that supported that scrambler therapy was an effective approach for treating established CIPN. After some internal debate as to whether I should look further into this treatment approach, which sounded quite strange to me, I did agree to study it. Having now treated more than 200 patients at Mayo, we published a paper on the use of this treatment for chemotherapy neuropathy, which concurred with Dr. Smith’s report, further supporting that this therapy was helpful for CIPN.

Q: What other published data support the value of scrambler therapy?

A: I am aware of 19 published reports regarding scrambler therapy, involving more than 800 patients. Seventeen of these are published manuscripts, whereas two are only published as meeting abstracts. These reports include clinical practice summaries, prospective non-randomized clinical trials and randomized controlled trials, including two trials that sought to double blind patients and investigators. The authors of 18 of the 19 reports concluded that scrambler therapy was a beneficial treatment approach, whereas one report — published only as a meeting abstract and only involving 14 patients — concluded that this was not an effective treatment. Of note, one relatively large randomized trial, with a non-blinded control arm consisting of optimizing medical management of pain, reported substantially more benefit from scrambler therapy than was observed in the control arm. Additionally, a relatively small placebo-controlled, patient-blinded trial reported a statistically significantly beneficial effect for scrambler therapy in a small number of patients with chronic low back pain. Thus, there are substantial data that support the value of scrambler therapy. Having said this, I readily admit that scrambler therapy has not yet been clearly proven to be beneficial. Ideally, additional randomized clinical trials will be reported to provide for more substantial clinical data regarding the true value of scrambler therapy. Dr. Smith is conducting one trial at Johns Hopkins and we, at Mayo, are gearing up for another one. This all takes time, energy and funds.

Q: Can you briefly discuss the findings from the clinical study you reported regarding the use of scrambler therapy in patients with established CIPN?

A: When we received the scrambler therapy machine, we decided to treat patients on a clinical trial as opposed to just using it for routine clinical practice. For this, we developed an open-label clinical trial to document our results and to learn how to provide this therapy. Prior to treating patients on this trial, we went to Rome for training. We then treated patients on this clinical trial, who had chronic pain or neuropathy with a pain and/or tingling score of at least 4 out of 10. In order to report data on a series of these patients, we took the first 37 patients who entered on this clinical trial who had CIPN as their designated clinical problem. We prospectively collected patient-reported outcome data on each of 10 days of treatment and then weekly for 10 weeks following that. Results, reported in Supportive Care in Cancer, illustrated that, during the treatment days, there was approximately a 50% reduction from baseline for pain, tingling and numbness scores. When we then followed the patients weekly, after the 10 days of therapy, the benefit, on the whole, persisted.

Q: Can you describe the treatment process and when beneficial results appear?

A: The area of pain/neuropathy is first defined and a set of leads is placed in normal sensation skin sites, close to the area of pain/neuropathy. The electrodes are then turned on with a gradual increase in intensity to a point where the patient is able to feel sensations, short of pain. When successful, the patient reports that the buzzing sensation has replaced an area of pain/neuropathy. This generally occurs within a minute or two. At times, electrodes need to be moved to obtain this sort of success. Sometimes, several sets of electrodes are needed to cover the area of discomfort. The scrambler machine stays on for about 30 minutes following successful electrode placements. The electricity is then turned off and the patient commonly reports that the pain/tingling is still markedly improved. After one treatment, the benefit is often relatively short-lived, lasting for minutes to hours. With repetitive days of treatment (standardly up to 10 treatments, although stopped earlier if the problem goes away completely and lasts overnight), the period of benefit increases until it lasts for a couple days. The benefit largely persists for weeks to months. Some patients relapse and can be successfully retreated, oftentimes only needing an additional few doses.

Q: Is this therapy routinely offered at Mayo Clinic?

A: Mayo recently began offering scrambler therapy as part of clinical practice. As with many new practice approaches, there are many questions that arise: How effective is the therapy? Who should be treated and for which conditions? How well is this approach covered by different insurance carriers? Admittedly, we do not have ideal answers for these and many other questions, but we are cautiously proceeding forward. There is considerable demand for scrambler therapy along with concerns that efficacy has not been proven and that the reported results from it sound too good to be true. But, these concerns are not too surprising, as there is often a wariness when a new therapy is initiated.

Q: Is this therapy routinely offered at places other than Mayo Clinic?

A: Yes, it is available at other select places. I understand there are more than 30 institutions in Italy and even more institutions in South Korea that provide scrambler therapy as a part of clinical practice. Multiple United States military institutions also offer scrambler therapy. In the United States, I estimate that there are between 15 and 30 sites that are actively offering this treatment. It should be noted that there is a learning curve in terms of making this therapy work. For example, in our paper where we looked at CIPN, even though we had reasonably good experience which included visiting the inventor in Rome and being trained by him, we did a whole lot better with the later patients we treated than we did the first 25% we treated.

Q: What type of feedback have you received on the therapy?

A: There are patient testimonials, which can be found on the Internet, whereby patients swear by this therapy. In line with this, I have seen some phenomenal results in patients. We have clinical trial data that asked patients, daily while they were receiving 2 weeks of outpatient therapy and then weekly for 10 weeks of follow-up, whether they would recommend this treatment to others. Approximately 80% of the replies noted that they would recommend it, 1% said that they would not and the rest said that they were unsure. There, admittedly, are some people who say this therapy did not work for them.

Q: How much of an issue is cost?

A: There are the issues regarding the cost of the machine, the cost of training and whether insurance companies cover this therapy. There are some insurance companies that cover the therapy, having realized that it is a lot cheaper than alternative therapies that might be employed for the same patient problem. This is certainly an evolving process. The cost can run anywhere between $200 and $500 per session, and up to 10 sessions may be recommended. This is less expensive than some other procedures and therapies employed for chronic pain, such as spinal cord stimulators. There are some patients who choose to pay for the treatments on their own, if not covered by insurance.

Q: Are there any side effects associated with this therapy? Do they outweigh the benefit, in your opinion?

A: There have not been many documented side effects with this therapy. People feel a buzzing sensation when the machine is working and sometimes this can be uncomfortable. If pain happens during the procedure, the signal intensity should be turned down and/or off. At times the electrode leads can be moved to an alternative site, sometimes by just a couple centimeters. Occasionally, patients may develop some skin irritation or bruising under the sites of the leads. There have been some patients who report more pain in the day or days following the treatment, but it is not apparent that this is more than the normal process of a waxing and waning of the baseline pain. Overall, the reports in the literature have been largely free of side effects.

Q: Is there anything else you would like to add?

A: Although if I consider myself to be a fairly conservative clinician and have not been shy about publishing negative results from many clinical trials, I do believe that scrambler therapy works. This contention is based on the knowledge that the majority of the reports in the literature are positive an also the personal experience I have observed in many patients, including seeing dramatic reductions of symptoms in some patients that did not derive similar benefit from previous treatment approaches. – by Jennifer Southall

Scrambler therapy is a pain management approach that uses a machine to block the transmission of pain signals by providing non-pain information to nerve fibers that have been receiving pain messages.

The first study on scrambler therapy was published in 2003 by a team of researchers led by Giuseppe Marineo, professor in delta research and development at University of Rome Tor Vergata in Italy. He and colleagues reported that scrambler therapy was effective at reducing pain symptoms in patients with severe, drug-resistant pain from terminal cancer.

Charles L. Loprinzi

The Calmare scrambler therapy device has since received FDA clearance in the United States for use in patients experiencing pain from cancer and chemotherapy, pain as a result of chronic diseases such as diabetes, multiple sclerosis and arthritis, back and neck pain, failed back surgery syndrome, and phantom limb pain among others.

HemOnc Today asked Charles L. Loprinzi, MD, Regis professor of breast cancer research at Mayo Clinic in Rochester, Minnesota, about the safety and efficacy of scrambler therapy, as well as his ongoing research efforts.

Question: Can you describe scrambler therapy and how it came about?

Answer: Scrambler therapy is an electro-cutaneous treatment. Although people may think of it as being similar to transcutaneous electrical nerve stimulation (TENS) therapy, scrambler therapy is felt to work through a different mechanism. TENS is thought to work through the gateway theory of pain relief, whereby normal touch sensations blocks pain sensations. Scrambler therapy, on the other hand, is proposed to provide normal-self, non-pain electrical information via nerves that have been transmitting chronic pain information. Through a process termed plasticity, this is able to retrain the brain so that it does not ascribe pain to the chronic pain area. Scrambler therapy consists of a machine, which looks somewhat like an electrocardiogram machine. Leads are placed on patients, around the areas of chronic pain. Scrambled electrical signals are then sent to the brain that perceives them as normal, non-pain signals. Via this process, the brain is retrained to think that there really is not pain in the area that is being treated.

Q: How and when did you become involved with this treatment approach?

A: I was introduced to scrambler therapy in 2010 by Thomas J. Smith, MD, now at Johns Hopkins University, who had heard about scrambler therapy and decided to try it in patients with chemotherapy-induced peripheral neuropathy (CIPN). He subsequently published a pilot trial that supported that scrambler therapy was an effective approach for treating established CIPN. After some internal debate as to whether I should look further into this treatment approach, which sounded quite strange to me, I did agree to study it. Having now treated more than 200 patients at Mayo, we published a paper on the use of this treatment for chemotherapy neuropathy, which concurred with Dr. Smith’s report, further supporting that this therapy was helpful for CIPN.

Q: What other published data support the value of scrambler therapy?

A: I am aware of 19 published reports regarding scrambler therapy, involving more than 800 patients. Seventeen of these are published manuscripts, whereas two are only published as meeting abstracts. These reports include clinical practice summaries, prospective non-randomized clinical trials and randomized controlled trials, including two trials that sought to double blind patients and investigators. The authors of 18 of the 19 reports concluded that scrambler therapy was a beneficial treatment approach, whereas one report — published only as a meeting abstract and only involving 14 patients — concluded that this was not an effective treatment. Of note, one relatively large randomized trial, with a non-blinded control arm consisting of optimizing medical management of pain, reported substantially more benefit from scrambler therapy than was observed in the control arm. Additionally, a relatively small placebo-controlled, patient-blinded trial reported a statistically significantly beneficial effect for scrambler therapy in a small number of patients with chronic low back pain. Thus, there are substantial data that support the value of scrambler therapy. Having said this, I readily admit that scrambler therapy has not yet been clearly proven to be beneficial. Ideally, additional randomized clinical trials will be reported to provide for more substantial clinical data regarding the true value of scrambler therapy. Dr. Smith is conducting one trial at Johns Hopkins and we, at Mayo, are gearing up for another one. This all takes time, energy and funds.

Q: Can you briefly discuss the findings from the clinical study you reported regarding the use of scrambler therapy in patients with established CIPN?

A: When we received the scrambler therapy machine, we decided to treat patients on a clinical trial as opposed to just using it for routine clinical practice. For this, we developed an open-label clinical trial to document our results and to learn how to provide this therapy. Prior to treating patients on this trial, we went to Rome for training. We then treated patients on this clinical trial, who had chronic pain or neuropathy with a pain and/or tingling score of at least 4 out of 10. In order to report data on a series of these patients, we took the first 37 patients who entered on this clinical trial who had CIPN as their designated clinical problem. We prospectively collected patient-reported outcome data on each of 10 days of treatment and then weekly for 10 weeks following that. Results, reported in Supportive Care in Cancer, illustrated that, during the treatment days, there was approximately a 50% reduction from baseline for pain, tingling and numbness scores. When we then followed the patients weekly, after the 10 days of therapy, the benefit, on the whole, persisted.

Q: Can you describe the treatment process and when beneficial results appear?

A: The area of pain/neuropathy is first defined and a set of leads is placed in normal sensation skin sites, close to the area of pain/neuropathy. The electrodes are then turned on with a gradual increase in intensity to a point where the patient is able to feel sensations, short of pain. When successful, the patient reports that the buzzing sensation has replaced an area of pain/neuropathy. This generally occurs within a minute or two. At times, electrodes need to be moved to obtain this sort of success. Sometimes, several sets of electrodes are needed to cover the area of discomfort. The scrambler machine stays on for about 30 minutes following successful electrode placements. The electricity is then turned off and the patient commonly reports that the pain/tingling is still markedly improved. After one treatment, the benefit is often relatively short-lived, lasting for minutes to hours. With repetitive days of treatment (standardly up to 10 treatments, although stopped earlier if the problem goes away completely and lasts overnight), the period of benefit increases until it lasts for a couple days. The benefit largely persists for weeks to months. Some patients relapse and can be successfully retreated, oftentimes only needing an additional few doses.

Q: Is this therapy routinely offered at Mayo Clinic?

A: Mayo recently began offering scrambler therapy as part of clinical practice. As with many new practice approaches, there are many questions that arise: How effective is the therapy? Who should be treated and for which conditions? How well is this approach covered by different insurance carriers? Admittedly, we do not have ideal answers for these and many other questions, but we are cautiously proceeding forward. There is considerable demand for scrambler therapy along with concerns that efficacy has not been proven and that the reported results from it sound too good to be true. But, these concerns are not too surprising, as there is often a wariness when a new therapy is initiated.

Q: Is this therapy routinely offered at places other than Mayo Clinic?

A: Yes, it is available at other select places. I understand there are more than 30 institutions in Italy and even more institutions in South Korea that provide scrambler therapy as a part of clinical practice. Multiple United States military institutions also offer scrambler therapy. In the United States, I estimate that there are between 15 and 30 sites that are actively offering this treatment. It should be noted that there is a learning curve in terms of making this therapy work. For example, in our paper where we looked at CIPN, even though we had reasonably good experience which included visiting the inventor in Rome and being trained by him, we did a whole lot better with the later patients we treated than we did the first 25% we treated.

Q: What type of feedback have you received on the therapy?

A: There are patient testimonials, which can be found on the Internet, whereby patients swear by this therapy. In line with this, I have seen some phenomenal results in patients. We have clinical trial data that asked patients, daily while they were receiving 2 weeks of outpatient therapy and then weekly for 10 weeks of follow-up, whether they would recommend this treatment to others. Approximately 80% of the replies noted that they would recommend it, 1% said that they would not and the rest said that they were unsure. There, admittedly, are some people who say this therapy did not work for them.

Q: How much of an issue is cost?

A: There are the issues regarding the cost of the machine, the cost of training and whether insurance companies cover this therapy. There are some insurance companies that cover the therapy, having realized that it is a lot cheaper than alternative therapies that might be employed for the same patient problem. This is certainly an evolving process. The cost can run anywhere between $200 and $500 per session, and up to 10 sessions may be recommended. This is less expensive than some other procedures and therapies employed for chronic pain, such as spinal cord stimulators. There are some patients who choose to pay for the treatments on their own, if not covered by insurance.

Q: Are there any side effects associated with this therapy? Do they outweigh the benefit, in your opinion?

A: There have not been many documented side effects with this therapy. People feel a buzzing sensation when the machine is working and sometimes this can be uncomfortable. If pain happens during the procedure, the signal intensity should be turned down and/or off. At times the electrode leads can be moved to an alternative site, sometimes by just a couple centimeters. Occasionally, patients may develop some skin irritation or bruising under the sites of the leads. There have been some patients who report more pain in the day or days following the treatment, but it is not apparent that this is more than the normal process of a waxing and waning of the baseline pain. Overall, the reports in the literature have been largely free of side effects.

Q: Is there anything else you would like to add?

A: Although if I consider myself to be a fairly conservative clinician and have not been shy about publishing negative results from many clinical trials, I do believe that scrambler therapy works. This contention is based on the knowledge that the majority of the reports in the literature are positive an also the personal experience I have observed in many patients, including seeing dramatic reductions of symptoms in some patients that did not derive similar benefit from previous treatment approaches. – by Jennifer Southall