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  Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 57  |  Issue : 1  |  Page : 93-97
 

Scrambler therapy: A ray of hope for refractory chemotherapy-induced peripheral neuropathy


Department of Onco-Anaesthesia and Palliative Medicine, Dr. B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

Date of Submission08-Jun-2018
Date of Decision05-Aug-2018
Date of Acceptance19-Aug-2018
Date of Web Publication26-Feb-2020

Correspondence Address:
Sachidanand Jee Bharati
Department of Onco-Anaesthesia and Palliative Medicine, Dr. B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_361_18

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 » Abstract 


Scrambler therapy (ST) is a novel noninvasive modality for treatment of chronic neuropathic and cancer pain using 5 artificial neurons. The principle with Scrambler Therapy is that synthetic “non-pain” information is transmitted by C fiber surface receptors. Chemotherapy-induced peripheral neuropathy can markedly deteriorate patient's quality of life and can also negatively affect compliance with the anticancer treatment. Chronic neuropathic pain presents a therapeutic challenge if resistant to pharmacological management opioids and other types of treatments. We have described here successful use of scrambler therapy in three cases of chemotherapy-induced peripheral neuropathy.


Keywords: Chemotherapy-induced peripheral neuropathy, pharmacological management, refractory


How to cite this article:
Ahuja D, Bharati SJ, Gupta N, Kumar V, Bhatnagar S. Scrambler therapy: A ray of hope for refractory chemotherapy-induced peripheral neuropathy. Indian J Cancer 2020;57:93-7

How to cite this URL:
Ahuja D, Bharati SJ, Gupta N, Kumar V, Bhatnagar S. Scrambler therapy: A ray of hope for refractory chemotherapy-induced peripheral neuropathy. Indian J Cancer [serial online] 2020 [cited 2020 Mar 30];57:93-7. Available from: http://www.indianjcancer.com/text.asp?2020/57/1/93/279171





 » Introduction Top


Chemotherapy-induced peripheral neuropathy (CIPN) is a distressing adverse effect that has been reported in up to 68% of patients after the administration of different classes of chemotherapeutic agents.[1] Various chemotherapeutic agents including taxanes, platinum compounds, vinca alkaloids, immunomodulatory agents, and proteasome inhibitor have been implicated in the causation of CIPN.[2] The most frequent clinical presentation of CIPN is sensory neuropathy characterized by pain and paraesthesia starting from fingers or toes which spread proximally in “glove and stocking” distribution.[3] These symptoms may begin weeks to months after the initiation of treatment and may reach a peak during or after the completion of treatment. The symptoms of CIPN not only reduce the quality of patient's life but may also lead to discontinuation of anticancer chemotherapy. The symptoms may either resolve after the completion of therapy or may persist forever due to irreversible neuronal damage.[4] Various pharmacological agents like amitriptyline, nortriptyline, topical baclofen-amitriptyline-ketamine gel, lamotrigine, gabapentin, pregabalin, venlafaxine, and duloxetine with variable success rates have been tried for the management of CIPN. Of all these agents, only duloxetine has been recommended for clinical practice in patients with painful CIPN.[5] The gravity of clinical situation is amplified further if the symptoms of CIPN are refractory to the pharmacological agents.

Device

Recently, Calmare device (i.e., MC5-A Scrambler Therapy) that has already been approved by the Food and Drug Administration for noninvasive treatment of chronic neuropathic and oncologic pain has been found to significantly reduce pain in refractory CIPN also without any evidence of toxicity. The technique was invented by Marineo in 2000 and derived its name from the Italian word “Calmare” which means “to soothe or ease.” This noninvasive cutaneous device used nerve fibers as passive means to convey a message of normality to the central nervous system (CNS) instead of creating interference in the nerve impulse from peripheral to CNS as with electric stimulation devices, for example, transcutaneous electric nerve stimulation (TENS) and spinal cord stimulation devices; hence, the process of scrambling, that is, mixing of information enables CNS to recognize “pain” as “nonpain” information.[6] The “Calmare device” consists of a multiprocessor apparatus that can use five sets of surface electrodes to treat the areas of pain. The device can produce up to 16 different electrical currents that simulate nerve action potentials. These currents are organized into algorithms that also consider factors such as previous outputs, frequency, duration, and amplitude of modulation.[7] The maximum frequency of the scrambler device is 52 Hz; thus, the mean energy delivered per se cond is less than most standard TENS device that operates a square wave with the possibility of using frequencies greater than 52 Hz.[7],[8] The different mechanisms by which scrambler therapy provides pain relief are by giving new ''nonpain'' information so that patients report new sensations like pressure, itching, “bee sting” sensations, and a flow of impulses in the pain area, absence of electrical stimulation of C-fiber, lack of paresthesias, quick analgesic response resulting from the transmission of nonpain information from receptors, spread of nonpain information along the lines of nerve transmission leading to the spread of sensation throughout the dermatome, and finally the sustained pain relief for days or months due to either resetting of calcium channels or remodulation of the pain system's response.[7] The intensity of stimulation is adjusted according to the patient's comfort. When the placement is correct, pain is usually replaced by a pleasant, vibratory, and/or humming sensation. Usually, the scrambler therapy is given for a total of sessions. In each session, the device runs for about 30–45 minutes. The duration of reported analgesia after the therapy keeps on increasing with each successive session and finally the patient attains adequate pain relief throughout the day. Pain relief is expected to persist for weeks to months after treatment. Booster sessions are administered if the patient relapses.[9]

Method

After taking written informed consent, the patients were scheduled to undergo a total of 12 sessions of scrambler therapy. Out of total of 12 sessions, 10 sessions were scheduled on consecutive days. Remaining two sessions, were scheduled on the follow up visits i.e., after 1 and 2 weeks of completion of 10 consecutive sessions of scrambler therapy. Before initiating scrambler therapy comfortable position of the patient was ensured. Pain was assessed by using numerical rating scale (NRS) and the areas where the patient felt pain were marked. The five set of electrodes were placed on normal tissue around the painful site and along the lines of pain or numbness [Figure 1]. The device was turned on and current intensity was increased to maximal strength tolerated by the patient. We assessed pain scores daily using NRS, before and after the administration of scrambler therapy. The change in the position of electrodes was permitted according to the change in the site of pain according to the assessment made before each session. Further follow-up was maintained with regular telephonic calls and on regular hospital visits. With the above background, we present here three cases of CIPN that were refractory to pharmacotherapy and finally had pain relief after administration of scrambler therapy.
Figure 1: Placement of electrodes in patients

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 » Case Reports Top


Case 1

A 42-year-old man, a case of gastric and testicular diffuse large B-cell lymphoma, was planned for six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) regimen. The patient tolerated first two cycles of chemotherapy well without developing any side effects. A few days after receiving the third cycle of chemotherapy, he developed pain in the bilateral upper and lower limbs that had typical glove and stocking pattern of distribution. Pain was burning in character, severe in intensity (NRS 8/10), and worse at night. Pain aggravated on sitting or lying down and relieved by standing or walking. It was associated with tingling and numbness of both hands and feet. The patient was prescribed duloxetine 30 mg at bed time for 3 days and advised to increase the dosage to 30 mg twice a day if adequate pain relief was not obtained. The patient was advised for follow-up after 1 week. When the patient reported to our pain clinic, he had inadequate pain relief with the medications prescribed and his NRS was still 7/10. After analyzing his current situation, we decided to increase the dosage of duloxetine to 60 mg twice a day and again advised to come for follow-up after 1 week. In spite of increasing the dosage of duloxetine to a maximum for 1 week, the patient's pain still persisted with the same intensity. The presence of severe neuropathic pain delayed the administration of next cycle of chemotherapy. Hence, based on the availability of current evidence we decided to manage refractory CIPN with scrambler therapy. The patient was administered a total of 12 sessions of scrambler therapy with continuous recording of NRS as explained above. NRS of the patient before and after each session has been summarized in [Table 1]. The NRS scores show that the patient had adequate pain relief after initiation of scrambler therapy.
Table 1: Numerical Rating Scale values during administration of scrambler therapy

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Case 2

A 65-year-old man, a case of low-grade central osteosarcoma of the left tibia, was planned for three cycles of cisplatin and doxorubicin based on neoadjuvant chemotherapy followed by surgery and later followed by three cycles of cisplatin and doxorubicin based on adjuvant chemotherapy. The patient completed neoadjuvant chemotherapy and also underwent tumor resection and endoprosthesis application. Before the administration of planned adjuvant therapy, the patient reported to our pain clinic with complaints of pain in the bilateral upper and lower limbs that had typical glove and stocking pattern of distribution. Pain was burning in character, severe in intensity (NRS 9/10), and worse at night. Pain was associated with tingling and numbness of both the hands and feet. The patient was prescribed duloxetine 30 mg HS for 3 days and advised to increase the dosage to 30 mg twice a day if adequate pain relief was not obtained. The patient was asked to come for follow-up after 1 week. When the patient reported to our pain clinic, he had inadequate pain relief with medications prescribed and his NRS was still 8/10. Hence, we decided to increase the dosage of duloxetine to 60 mg twice a day and asked to come for follow-up again after 1 week. In spite of increasing the dosage of duloxetine to a maximum for 1 week, the patient's pain still persisted with same intensity. The presence of severe neuropathic pain even delayed the administration of adjuvant chemotherapy. Hence, we managed refractory CIPN with scrambler therapy. We administered a total of 12 sessions of scrambler therapy with daily recording of NRS before and after the procedure as summarized in [Table 1]. NRS scores indicate that the patient had adequate pain relief after administration of scrambler therapy.

Case 3

A 40-year-old man, a case of metastatic adenocarcinoma of the stomach, was planned for three cycles of cisplatin and 5-fluorouracil-based palliative chemotherapy. After receiving palliative chemotherapy he developed complaints of pain in the bilateral upper and lower limbs that had typical glove and stocking pattern of distribution. Pain was burning in character, severe in intensity (NRS 9/10), and worse at night. Pain was associated with both tingling and numbness of hands and feet. At the time of first visit to our pain clinic, the patient was prescribed duloxetine 30 mg HS for 3 days and advised to accelerate the dosage to 30 mg twice a day if adequate pain relief was not obtained. When the patient reported to our pain clinic 1 week later for follow-up, he had inadequate pain relief with medications prescribed and his NRS was still 8/10. Thus, we decided to increase the dosage of duloxetine to 60 mg twice a day and asked to come for follow-up again after 1 week. In spite of increasing the dosage of duloxetine to a maximum for 1 week, the patient's pain still persisted with same intensity. We decided to manage this refractory CIPN with scrambler therapy. We administered a total of 12 sessions of scrambler therapy with daily recording of NRS before and after the procedure as summarized in [Table 1]. The declining trend of NRS scores clearly indicates that the patient had adequate pain relief after the initiation of scrambler therapy.


 » Discussion Top


Peripheral neuropathy caused by administration of chemotherapeutic agents is a matter of prime concern. The increased use of colony-stimulated factors has allowed the use of higher doses of chemotherapeutic agents. The neuropathic symptoms associated with CIPN affect both sensory and motor components. This results in pain, restricted limb motility, and reduced ability of the individual to perform the activities of daily living. Taking into consideration the mobility aspect separately, the neuropathic symptoms disrupt fine motor sensations, proprioception. and balance. The undesirable effect on proprioceptive input negatively affects the postural stability, balance, and gait patterns and increase the risk of falls.[10],[11] Falls are a common concern in cancer survivors as they fall at 25%–30% higher rate than that of the general population.[12] These falls can be injurious and also associated with increased risk of death in cancer population.[13] The presence of CIPN in a patient not only leads to the loss of functional abilities and deteriorates the quality of life but also affects the treatment plan. CIPN may present a therapeutic challenge if the symptoms are not adequately controlled by pharmacological treatment. Scrambler therapy can be a solution in such an intricate scenario.

Scrambler therapy has been used for providing pain relief in a vast variety of chronic neuropathic pain conditions. The spectrum of conditions for which scrambler therapy is being employed for providing adequate pain relief ranges from postsurgical neuropathic pain,[7] postherpetic neuralgia,[7] spinal cord stenosis,[7] failed back surgery syndrome,[14] sciatic and lumbar pain,[14] trigeminal neuralgia,[14] pudendal neuropathy,[14] brachial plexus neuropathy,[14] visceral pain from abdominal cancer,[15] human immunodeficiency virus-related peripheral neuropathy,[16] congenital myopathy,[17] chronic central neuropathic pain after stroke and radiotherapy,[18] management of burn scar pruritus,[19] management of shoulder joint pain after arthroscopic rotator cuff repair,[20] painful degenerative gonarthritis,[21] refractory pain due to skeletal and visceral metastasis,[22] complex regional pain syndrome[23] to amyloid associated neuropathy.[24] Recently, few pilot trials have been done to assess the efficacy of scrambler therapy in relieving pain associated with CIPN.

Smith et al.[8] in 2010 carried out a pilot trial of patient-specific cutaneous electrostimulation device (MC5-A Calmare®) in patients suffering from CIPN and found that scrambler therapy dramatically reduced pain scores in patients suffering from refractory CIPN without any adverse effects. Another single-arm trial conducted by Coyne et al.[25] in 2013 assessed the efficacy of scrambler therapy in the treatment of cancer pain syndromes and chronic CIPN, and reported clinically important and statistically significant improvements in the pain scores.

An open-labeled, single-arm, exploratory study done by Lee et al. in 2016 determined the effectiveness of “Calmare therapy” in patients with various types of cancer-related neuropathic pain including neuropathic radiculopathy caused by metastatic bone lesion, CIPN, and postsurgical neuropathic pain (e.g., postmastectomy pain with intercostal neuralgia or neuropathic post-thoracotomy pain). It was found that the administration of scrambler therapy was associated with both the reduction in 11-point NRS pain score and consumption of opioids at follow-up after 1 month.[26] Furthermore, in the pilot evaluation of scrambler therapy for the treatment of CIPN done by Pachman et al.[27] in 2015, it was found that the patients after receiving scrambler therapy had 53% reduction in pain scores, 44% reduction in tingling, and 33% reduction in numbness without any adverse effects.

A prospective, observational study done by Kashyap et al. on 20 patients with chronic pain due to malignancy who were not responding to oral analgesics. The patients were aged between 18 and 70 years with a life expectancy of >3 months. The pain was bony, neuropathic, or mixed type and had visual analog scale score of >4 on oral analgesics. After the administration of a total of 12 sessions of scrambler therapy, all patients had good pain relief (P< 0.01) and improvement in all four domains of quality of life, that is, physical, psychological, social, and environmental health (P< 0.01) was observed.[28]

On the basis of the results of literature search, we decided to use scrambler therapy for our patients suffering from refractory CIPN. After the administration of 12 sessions of scrambler therapy, our patients had adequate pain relief [Figure 2]. Hence, the results observed in our cases were concordant with the results obtained from various studies mentioned above. Moreover, the scrambler therapy is a cost-effective technique which is freely available in public sector and costs Rs 300–500 per sitting in the private sector.
Figure 2: Numerical rating scale values during the administration of scrambler therapy

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 » Conclusion Top


Scrambler therapy seems to be a promising noninvasive technique for the management of CIPN in cancer survivors which is refractory to the pharmacological treatment. The overall consumption of pain medications is also reduced. The resolution of symptoms not only improves the patient's quality of life and adherence to treatment, but also prevents injurious falls in cancer survivors. The results obtained from the above cases must be confirmed by conducting larger randomized controlled trials.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain 2014;155:2461-70.  Back to cited text no. 1
    
2.
Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, et al. Chemotherapy-induced peripheral neurotoxicity: A critical analysis. CA Cancer J Clin 2013;63:419-37.  Back to cited text no. 2
    
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Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 2006;33:15-49.  Back to cited text no. 3
    
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Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropathy: Pathogenesis and emerging therapies. Support Care Cancer 2004;12:619-25.  Back to cited text no. 4
    
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Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014;32:1941-67.  Back to cited text no. 5
    
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Serafini G, Marineo G, Sabato AF. “Scrambler therapy”: A new option in neuropathic pain treatment? Pain Clin 2000;12:287-98.  Back to cited text no. 6
    
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Marineo G, Iorno V, Gandini C, Moschini V, Smith TJ. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: Results of a pilot, randomized, controlled trial. J Pain Symptom Manage 2012;43:87-95.  Back to cited text no. 7
    
8.
Smith TJ, Coyne PJ, Parker GL, Dodson P, Ramakrishnan V. Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare®) for chemotherapy-induced peripheral neuropathy. J Pain Symptom Manage 2010;40:883-91.  Back to cited text no. 8
    
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Majithia N, Smith TJ, Coyne PJ, Abdi S, Pachman DR, Lachance D, et al. Scrambler therapy for the management of chronic pain. Support Care Cancer 2016;24:2807-14.  Back to cited text no. 9
    
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Wampler MA, Topp KS, Miaskowski C, Byl NN, Rugo HS, Hamel K, et al. Quantitative and clinical description of postural instability in women with breast cancer treated with taxane chemotherapy. Arch Phys Med Rehabil 2007;88:1002-8.  Back to cited text no. 10
    
11.
Winters-Stone KM, Torgrimson B, Horak F, Eisner A, Nail L, Leo MC, et al. Identifying factors associated with falls in postmenopausal breast cancer survivors: A multi-disciplinary approach. Arch Phys Med Rehabil 2011;92:646-52.  Back to cited text no. 11
    
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Mohile SG, Fan L, Reeve E, Jean-Pierre P, Mustian K, Peppone L, et al. Association of cancer with geriatric syndromes in older Medicare beneficiaries. J Clin Oncol 2011;29:1458-64.  Back to cited text no. 12
    
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Wildes TM, Ruwe AP, Fournier C, Gao F, Carson KR, Piccirillo JF, et al. Geriatric assessment is associated with completion of chemotherapy, toxicity, and survival in older adults with cancer. J Geriatr Oncol 2013;4:227-34.  Back to cited text no. 13
    
14.
Sabato AF, Marineo G, Gatti A. Scrambler therapy. Minerva Anestesiol 2005;71:479-82.  Back to cited text no. 14
    
15.
Marineo G. Untreatable pain resulting from abdominal cancer: New hope from biophysics? JOP 2003;4:1-0.  Back to cited text no. 15
    
16.
Smith TJ, Auwaerter P, Knowlton A, Saylor D, McArthur J. Treatment of human immunodeficiency virus-related peripheral neuropathy with scrambler therapy: A case report. Int J STD AIDS 2017;28:202-4.  Back to cited text no. 16
    
17.
Congedi S, Spadini S, Di Pede C, Ometto M, Franceschi T, De Tommasi V, et al. Use of scrambler therapy in acute paediatric pain: A case report and review of the literature. Case Rep Pediatr 2016;2016:2628919.  Back to cited text no. 17
    
18.
D'Amato SJ, Mealy MA, Erdek MA, Kozachik S, Smith TJ. Scrambler therapy for the treatment of chronic central pain: A case report. A A Pract 2018;10:313-5.  Back to cited text no. 18
    
19.
Joo SY, Cho YS, Cho SR, Kym D, Seo CH. Effects of pain scrambler therapy for management of burn scar pruritus: A pilot study. Burns 2017;43:514-9.  Back to cited text no. 19
    
20.
Lee DK, Kim EK. Effect of pain scrambler therapy on shoulder joint pain and range of motion in patients who had undergone arthroscopic rotator cuff repair for the first time. J Phys Ther Sci 2016;28:2175-7.  Back to cited text no. 20
    
21.
Jeong HJ, Lee DK, Kim YN, Hwang TY. The effects of pain scrambler therapy on the pain and quality of life of degenerative gonarthritis patients. J Phys Ther Sci 2018;30:479-80.  Back to cited text no. 21
    
22.
Notaro P, Dell'Agnola CA, Dell'Agnola AJ, Amatu A, Bencardino KB, Siena S, et al. Pilot evaluation of scrambler therapy for pain induced by bone and visceral metastases and refractory to standard therapies. Support Care Cancer 2016;24:1649-54.  Back to cited text no. 22
    
23.
Raucci U, Tomasello C, Marri M, Salzano M, Gasparini A, Conicella E, et al. Scrambler therapy(®) MC-5A for complex regional pain syndrome: Case reports. Pain Pract 2016;16:E103-9.  Back to cited text no. 23
    
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Warner NS, Watson JC, Bendel MA, Moeschler SM. Refractory pain management in amyloid-associated peripheral neuropathy. Reg Anesth Pain Med 2018;43:434-7.  Back to cited text no. 24
    
25.
Coyne PJ, Wan W, Dodson P, Swainey C, Smith TJ. A trial of scrambler therapy in the treatment of cancer pain syndromes and chronic chemotherapy-induced peripheral neuropathy. J Pain Palliat Care Pharmacother 2013;27:359-64.  Back to cited text no. 25
    
26.
Lee SC, Park KS, Moon JY, Kim EJ, Kim YC, Seo H, et al. An exploratory study on the effectiveness of “Calmare therapy” in patients with cancer-related neuropathic pain: A pilot study. Eur J Oncol Nurs 2016;21:1-7.  Back to cited text no. 26
    
27.
Pachman DR, Weisbrod BL, Seisler DK, Barton DL, Fee-Schroeder KC, Smith TJ, et al. Pilot evaluation of scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy. Support Care Cancer 2015;23:943-51.  Back to cited text no. 27
    
28.
Kashyap K, Joshi S, Vig S, Singh V, Bhatnagar S. Impact of scrambler therapy on pain management and quality of life in cancer patients: A study of twenty cases. Indian J Palliat Care 2017;23:18-23.  Back to cited text no. 28
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