while these drugs kill tumor cells , they 
 can also cause adverse effects during their use , such as nausea , vomiting , diarrhea , 
 constipation , alopecia , fatigue , skin alterations , and neurotoxicity , among others .
chemotherapy - induced peripheral neuropathy ( cipn ) is a nuisance and a limiting side effect 
 for patients , since the symptoms of pain , dysesthesia , and paresthesia generated by 
 chemotherapy can mean a reduction in the functionality and quality of life for cancer 
 patients .
moreover , these side effects may compromise the treatment of the disease and lead 
 to reduced doses of drugs or treatment discontinuation2 , 3 .
the current recommendations of the american society of clinical oncology ( asco)4 point out that there are not yet any 
 strongly recommended drugs available to prevent cipn , given the lack of consistent and 
 high - quality research on the issue .
chus5 
 review about the effects of antidepressant drugs and anticonvulsants for the control of cipn 
 confirm asco s data .
therefore , the treatment of these disorders could ideally be done 
 without the use of drugs by applying non - pharmacological treatments , which would have the 
 advantage of not compromising the different body systems already burdened by 
 chemotherapy .
transcutaneous electrical nerve stimulation ( tens ) has arisen as an alternative to drug 
 treatment for the control of peripheral neuropathies .
the rationale for the use of tens is 
 based on studies showing that electrical stimulation has shown a positive effect on rat s 
 nerve regeneration , revealing a higher number of myelinated fibers , axon density , and blood 
 vessels in the total nerve area compared to control groups6 .
when using transcutaneous electrical stimulation in mice s 
 peripheral nerve injuries , the density , fiber diameter , and degree of myelination are also 
 similar to animals that have not suffered injuries7 .
a case - control study evaluated the effect of tens on peripheral neuropathic pain induced by 
 chemotherapy in patients with different types of cancer , pointing out beneficial effects in 
 reducing pain during tens application without generating side effects8 .
silva9 
 used tens in the treatment of intercostobrachial pain developed after breast cancer surgery 
 to show that , in addition to pain relief , tens produced changes in somatotopic organization 
 in the parietal cortex after application , causing increased attention to painful processes . 

other symptoms of cipn , such as paresthesia and decreased quality of life of these 
 patients , have not been evaluated in previous controlled studies .
therefore , this study aims 
 to evaluate the effects of tens on symptoms of numbness and tingling and the frequency of 
 symptoms and its impact on the daily life activities of patients with cipn .
this two - arm clinical trial was randomized , placebo - controlled , and double - blind .
it was 
 conducted in cancer patients who developed symptoms of cipn after the first chemotherapy 
 cycle .
the patients were recruited in barretos cancer hospital , institute of cancer of the 
 state of so paulo , and so francisco university hospital .
this study was approved by the 
 research ethics committee of the faculty of medicine , university of so paulo , under 
 protocol n 341/13 .
it was registered at clinicaltrials.gov before the research began , under 
 registration number ntc 02107417 .
all participants were informed about the objectives of the 
 study and signed a consent form to participate in the study .
the study included patients between the ages of 18 and 70 who met the following inclusion 
 criteria : being subjected to chemotherapy treatment with drugs with a high to moderate 
 degree of neurotoxicity , experiencing neuropathic pain and/or peripheral sensory neuropathy 
 of grade i or grade ii on the common terminology criteria for adverse events ( ctcae ) scale , 
 exhibiting symptoms of peripheral neuropathy after the first cycles of chemotherapy with at 
 least two points on the visual analog scale of paresthesia and/or pain , and having a present 
 performance status of ecog 2 ( karnofsky50% ) .
exclusion criteria were : having sensitivity disorders before chemotherapy treatment , having 
 skin lesions on the site of application of the electrodes , exhibiting cognitive difficulties 
 or trouble understanding how to fill out questionnaires , or being cardiac pacemaker users or 
 diabetes mellitus patients . the study sample consisted of 24 patients with diagnoses of breast and colorectal cancer 
 undergoing a chemotherapy treatment containing in its protocol the chemotherapeutic agents 
 paclitaxel or oxaliplatin .
patients were divided into 2 groups : active tens ( gat ) and 
 placebo tens ( gpt ) .
the flow diagram of the research the entry of patients in each experimental group was performed randomly by the site 
 www.random.org before the start of treatment .
patients were subjected to the following tens 
 ( ibramed , neurodyn porttil ) parameters : symmetrical biphasic waveform with modulating 
 frequencies ranging from 7  hz to 65  hz , a pulse width of 200  s at the highest tolerable 
 current intensity with an application time of 60 minutes . the stimulation was performed with 
 individual self - adhesive electrodes with an area of 5  cm in the region where the 
 patient had symptoms of neuropathy , typically , the ends of the upper limbs and/or lower 
 limbs . in the application of active tens ,
the patient was instructed to increase the 
 stimulation intensity each time the intensity reduced during the 60 minutes of 
 application10 . in tens placebo 
 application
, patients received the same schedule of active tens , but the equipment was 
 produced to apply the current for only 30 seconds and then the intensity began to decrease 
 during the next 15 seconds until reaching zero11 .
we used the following instruments for data collection : -sociodemographic and clinical data form to characterize the sample profile with the 
 following data : gender , age , race , education , type of cancer , occupational status and 
 disease status .
tnm rating ( t , refers to the size and extent of the main tumor ; n refers to 
 the number of nearby lymph nodes that have cancer ; m refers to metastasis ) , treatments 
 conducted ( surgical , radiotherapy , hormonal , chemotherapy , other types of medication , 
 acupuncture ) and affected segment by neuropathy ( upper limb and/or lower limb ) were also 
 used to create the profiles .
items of the 
 questionnaire used to assess the symptoms of cipn were paresthesia ( grade i , ii , and iii ) , 
 peripheral sensory neuropathy ( i , ii , iii , iv , and v ) , and dysesthesia ( grade i , ii , and 
 ii ) .
-performance status scale ecog ( eastern cooperative oncology group ) to assess the 
 functional capacity of oncologic patients , with the following scores and activity levels : 0 ) 
 completely active ; able to perform all their activities without restriction .
( karnofsky 
 90100% ) ; 1 ) restriction of rigorous physical activities , but able to perform light work and 
 of a sedentary nature ( karnofsky 7080% ) ; 2 ) able to perform all self - care , but unable to 
 carry out any work activity but able to remain standing approximately 50% of waking hours 
 ( karnofsky 6050% ) ; 3 ) capable of only limited self - care , confined to bed or chair more than 
 50% of waking hours karnofsky 3040% ) ; 4 ) completely unable to perform self - care , totally 
 confined to bed ( karnofsky 1020%)12 .
-chemotherapy induced neurotoxicity questionnaire ( cinq ) for the evaluation of symptoms of 
 pain and dysesthesia and paresthesia of upper and lower limbs .
cinq is an instrument 
 containing 20 items to evaluate the symptoms divided into 2 categories : symptoms of acute 
 and chronic neuropathy in the lower extremities ( 10 items ) and symptoms of acute and chronic 
 neuropathy in upper extremities ( 10 items ) .
this questionnaire evaluates the frequency of 
 symptoms ( cinqa ) and the symptoms interference with patients daily activities ( cinqb ) .
questionnaires were administered before the treatment ( assessment 1 : ax1 ) and after 15 
 ( ax2 ) , 30 ( ax3 ) , and 45 ( ax4 ) days of treatment .
the data were presented using measures of central tendency ( mean and median ) and dispersion 
 ( standard deviation ) for quantitative variables and relative percentages for categorical 
 variables .
pearson s  test was used to verify the association between the 
 categories of the study and , when necessary , resorted to fisher s exact test .
comparisons of 
 the vas scores between groups were performed using the nonparametric statistical 
 mann - whitney u test and comparison of vas along with the assessments by friedman anova .
the 
 q - cochran test was used to determine differences in the cinq responses among the evaluations 
 ( ax1 , ax2 , ax3 and ax4 ) .
the comparison of the sums of scores of cinq questions among the 
 assessments was done using hierarchical linear models adjusted for restricted maximum 
 likelihood .
the mean age in ptg was 46.3  13.7 and 52.7  9 in atg , without significative differences 
 between them . assessing the functional status of the active tens group patients
, we found 
 that 10 patients were between 0 and 1 ecog degrees , with no or some functional limitations , 
 while only 1 had more marked limitations related to the inability to work . in the placebo 
 tens group , 8 patients had ecog 01 and 5 ecog 2 .
the sample characteristics are summarized in table 
 1table 1.patient characteristicsplacebo tens ( n=13)active tens ( n=11)total ( n=24)%nn%n%genderfemale215.4327.3520.8male1184.6872.71979.2marital statussingle430.800.0416.7married861.51090.91875.0divorced17.719.128.3widowed00.000.000.0race / ethnicitywhite646.2981.81562.5asiatic00.000.000.0black323.100.0312.5admixture430.7218.2625.0educationelementary or less430.8872.71250.0middle school646.219.1729.2high school215.419.1312.5college or higher17.619.128.3worksyes323.1545.5833.3no1076.9654.51666.7stopped workingyes969.2654.51562.5no430.8545.5937.5fisher s exact test .
the experimental groups showed no significant differences with regard to 
 gender , marital status , race , education , employment status , or reductions in their 
 occupational activity due to the treatment .
table 2table 2.distribution of characteristics of the type and cancer stage according treatment 
 groupstens placebo ( n=13)tens ativo ( n=11)total ( n=24)n%n%n%type of tumorbreast969.2436.41354.2colorectal430.8763.61145.8tt100.019.114.2t2646.2218.2833.3t3646.2763.61354.2t417.619.128.3nn0430.8545.5937.5n1646.2545.51145.8n2323.019.0416.7n300.000.000.0mm0646.2981.81562.5m1538.5218.2729.2m300.000.000.0mx215.300.028.3 test pearson , * p>0.01 shows the disease characteristics among groups in relation to cancer type and 
 disease stage .
no significant differences were observed between the groups in terms of these 
 characteristics ( p>0.05 ) .
 test pearson , * p>0.01 the data relating to the type of chemotherapy performed , different types of therapeutic 
 treatments undertaken by the patient , and the region in which the patient developed 
 neuropathy are presented in table 3table 3.distribution of the type of treatments performed by patients and the body region 
 affected by cipn between groupsplacebo tensactive tenstotaln%n%n%chemotherapyadjuvant1076.9763.61770.8neo - adjuvant215.4436.4625.0paliative17.700.014.2surgeryyes1184.6763.61875.0no215.4436.4625.0radiotherapyyes215.4218.2416.7no1184.6981.82083.3hormone therapyyes215.4218.2416.7no1184.6981.82083.3immunotherapyyes00.000.000.0no13100.011100.024100.0acupunctureyes17.700.014.2no1292.311100.02395.8other medicationsyes753.8763.61458.3no646.2436.41041.7involvementmmss969.2763.61666.7mmii430.8436.4833.3fisher s exact test , * p>0.05 .
no significant differences were observed in the distribution of the 
 characteristics between the groups in any of the variables described ( p>0.05 ) .
fisher s exact test , * p>0.05 table 4table 4.comparison of mean and standard deviation of the frequency of symptoms ( cinqa ) 
 and interference of symptoms in patients daily activities ( cinqb ) during treatment 
 with tens in the experimental groupsplacebo tens active tens time groupcinqaax 113.53 ( 9.29)12.18 ( 8.28)0.59*ax 211.06 ( 5.02)8.80 ( 4.87)ax 39.63 ( 8.46)8.67 ( 4.33)ax 46.87 ( 6.40)7.00 ( 4.31)cinqbax 19.61 ( 7.73)11.27 ( 8.66)0.85*ax 28.18 ( 6.61)7.59 ( 4.67)ax 38.46 ( 8.28)6.43 ( 4.19)ax 45.50 ( 5.93)7.00 ( 4.58)*p - value related to hierarchical linear mixed effect models .
ax- ( assessment ) shows the behavior of cinq scores over the application of tens during the 45 
 treatment days for the placebo and active groups , indicating that there was no difference 
 between groups during the treatment performed in any assessment carried out , both in terms 
 of the frequency of symptoms ( p=0.5906 ) and daily living activities ( 0.8565 ) .
table 5table 5.comparison of vas of pain and numbness / paresthesia intra- and inter - group during 
 tens treatment in experimental groupsplacebo tensactive tens median ( iqr)median ( iqr)pain vas ax10.0 ( 0.00.0)0.0 ( 0.05.0)pain vas ax20.0 ( 0.00.0)0.0 ( 0.01.0)pain vas ax30.0 ( 0.00.0)0.0 ( 0.01.0)pain vas ax40.0 ( 0.02.0)0.0 ( 0.01.0)p value0.690.632vas numb / pares ax12.0 ( 2.06.5)4.0 ( 1.07.0)vas numb / pares ax25.0 ( 0.08.0)1.0 ( 1.03.0)vas numb / pares ax31.0 ( 0.05.0)5.0 ( 1.07.0)vas numb / pares ax41.5 ( 0.03.8)2.0 ( 1.02.0)p value0.240.01iqr interquartile range ( 25th .
75th percentile);p values from mann - whitney u test for comparison between assessment*p values from friedman test for comparison between groups shows the comparison of vas of pain and paresthesia intra- and inter - group 
 during treatment with tens in the experimental groups . *
75th percentile ) ; p values from mann - whitney u test for comparison between assessment * p values from friedman test for comparison between groups
the results of this study show that the use of tens with modulating frequencies between 
 7  hz to 65  hz indicated no significant difference in the symptoms of paresthesia and the 
 impact of these symptoms on the daily activities among the groups who received applications 
 of active or placebo tens .
these symptoms , however , do not increase during the three cycles 
 subsequent to the onset of chemotherapy neuropathy symptoms .
these data corroborate the study of 
 wolf13 and pachman14 , indicating that numbness and tingling are the most 
 frequent symptoms of cipn .
the hands were more affected than the feet by the symptoms of 
 neuropathy , which was corroborated by zanville s study15 .
review16 states that one of the assumptions for the development of cipn in 
 hands and feet relates to the fact that these neurons have long axons and are highly 
 dependent on transport proteins and other nutrients to work correctly .
taxanes can lead to 
 disruption of microtubules and mitochondria , leading to a deficit in cell nutrition and 
 subsequent cell death .
platinum - based drugs can also contribute to cell death by inhibiting 
 adn synthesis .
the effects of tens on nerve regeneration in rats show a positive effect of low frequency 
 tens in this process , presenting density , fiber diameter , and a degree of myelination of 
 neurons similar to the uninjured rats of the control group7 .
it has been hypothesized that these results relate to the effect of 
 tens in the modulation of ca2 + levels and of injured neurons through voltage - dependent 
 channels after nerve injury , factors that would contribute to a decrease in the frequency of 
 the firing of these neurons and stimulate production of neurotrophic factors ( bdnf , ngf , and 
 vegf ) and other transcription factors17 . 
 in our study , we use modulating frequencies ranging between 7 and 65  hz . as there are no 
 studies evaluating the symptoms of paresthesia and the impact of symptoms on daily 
 activities , we could not compare the results of our study with others to verify if other 
 tens frequencies would produce better effects on the outcomes .
an interesting finding of our study is that there was no significant difference between the 
 active tens and tens placebo groups in the studied variables .
it was expected that the 
 symptoms of paresthesia and pain would get worse during the chemotherapy cycles and this may 
 not have happened due to the fact that patients expected to receive treatment for neuropathy 
 symptoms resulting from chemotherapy .
this effect was also observed in rakel s study11 for post - surgery pain due to total knee 
 arthroplasty .
worsening neuropathy symptoms would be expected since the development of 
 symptoms may occur after the first chemotherapy cycle , worsen after performing subsequent 
 cycles , and even after the end of treatment18 .
pachman14 , 19 points out that the development of neuropathy after the first 
 treatment cycle with oxaloplatin is a risk factor for the worsening of these symptoms in 
 subsequent cycles .
patients treated with paclitaxel also have worsening neuropathy symptoms 
 over the course of chemotherapy cycles20 . 

the fact that the patients in this study have not presented worsening symptoms may show a 
 tens placebo effect on cipn .
studies show that tens placebo operates effectively in 
 modulating pain11 , 21 . as the current in placebo tens
is applied in the same way as in 
 active stimulation , but for a period of 30 seconds and then decreasing for the next 15 
 seconds until reaching zero intensity , the fact that the stimulation performed with placebo 
 tens mimics the application of the active tens may have contributed to this placebo effect . 

the application of tens placebo thus carried out is important since many patients have heard 
 that tens produces a feeling of a  small electric shock  and the intensity decreases as the 
 application time goes on .
some studies , conducting the placebo tens without 
 electrostimulation ( patient does nt feel any sensation ) , show a significant difference 
 between the group of active tens and the placebo stimulation group in the studied 
 parameters , in favor of the active tens22 , 23 .
other studies should be performed with 
 high or low frequency tens to verify these effects .
clinical studies show an efficiency of application of transcutaneous electrical stimulation 
 on the quality of life of patients with cipn24 , 25 ; however , these studies were not 
 placebo - controlled , not allowing for the analysis of the placebo effect on quality of life . 

our study found no improvement in the impact of cipn in the daily activities of patients 
 between the active tens groups and placebo group , suggesting that the placebo effect may 
 also have contributed to the fact that there was no impairment in the performance of daily 
 life activities of these patients over the course cycles of chemotherapy .
our study has some limitations , such as not accompanying the patients throughout the 
 chemotherapeutic treatment and not evaluating the effect of tens on other types of cancer 
 and neurotoxic drugs .
the application of tens with modulating frequencies between 7  hz to 65  hz in patients with 
 breast and colorectal cancer showed no significant difference in terms of the symptoms of 
 paresthesia and the impact on daily life activities between the groups that received 
 application of active tens and those that received a placebo for chemotherapy treatments 
 with oxaloplatin and paclitaxol .
there was no worsening of symptoms in subsequent cycles of 
 the onset of cipn symptoms .
 [ purpose ] the aim of this double - blind , randomized and placebo - controlled study is to 
 investigate the effects of transcutaneous electrical nerve stimulation for reducing the 
 side effects of chemotherapy - induced peripheral neuropathy in cancer patients undergoing 
 chemotherapy with oxaloplatin or paclitaxel . 
 [ subjects and methods ] twenty - four patients 
 were randomly allocated into two groups : active or placebo stimulation . 
 all patients were 
 assessed for pain , numbness / tingiling , frequency of symptoms , and quality of life . the 
 transcutaneous electrical nerve stimulation device was applied daily with modulating 
 frequencies ranging between 7  hz and 65  hz in distal limb regions during three cycles of 
 chemotherapy ( 45 days ) . 
 the other stimulation parameters were : pulse duration of 200 sec , 
 intensity at the highest tolerable level , and increases in intensity when it diminished . 
 
 [ results ] the data showed no difference between active or placebo groups in terms of pain , 
 numbness / tingling , frequency of symptoms or impact on daily life activities . 
 [ conclusion ] 
 these results suggest that transcutaneous electrical nerve stimulation applied in the 
 frequency variation mode was not proven to be effective to improve the symptoms of 
 chemotherapy - induced peripheral neuropathy during chemotherapy cycles . 
 there was no 
 worsening of symptoms in subsequent cycles of the onset of symptoms of the disease . 
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION