Transcutaneous Electrical Nerve Stimulation vs. Transcutaneous Spinal Electroanalgesia for Chronic Pain Associated with Breast Cancer Treatments

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1 410 Journal of Pain and Symptom Management Vol. 33 No. 4 April 2007 Original Article Transcutaneous Electrical Nerve Stimulation vs. Transcutaneous Spinal Electroanalgesia for Chronic Pain Associated with Breast Cancer Treatments Karen A. Robb, PhD, MCSP, Di J. Newham, PhD, MCSP, and John E. Williams, MBBS, FRCS Division of Applied Biomedical Sciences Research (K.A.R., D.J.N.), School of Biomedical and Health Sciences, King s College London; and The Pain Management Team (J.E.W.), The Royal Marsden Hospital, London, United Kingdom Abstract Chronic pain associated with breast cancer treatment is becoming increasingly recognized. Patients with this condition can experience significant physical and psychological morbidity and may benefit from nonpharmacological interventions as part of a multidisciplinary team approach. We compared the effectiveness of transcutaneous electrical nerve stimulation (TENS), transcutaneous spinal electroanalgesia (TSE), and a placebo (sham TSE) in a randomized controlled trial. The study sample comprised 41 women with chronic pain following breast cancer treatment, and outcome measures included pain report, pain relief, pain interference, anxiety and depression, arm mobility, and analgesic consumption. There was little evidence to suggest that TENS or TSE were more effective than placebo. All three interventions had beneficial effects on both pain report and quality of life, a finding that may be due to either psychophysical improvements resulting from the personal interaction involved in the treatment or a placebo response. Although electrical stimulation appears to be well tolerated in this population, further research is needed to establish its effectiveness for chronic cancer treatment-related pain. J Pain Symptom Manage 2007;33:410e419. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Electrical stimulation, transcutaneous electrical nerve stimulation (TENS), transcutaneous spinal electroanalagesia (TSE), RCT, chronic pain, breast cancer, cancer pain Address reprint requests to: Karen A. Robb, PhD, MCSP, Division of Applied Biomedical Sciences Research, School of Biomedical and Health Sciences, Shepherds House, Guys Campus, King s College London, London SE1 1UL, United Kingdom. karen.robb@bartsandthelondon.nhs.uk Accepted for publication: September 13, Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Introduction There are many reasons why a patient with breast cancer may experience pain. These include pain associated with the disease, pain associated with the cancer treatments, and associated comorbid conditions. 1 Treatmentrelated pain problems are becoming increasingly recognized and have been investigated by many authors. 2e8 The bulk of this research /07/$esee front matter doi: /j.jpainsymman

2 Vol. 33 No. 4 April 2007 TENS vs. TSE for Chronic Pain in Breast Cancer Patients 411 addresses postsurgical sequelae, such as postmastectomy pain syndrome (PMPS) and highlights that pain can coexist with a range of other symptoms, including sensory disturbances, edema, loss of shoulder mobility, and anxiety and depression. Pain problems following radiotherapy have also been reported in a small minority of women who experience chronic neuropathic pain and severe side effects, including arm weakness and sensory disturbances. Women with radiation-induced brachial plexopathy (RIBP) gained much attention in the last decade and campaigned strongly for improved understanding and better management of their condition. 4 It has been suggested that pain problems following breast cancer treatment are underrecognized and undertreated, 7,9 with many women taking no medication for their pain. Clinical experience suggests that many women are hesitant to take medication due to concerns about unwanted side effects. This is reflected in the literature, with drugs such as amitriptyline showing good analgesic effect but poor side effect profiles. 10 Although cancer pain management predominately uses the biomedical approach, such as drug therapy, or other medical or surgical treatments, 11 there is strong evidence that chronic pain problems demand a more biopsychosocial approach. Evidence for a biopsychosocial model of cancer treatment-related pain has been presented, 12 and recent research has demonstrated the complex, multidimensional nature of cancer treatmentrelated pain and the need for innovative approaches. 13 Transcutaneous electrical nerve stimulation (TENS) has been widely used for many years to manage a range of acute and chronic pain problems. There are currently five Cochrane systematic reviews addressing the use of TENS for noncancer pain, 14e18 as well as excellent review articles. 19e21 There is some controversy over the use of TENS in chronic pain, with most review papers citing the need for further research using large multicenter, randomized controlled trials (RCTs). Unfortunately, when examining TENS use in cancer pain, the evidence is inconclusive, with very few studies and only one systematic review. 22 In recent years, there also has been some attention given to transcutaneous spinal electroanalgesia (TSE), 23 a method of electrical stimulation that uses electrodes placed over the spine and operates at a higher frequency than traditional TENS. With TSE stimulation, there is no sensory stimulation, making it easier to perform blind assessments within a clinical trial. There is a paucity of research evidence on TSE and the underlying mechanisms of action are largely unknown. One RCT examined its use in pain due to critical limb ischemia, 24 but found no improvements in pain or physical activity after regular use for one week. This was a small study and it is clear that further work is needed to evaluate the effects of TSE. We are not aware of any controlled trials that compare nondrug electrical treatments for chronic pain associated with breast cancer. We examined the effect of both TENS and TSE for women with pain problems secondary to breast cancer treatment to establish whether they had potential as part of a multidisciplinary management approach. Methods Study Design This study used a double-blind, randomized, controlled, crossover trial design with a singleblind arm (see Intervention) and was conducted in accordance with the Declaration of Helsinki (Fig. 1). Patients were randomized with the help of a trial assistant and a computer-generated random number chart. Randomization was stratified according to the degree of average pain documented on the Brief Pain Inventory (BPI) question three (see Outcome Measures). Scores were classified based on previous work: 25 mild pain (0e4), moderate pain (5e6), and severe pain (7e10). Sample Patients were eligible for the trial if they had a history of breast cancer and chronic pain for at least six months duration and secondary to treatment for breast cancer. Patients were not eligible if they were under 18 years of age, had evidence of recurrent cancer, were incompetent or unable to follow the author s instructions, had pain due to a neurological condition (e.g., stroke), had complete lack of

3 412 Robb et al. Vol. 33 No. 4 April 2007 Is patient suitable for trial? Yes No Further treatment decided Patient Information Sheet given 2 weeks thinking time allowed Yes Is patient willing to continue No Is more No thinking time required Yes Consent Process Baseline assessment Completion of BPI and HAD Questionnaires Randomization Process a to determine order of treatment (n=49) a Randomization stratified according to average pain (BPI), i.e., mild, moderate, severe. Randomized to 1 of 6 groups of Rx: Gp 1 Gp 2 Gp 3 Gp 4 Gp 5 Gp 6 Gp1) TENS, TSE, Pl; Gp2) TENS, Pl, TSE; (n=9) (n=6) (n=9) (n=10) (n=7) (n=8) Gp3) TSE, TENS, Pl; Gp4) TSE, Pl, TENS; Gp5) Pl, TSE, TENS; Gp6) Pl, TENS, TSE Comprehensive instructions on use of allocated machine 3 weeks of home treatment Review by physiotherapist Completion of assessments and outcome measures No Has patient received all 3 treatments? Yes Final assessment and Patient Satisfaction Questionnaire (n= 41) Review procedure (n= 41) Fig. 1. Summary of trial methodology.

4 Vol. 33 No. 4 April 2007 TENS vs. TSE for Chronic Pain in Breast Cancer Patients 413 skin sensation in the areas to be treated, or had previous experience of TENS or TSE. All patients were given written and verbal information prior to commencing the trial and all gave full verbal and written consent to participate. Patients were advised to keep other pain treatments stable during the trial and a letter was sent accordingly to their general practitioner. Interventions All patients received two potentially active treatments (TENS and TSE) and one placebo in an order determined by randomization. The TENS machines were dual channel stimulators with self-adhesive pads (Spembly Medical Limited). The TSE and placebo machines were manufactured by Advanced Pain Management Ltd. The placebo devices were identical to the active machines but were disabled by the use of disabled wires. The wires were individually coded, and this information was held secure by the trial assistant until the trial was complete. Patients were taught to use each intervention after full assessment. Neither the author (K. R.) nor the patients were aware of when a placebo machine was being used. Procedure for TENS. Patients were requested to put the electrodes in the area of pain identified by prior examination, avoiding areas of anesthesia and/or allodynia. The TENS was selected to operate in continuous mode with a strong but comfortable paresthesia. Clinical experience and the literature suggest that conventional TENS is the most commonly used and we advised high-frequency, lowintensity stimulation. Patients were advised to start off with a short treatment to assess potential side effects and then to use as needed, when in pain. They were encouraged to manipulate TENS parameters to find the optimal treatment parameters for their pain. This method of trial and error reflects routine clinical practice. On completion of this part of the trial, protocol photographs were taken (with verbal and written consent) of preferred electrode placement. Procedure for TSE and Placebo. Instructions on use were based on the instruction booklet, with pain in the neck, arm, or hand treated with two pads paravertebrally at the C3eC4 level, and all pains below treated with two pads over the spinous processes of T1 and T10. Treatment times were advised to be 10e30 minutes on full intensity. The frequency of treatment depended on when pain was experienced. Patients used each treatment at home for three weeks, with a one-week washout period. Patients kept a pain diary reporting date and time of use, parameters of treatment, % pain relief, and analgesics used. Patients were telephoned after one week to monitor progress and were reviewed in person after three weeks. Outcome Measures The main outcome measures used were as follows. The BPI Short Form 26 (our primary measure), measured pain, its interference with daily activities, and pain relief. This was completed at baseline, then weekly thereafter while receiving treatment. Posttreatment assessments were completed at 3, 6, and 12 months. The Hospital Anxiety and Depression (HAD) Scale 27 was completed at baseline, then weekly thereafter while receiving treatment. Post-treatment assessments were completed at 3, 6, and 12 months. Range of movement at the ipsilateral shoulder joint (flexion and abduction in degrees) was measured at baseline and at the end of each intervention. Information from pain diaries documented the use of all three machines, including pain relief and analgesic consumption, and was completed daily. A brief questionnaire was designed to assess patient satisfaction with each intervention and was recorded on completion of all three arms of the trial. Statistical Analysis All data were analyzed using the Statistical Package for Social Sciences Program (SPSS, Version 10, King s College, London, UK). Outcome measures were examined using both descriptive statistics and statistical tests. The main statistical tests used were the Friedman test and the Wilcoxon Signed Ranks test, with some use of the Mann-Whitney and Chi-squared tests. These are well suited to nonparametric

5 414 Robb et al. Vol. 33 No. 4 April 2007 data. 28 Statistical significance was set at an alpha of Results Demographic Data Forty-nine women commenced the trial and 41 completed the study. The reasons for noncompletion were pain increased (n ¼ 2), pain resolved (n ¼ 2), skin reaction (n ¼ 1), and other (n ¼ 3). About 50% of the women had PMPS, approximately 20% had RIBP, and the rest had a mixed clinical picture. The mean age was 58 years (median 59, range 38e60 years) and the mean duration of pain was 51 months (median 31, range 6e182 months). All of the women had received surgical treatment for breast cancer; 93% had also undergone radiotherapy, 37% had received chemotherapy, and 37% had received all three treatments. The majority (87%) were Caucasian, married (61%), and working (44%), as opposed to retired (32%) or not working (24%). The majority had received some form of postoperative physiotherapy (61%). The amount of previous physiotherapy varied greatly and could not always be recalled. Women lost to follow-up were broadly similar. Baseline Measures Median scores for the group are presented, as the data had a skewed distribution. The worst pain score (0e10 VAS) at baseline was 7 (severe), average pain was 6 (moderate), and pain relief with current medications/treatments was 40%. The anxiety score was 8 (borderline abnormal) and the depression score was 5 (normal). The range of ipsilateral shoulder movement was 130 flexion and 140 abduction. The majority of women (34%) were using simple analgesics, 27% were taking World Health Organization Group 2 analgesics, 5% were using Group 3, and 27% were not using any medication at all. Although no statistically significant differences were found in the group lost to follow-up, the median anxiety (11 vs. 8) and depression scores (8 vs. 5) were higher in this group; this was potentially clinically significant and may explain why these women were less able to deal with the demands of the trial. A summary of the baseline measures is shown in Table 1. Table 1 Summary of Baseline Outcome Measures for the 41 Patients Who Completed the Trial Outcome Measure Median Range Worst pain 0e10 7 3e10 Average pain 0e10 6 3e10 Least pain 0e10 4 1e10 Pain relief (%) 40 0e80 Anxiety 0e21 8 0e21 Depression 0e21 5 1e16 Interference score 0e e58 Shoulder flexion a e160 Shoulder abduction a e180 a Degrees of movement. Group Comparisons Maximum, median, and final recorded scores for all outcomes were examined. No significant differences were found between groups for worst pain, least pain, or average pain scores. No significant differences were found in pain relief scores from the weekly BPI or pain diaries. The TENS resulted in significantly lower maximum pain interference scores (Wilcoxon P ¼ 0.04), although there were no significant differences when least and last recorded interference scores were compared. There were no significant differences between groups for anxiety, depression, or shoulder range of movement. When examining the brief questionnaire, TENS was considered significantly more effective than TSE or placebo (Chi-squared P < 0.001) (Table 2). All three machines were considered easy to use and well explained by the majority of women. Twenty-six women (63%) decided to continue with treatment; of these, the majority (51%) requested to continue with the TENS machine, 23% with the TSE, and 33% with the placebo. Overall, few women thought they knew which was the placebo arm. Table 2 Results from the Brief Questionnaire: Effectiveness of Each Intervention Placebo TENS TSE Effectiveness Frequency % Frequency % Frequency % Very effective Effective Not effective Total A significant difference was found between TENS and TSE and TENS and placebo (Chi-squared P < 0.001) when examining the data for patients who scored effective.

6 Vol. 33 No. 4 April 2007 TENS vs. TSE for Chronic Pain in Breast Cancer Patients 415 Pre- and Post-treatment Comparisons Transcutaneous Electrical Nerve Stimulation. Women reported significantly lower worst (P < 0.001) and average pain (P < 0.001), anxiety (P < 0.01), and interference scores (P < 0.001), and significantly greater shoulder flexion (P < 0.05) with use of the TENS. Worst pain scores dropped from the severe to the moderate category and anxiety scores dropped from borderline normal to within the normal range. The increase in shoulder flexion was negligible and showed statistical, but not probable, clinical significance (Table 3). Transcutaneous Spinal Electroanalgesia. Women reported significantly lower worst (P < 0.001) and average pain, (P < 0.001) and interference scores (P < 0.01) with use of the TSE than they did at baseline. Worst pain scores dropped from the severe to the moderate category. Pain relief did not improve with the TSE and a similar result was found to that of the placebo. Placebo. Women reported significantly lower worst (P < 0.01) and average pain (P < 0.001), interference (P < 0.01) and anxiety scores (P < 0.05) with use of the placebo than they did at baseline. Worst pain scores dropped from the severe to the moderate category and anxiety dropped from borderline to within normal range. Analgesic use remained constant in 29 patients (71%) representing all three diagnostic groups. Twelve patients (29%) indicated that their analgesic requirements were less and these patients also came from all diagnostic groups. The majority of this group (58%) reported taking less daily medication. Five patients in this group (42%) managed to discontinue their medication altogether; four of these were using only simple analgesics prior to the trial, although one woman was using strong opioids and adjuvants. Other Important Findings Some important qualitative data emerged from this trial. Formal analysis methods were not used but some clear themes appeared. Other body pains often complicated matters and assessing pain relief was not easy. Psychological factors were considered very important by patients. A majority of women expressed a fear of cancer recurrence, which affected pain and anxiety levels. The most significant finding was that the majority of women (95%), on completion of the trial, reported great benefit from the opportunity to discuss their pain problem(s) in detail, that is, to have their pain validated. They reported dissatisfaction with consultations elsewhere and the majority admitted knowing little about the cause(s) of their pain and the potential for treatment. Long-Term Follow-Up The number of subjects who actually continued with devices on completion of the trial was TENS (n ¼ 15), TSE (n ¼ 5), and placebo (n ¼ 6). This was less than suggested by the brief questionnaire. Five women (12%) died from their disease and the remainder were unavailable. Table 3 Median Values (Range) for Outcome Measures at Baseline and Day 21 for Each Intervention Scores at Baseline and After 21 Days for Each Experimental Group Baseline Median (Range) Placebo Median (Range) TSE Median (Range) TENS Median (Range) Worst pain 0e10 7 (3e10) 6 (1e10) a 6(1e10) b 6(2e9) b Average pain 0e10 6 (3e10) 5 (1e8) b 5(1e8) b 5(1e8) b Least pain 0e10 4 (1e10) 4 (1e9) 3 (1e8) 3 (1e8) Pain relief (%) 40 (0e80) 30 (0e90) 30 (0e100) 50 (0e100) Interference score 0e70 32 (8e58) 22 (7e57) a 27 (7e63) a 22 (7e56) b Anxiety score 0e21 8 (0e21) 7 (0e18) c 6(0e21) 7 (0e17) a Depression score 0e21 5 (1e16) 4 (0e14) 5 (0e16) 4 (0e12) Shoulder flexion ( ) 130 (40e160) 130 (45e170) 135 (45e175) 135 (40e170) c Shoulder abduction ( ) 140 (40e180) 125 (45e180) 135 (40e180) 130 (45e180) Comparisons were made using the Wilcoxon test and statistical significance is shown by superscript ( a P < 0.01; b P < 0.001; c P < 0.05). There were few differences between the three treatments.

7 416 Robb et al. Vol. 33 No. 4 April 2007 Subjects Using TENS. The majority were still using the machine with good effect at 3 (n ¼ 14, 93%) and 12 months (n ¼ 10, 66%). Subjects Using TSE. Three women (60%) were still using the TSE at 3 and 12 months. Subjects Using Placebo. Four (67%) and two subjects (50%) were still benefiting from treatment at 3 and 12 months, respectively. Subjects Who Did Not Continue with a Device. The majority reported no change in pain. Discussion These women were a particularly challenging group of patients, as they displayed the anxieties and concerns so commonly associated with breast cancer survivors, such as fear of recurrence and hypervigilance, and also had characteristics representative of chronic pain patients, such as anxiety and depression, and excessive pain reporting. This meant that the pain problem(s) they described were very individualized and often multifactorial. They were considered to be representative of the breast cancer population of their age, cancer treatment, and social demographics, but there were many pretreatment variables, which may have affected their prognosis. The presence of a chronic treatment-related and painful condition meant that these women were constantly reminded of their disease, probably more so than other breast cancer survivors would be. Much of the literature on pain associated with breast cancer treatment describes the subjects in a similar way. 13 No significant differences existed between the two treatments and placebo using pain report alone. However, examining pre- and posttreatment results, all three interventions improved worst and average pain scores compared with baseline. This may have been regression to the mean, as patients could have entered this trial when their pain levels were high. For worst pain, results were identical for each intervention, clinically significant, and represented a drop from the severe to the moderate pain category. This is an important finding, as pain severity, in particular worst pain, has been shown to be closely linked with pain interference 29,30 and is one of the most important measures in pain research. These results suggest that all three interventions helped control exacerbations of pain throughout a three-week trial, although they did not show that one intervention was more effective. It was evident that patients encountered difficulties with reporting pain relief, as there were inconsistencies between pain relief scores recorded with the pain diaries and the BPI forms. Pain relief for all three interventions was consistently higher with the BPI, which relied on accurate memory of, and the patients ability to summarize, pain relief. It has previously been shown that reports of perceived pain relief do not necessarily reflect true changes in pain. 31 This is probably true for this study, as pain relief scores did not reflect the changes in pain report during treatment with each intervention. It was difficult to analyze improvements in psychological status, as the baseline scores were not particularly high. Although statistical analysis revealed no significant differences between groups, comparisons of pre- and posttreatments highlighted that after TENS and placebo, patients were scoring lower anxiety scores (the TSE result was almost significant). There are three possible reasons for this, which may coexist and all have potential clinical significance: 1. The reduction in anxiety scores was related to the pain reports. If patients were experiencing less pain with treatments, they would presumably have felt less anxiety and more positive about their condition. 2. Patients gained an internal locus of control with the use of these machines. Sense of control has been an important feature in the study and management of chronic pain. 32,33 Use of devices such as TENS is, in some respects, a self-management approache, as they encourage more active patient participation. 3. The reduction in anxiety scores was related to pain interference (see below). As basic functioning improved, patients felt more positive as they were able to do more and this may have alleviated some of their anxiety.

8 Vol. 33 No. 4 April 2007 TENS vs. TSE for Chronic Pain in Breast Cancer Patients 417 It is important to recognize that the majority of women reported great benefit from the opportunity to have their pain validated. This has great significance, as it identifies an important clinical need. The therapeutic value of offloading pain problems to an experienced health care professional with an interest in pain, the time to discuss matters fully, and the skill to recommend treatment options has been recognized and has been reported with strong emphasis. 34 The authors believe that health care professionals with knowledge of oncology and pain are ideally suited to such a therapeutic intervention, but also recognize that the management of such patients can be time-consuming and emotionally demanding. This level of therapeutic involvement may not be possible in many nonspecialist centers. Previous research has shown that interference and worst pain scores are positively correlated. 29,30 All machines resulted in an improvement in scores from baseline. Reductions in pain interference meant that patients were more able to perform activities of daily living without difficulty while using the machines. This may have a direct effect on improving quality of life. Although no clinically significant improvements in arm mobility were found, it is important to recognize that arm morbidity was related to other factors, such as fibrosis from surgery and radiotherapy. Not all women had received physiotherapy post-treatment for breast cancer and many were concerned about losing functional ability. This suggests a clear need for physiotherapy review to support physical and psychosocial needs, as suggested by previous authors. 4,35 Generally, it appears that patients found all machines easy to use and very few reported difficulties with electrode placement. The help of friends, family or carers was sometimes necessary. On the whole, electrode placement was found to be satisfactory. Although the majority of patients (n ¼ 26, 63%) chose to continue with their preferred intervention and most of them chose TENS (n ¼ 15, 58%), it is important to recognize the six patients who chose the placebo as their preferred treatment, as the power and significance of placebo treatments are well documented. 36,37 The longterm follow-up data, however, indicated that in two patients, the beneficial effects of placebo machines lasted for one year after the trial. This is a surprising finding and the authors are not aware of any other studies, which have investigated long-term effects of placebo electrical stimulation. There are several acknowledged limitations to this study. Although blinding procedures were in place, assessments were not blinded and the assessor knew when a TENS machine was supplied. Both of these factors could have added bias to the results. Low patient numbers reduced the statistical power of the study and subjects were a heterogeneous group, which is a common problem with pain research and can make interpretation difficult. It was impossible to guarantee compliance with interventions and future work should use devices with built-in monitoring of usage time. A criticism could be that treatment was not standardized, but the authors believe that allowing patients to use trial and error and dose titration is a more sensible approach, as it mimics accepted clinical practice. Finally, follow-up assessments may have been more informative if done in person as opposed to over the telephone, although this would have been time-consuming. Overall, results from this study indicate that electrical stimulation is well tolerated in women with chronic pain related to breast cancer treatment and warrants further study. The majority of women improved as a result of the trial. One interpretation of our results could be that the methods of real stimulation were no better than placebo. There is insufficient evidence to suggest that TENS is more effective than TSE or placebo although the majority of patients chose to continue with this device. The reason for improvements remains unclear, but the most obvious possibilities are psychophysical improvements due to the personal interaction or a placebo response. There are some potentially important implications for clinical practice. The multidisciplinary team has an important role in the management of chronic pain associated with breast cancer treatments. The importance of their involvement with breast cancer patients at the immediate and later postoperative/postradiotherapy stage must be recognized. It seems important to educate patients about movement and exercise and pain management

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