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Transcutaneous electrical nerve stimulation for treatment of sarcoma cancer pain

Practice Points

Jeffrey Loh*1 & Amitabh Gulati2 „„ The application of transcutaneous electrical nerve stimulation (TENS) at neurotomal or myotomal patterns

for sarcoma-related pain may be a safe and effective method of increasing functionality and reducing pain. „„ TENS in a high-frequency setting (greater than 80 Hz) tends to have good efficacy in pain control. „„ While clinically significant pain improvement (greater than 30% on the visual analog scale) may not

always be achieved, it is common to see functional improvement during the activation of TENS. „„ Educating patients to use TENS treatments for daily use during painful activity, usually four- to six- times

a day for 30–60 min for each application, is advised. „„ A trial visit seems to improve compliance and success of TENS in cancer patients suffering from pain and

dysfunction.

SUMMARY Background: Pain is often the initial presenting symptom with sarcomas. Upon resection of a sarcoma, most patients experience a resolution of their pain. However, in those patients with continued pain, treatment often requires multiple medications with moderate benefit. Aims: The authors present eight  patients who suffer from continued sarcoma-related pain following resection of their initial cancer. Methods: For each patient, we describe the use of transcutaneous electrical nerve stimulation (TENS) for the treatment of sarcoma-related pain. Each patient was brought to the pain clinic for an initial four-lead trial of TENS lasting 30 min to determine the TENS setting that provided greatest pain relief. Patients were educated about the application and use of their TENS unit, which they selfutilized at home. Patients’ pain response was monitored prior to the initial TENS trial and after 2 months of TENS use. Results: Seven out of eight patients had a qualitative or quantitative reduction in their sarcoma-related pain. Three out of the seven patients demonstrated clinically significant (>30%) pain relief, while the other four patients demonstrated increased physical functionality and pain relief, during movement and rest. No patients experienced any adverse effects; however, TENS was stopped in one patient who had a beneficial response to TENS as that patient was found to have recurrent, widespread metastases of her sarcoma. Conclusion: Initial results indicate that TENS provides an easy-to-use, inexpensive t­herapeutic tool that can be used an adjunct in the treatment of sarcoma-related cancer pain. Future studies consisting of a large, randomized trial will be necessary to validate the efficacy of TENS in this patient population. Department of Anesthesiology & Pain Management, University of California Los Angeles, 1245 16th Street, Suite 225, Los Angeles, CA 90404, USA 2 Department of Anesthesiology & Critical Care, Memorial Sloan Kettering Cancer Center, New York, NY, USA *Author for correspondence: Tel.: +1 310 794 1841; Fax: +1 310 319 2263; [email protected] 1

10.2217/PMT.13.15 © 2013 Future Medicine Ltd

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case report  Loh & Gulati Soft tissue sarcomas present a unique challenge in the treatment of cancer pain. Approximately 2380 new cases of bone cancer and 10,390 cases of soft tissue sarcomas are diagnosed annually in the USA [1]. The initial and most common presenting symptom for these cancer patients is pain [1–5]. While surgical resection of the sarcoma can often provide improved pain relief [5], in certain sarcomas, 54% of patients continue to experience pain that is unrelieved with analgesics [6]. Transcutaneous electrical nerve stimulation (TENS) is a safe, noninvasive modality for the treatment of pain. Studies have verified the efficacy of TENS in the treatment of acute and chronic pain [7]. However, studies on the use of TENS in cancer pain are lacking [8]. Recent studies on metastatic bone cancer pain have shown decreased movement-related pain in patients with the use of TENS [9,10]. Currently, no studies have evaluated the efficacy of TENS in the treatment of sarcoma-related cancer pain. The authors present a case series of TENS used in the treatment of sarcoma-related cancer pain, specifically detailing the different methods by which to apply TENS and the different methods by which TENS may work. Methods Eight patients suffering from refractory sarcomarelated cancer pain received TENS as a possible adjunct in the treatment of their pain. In each case, patients had no history of seizures and

had no implanted stimulating device (such as a cardiac pacemaker). Patients were usually on a multimodal treatment plan, and had a focal area of pain that was not fully managed with their current treatment. The primary TENS device used was the EMPI® Select™ DJO Global (EMPI, MN, USA) device; however, no financial arrangement was established with the ­company for this study. Each patient was brought to the pain clinic for a single trial of TENS. At each trial, the authors determined the TENS settings and intensities that provided a noticeable improvement on pain perception and functional abilities, by examining the efficacy of pain relief obtained for each of the preset TENS settings provided, and by adjusting the current applied. Each patient trial consisted of a four-lead trial performed for 30 min. Electrode pads (2.0 × 3.5 inch) were typically applied over the region of discomfort. In patients where the electrode pad would not fit over the region of discomfort, the pads were applied at a location that provided neural innervation to the affected region. Electrode pad placement was also adjusted in patients with one-sided buttock pain, such that two out of the four pads were placed around the sacroiliac joint. Only high-frequency TENS (greater than 80 Hz) was offered to patients. Patients reporting subjective pain relief during the TENS trial were educated in using the TENS unit for a minimum of four- to sixtimes a day for 30 min to 1 h. Patients selected their own settings at home, using a strong, but

Table 1. Demographics of transcutaneous electrical nerve stimulation sarcoma patients. Patient

Age (years)

Sex

Pain medications

Pain location

TENS setting

1 2

57 52

F M

Low back and left groin Left knee

Low back Knee

3

72

M

Right neck/shoulder

Back

4

27

F

Left hand

Hand/wrist

5

70

F

Oxycodone Oxycodone ER and oxycodone Fentanyl and hydrocodone plus acetaminophen Fentanyl, hydrocodone plus acetaminophen, and gabapentin Methadone and oxycodone

Low back/hip

6

62

M

Low back and left buttock Low back and left knee

7 8

49 76

F F

Left neck/shoulder Right buttock

Back Low back/hip

Methadone, pregabalin and hydromorphone Methadone and pregabalin Oxycodone plus acetaminophen, and gabapentin

Low back/hip

ER: Extended release; F: Female; M: Male; TENS: Transcutaneous electrical nerve stimulation.

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Transcutaneous electrical nerve stimulation for sarcoma pain  comfortable, intensity. The EMPI device has five presets that patients could choose with ease regarding their active settings. Patients were taught how to change between continuous, burst and various modulation settings and time points; however, the device has an internal setting for pulse width that is not user controlled. As pain relief from TENS is typically rapid in onset, and the duration of relief can often be short lasting in nature, patients were advised to apply electrodes in the morning and remove them at night, allowing them to use the device as needed throughout the day. Prior to the trial, patients were given a standard pain questionnaire at the authors’ institution, which incorporated a visual analog scale (0–100 mm continuous measured scale) score, numerical rating pain scale, portions of the McGill pain questionnaire (a set of 15 neuropathic pain symptoms in the following scale: none/mild/moderate/severe), and the

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Table 2. Outcomes of transcutaneous electrical nerve stimulation in sarcoma patients. Patient

TENS successful

Post-TENS course

1 2 3

Yes Yes Yes

Pain qualitatively improved Decreased opioid requirements Pain decreased by 16.7%

4 5 6 7 8

Yes Yes Yes Yes No

Pain resolved 100% Pain decreased by 50% Pain decreased by 85% Pain decreased by 10% Pain unchanged

TENS: Transcutaneous electrical nerve stimulation.

Brief Pain Inventory short form questionnaire. Re­a ssessment of the patient’s response occurred between 1 and 2 months. Functional improvement was also recorded at the revisit. Written approval for use of the short form McGill q­uestionnaire was obtained for use in this study.

Front view

Back view

TENS unit

R

L

L

R

Figure 1. Arrangement of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for lumbar paraspinal pain. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation.

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case report  Loh & Gulati Front view

R

Back view

L

L

R

TENS unit

Figure 2. Arrangement of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for knee pain. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation.

Results Eight case presentations are presented below. In all cases but one, TENS demonstrated clinical efficacy in improving pain symptoms, both at movement and rest, per patient report. However, when quantitatively analyzing the improvements made by patients, only three patients demonstrated clinically significant changes in pain reduction scores (>30% pain relief). Both visual analog scale and numerical rating pain scores were used to determine whether patients had quantitative improvement. In the four other cases where patients reported benefit, improvements were seen either through improved physical functionality or decreases in pain medication consumption. In the seven cases where TENS proved beneficial, therapy was stopped for one patient. That patient was discovered to have recurrent, widespread sarcoma at locations other than at the TENS application site. All other patients otherwise experienced no adverse affects with the use of TENS. TENS

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demographics can be seen in Table 1 and TENS outcomes can be seen in Table 2. „„ Case 1

A 57-year-old woman with a history of myxofibro­sarcoma of the left groin underwent two soft tissue resections of her left groin region. The patient complained of low back pain and left groin pain that radiated to her anterior thigh and caused cramping of her left buttock. Her pain was worsened by her radiation therapy, and her medication regimen consisted of oxycodone and gabapentin. TENS electrode pads were applied to her paraspinal muscles bilaterally at L2 and L5 (Figure 1). At her 2-month follow-up, the patient reported no quantitative change in her pain, but did note a qualitative improvement of her pain. „„ Case 2

A 52-year-old man with a history of malignant fibrous histiosarcoma underwent two soft

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Transcutaneous electrical nerve stimulation for sarcoma pain  tissue resections of his left femur. The patient’s postoperative pain was controlled with oxycodone extended release and oxycodone, but the patient complained of worsening stiffness at his surgical site. TENS electrode pads were applied to the four quadrants of his left knee (Figure 2). At the 2-month follow-up visit, the patient’s pain severity remained unchanged. However, the patient was able to decrease his oxycodone extended release consumption by 33% and was able to fully eliminate his use of oxycodone. The patient also noted an increased range of mobility in his knee with the use of TENS. „„ Case 3

A 72-year-old man with a history of fibrosarcoma of his right upper extremity. The patient had an above the elbow amputation, with good postoperative pain control on cyclobenzaprine and acetaminophen. The patient complained

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of new onset shoulder and neck pain due to impaired mobilization of his shoulder. TENS electrode pads were applied over his right rotator cuff insertion point and his right trapezius musculature (Figure 3). By 2 months, pain severity decreased by 16.7% and the patient reported improved mobility in his right shoulder. „„ Case 4

A 27-year-old woman with epithelial sarcoma of her left hand underwent soft tissue resection of her left palm. Upon starting post­operative hand therapy, the patient noted increasing pain, uncontrolled with hydrocodone plus acetaminophen, baclofen and a fentanyl patch. TENS electrode pads were applied to the anterior and posterior aspect of her left upper arm, as well as along the lateral aspect of her left trapezius muscle (Figure 4). By her 2-month visit, the patient reported complete resolution of her pain with the use of TENS (Table 2).

Front view

Back view

TENS unit

R

L

L

R

Figure 3. Arrangement of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for right neck and shoulder pain. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation.

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case report  Loh & Gulati Front view

Back view

TENS unit

R

L

L

R

Figure 4. Arrangement of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for left hand pain. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation. „„ Case 5

A 70-year-old woman with chronic back and pelvic pain continued to suffer from muscular and scar pain after resection of a myxofibro­sarcoma of her left leg. Her medication regimen consisted of methadone and oxycodone, which provided moderate pain relief. TENS electrode pads were applied bilaterally to her L3–L5 para­spinal region (Figure 1). At her 2-month follow-up visit, the patient reported a 50% decrease in pain with the use of TENS. „„ Case 6

A 70-year-old man with history of chordoma complained of low back and sacral pain associated with a nonhealing operative wound related to his radiation therapy. The patient also had a history of left knee pain after enduring multiple knee surgeries. His medication regimen consisted of methadone, hydromorphone and pregabalin, which resulted in

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unwanted sedation and moderate pain relief. Two TENS electrodes were applied to his low lumbar/sacral region and two electrodes were applied to his left knee (Figure 5). At his 2-month follow-up visit, the patient reported a decrease in his pain by 85%. „„ Case 7

A 49-year-old woman with a history of metastatic myxoliposarcoma underwent resection of her sarcoma at multiple sites. The patient presented with neck pain and an associated C7 radiculopathy that was unimproved by pregabalin and acetaminophen with codeine. The patient had two TENS electrodes applied to her left paraspinal muscle at C6 and T1 and two electrodes placed at the proximal aspect of the lateral malleous and the distal aspect of the antecubital fossa (Figure 6). The patient reported a 10% decrease in her pain by 2 months, but treatment was stopped out of safety concerns, as the

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Transcutaneous electrical nerve stimulation for sarcoma pain  patient was found to have metatstatic recurrence of her disease at sites other than where TENS was applied. „„ Case 8

A 76-year-old woman with a history of malignant fibrous histiocytoma that required multiple resections with the patient eventually undergoing a right hemipelvectomy. The patient post­ operatively suffered from phantom limb pain that was minimally improved with carbamazepine, sublingual fentanyl and gabapentin. Two TENS electrodes were applied to her right buttock region along the path of her sciatic nerve (Figure 7). At her 2-month follow-up visit, the patient reported no improvement in her pain had discontinued the use of her TENS unit. Discussion The treatment of sarcoma pain with the use of TENS is an application for cancer pain,

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to the authors’ knowledge, that has not been described. In all cases but one, TENS provided a quantitative or a qualitative improvement in a patient’s cancer pain. TENS is thought to stimulate large diameter afferents (A-b nerve fibers), which subsequently inhibits nociceptive fiber (A-d and C fiber) evoked responses in the dorsal horn [11,12]. Chen and Johnson show that high-frequency TENS (80 pulses per second) elevated pressure-pain thresholds greater than low-frequency TENS (3 pulses per second), as a stronger afferent input to the CNS created a stronger segmental inhibition of nociceptive transmission of second-order neurons [13]. Alternative mechanisms of pain relief by TENS have been proposed. Marchand et al. describe caffeine, an adenosine receptor ant­ agonist, effectively inhibiting the analgesic effects of TENS [14]. Thus, adenosine, which is commonly found in larger diameter neurons, may have a role in the analgesic effects of TENS.

Front view

Back view

TENS unit

R

L

L

R

Figure 5. Arrangement of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for low back and left knee. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation.

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case report  Loh & Gulati Front view

Back view

TENS unit

R

L

L

R

Figure 6. Arrangement of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for left neck and arm pain. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation.

Han et al. showed that low-frequency TENS stimulates the release of methionine enkephalin, while high-frequency TENS stimulates the release of dynorphin A, both of which are agonists for different subtypes of opioid receptors [15]. Studies have further defined the specific receptors activated by TENS with low-frequency TENS producing antihyperalgesia through µ opioid receptors and high-frequency TENS producing anti­hyperalgesia through d opioid receptors, both at the spinal and supraspinal level [16–18]. In many of the authors’ patients, decreased use of opioids was observed. While TENS definitively modifies pain perception at a central level, TENS also affects pain at a peripheral level [11,19]. This dual location for pain modification allows TENS to be applied along multiple different stimulation points. Studies have shown that TENS applied to Chinese acupoints or to dermatomes effectively increases a subject’s pain threshold [20], and

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effectively lowers postoperative pain in surgical patients [21–23]. Acupoint application of TENS has also been shown to effectively increase the functional capabilities in patients suffering from neurological deficits post-stroke [24,25]. TENS has also proven to be effective in the treatment of acute and chronic pain when applied to a region innervated by a specific peripheral nerve [26,27]. The efficacy of TENS at different application points proved beneficial, as the authors were able to effectively treat the patients’ pain at the dermatomal or peripheral nerve level depending on their clinical presentation. The effect of TENS on blood flow remains unresolved. Recent studies indicate that elevated blood flow at the TENS stimulus site is the result of increased muscle activity, and that high-frequency or low-frequency TENS below motor threshold have no clinically significant effect on blood flow [28,29]. As tumor growth is dependent on angiogenesis and blood flow [30,31], the effect

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Transcutaneous electrical nerve stimulation for sarcoma pain  of TENS on blood flow in the cancer population is controversial. Although, the authors feel high-frequency TENS (above 80 Hz) should have minimal effect on blood flow and feel this is safe in their treated patient population, they discontinued TENS in their patient with recurrent metastatic disease, as no standards of care regarding the use of TENS in patients with active cancer have been determined. The authors initial results prove promising for the use of TENS in the treatment of sarcomarelated cancer pain. TENS provides an easy, inexpensive method for treating pain with minimal risk to the user. Further research is needed to determine the efficacy of TENS in this patient population, with our initial results supporting the development of larger clinical trials. Given the difficulty of implementing and blinding placebo TENS, the authors believe future trials of crossover design would best establish the efficacy of TENS on sarcoma pain.

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Conclusion & future perspective In our clinical setting, our case series indicates the potential to improve pain and quality of life in patients with bone pain from sarcoma with the use of TENS. We believe a clinical trial educating the patient in the use of TENS is an effective method for TENS to be introduced as a treatment modality. The use of TENS as a goal-directed therapy to improve functionality seems to be the best use of TENS in sarcoma patients. Further research involving TENS is needed in a randomized or crossover fashion in a prospective study to better identify the use of TENS in the cancer pain population Informed consent disclosure The authors state that they have obtained verbal and written informed consent from the patients for the inclusion of their medical and treatment history within this case report.

Front view

Back view

TENS unit

R

L

L

R

Figure 7. Arrange of transcutaneous electrical nerve stimulation electrode pads and stimulation leads for buttock pain. L: Left; R: Right; TENS: Transcutaneous electrical nerve stimulation.

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case report  Loh & Gulati Financial & competing interests disclosure This case report was funded by the Department of Anesthesiology and Critical Care at Memorial Sloan Kettering Cancer Center. The authors have no other relevant affiliations or financial involvement with any organization or nerve stimulation (TENS) for cancer bone pain. J. Pain 11(4), 351–359 (2009).

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