Benefit of Tonic Versus Burst Spinal Cord Stimulation for Chemo-Induced Peripheral Neuropathy Using Psychophysical Testing

Benefit of Tonic Versus Burst Spinal Cord Stimulation for Chemo-Induced Peripheral Neuropathy Using Psychophysical Testing | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Benefit of Tonic Versus Burst Spinal Cord Stimulation for Chemo-Induced Peripheral Neuropathy Using Psychophysical Testing Saba Javed, Serena Jiyeon Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5915887/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Chemotherapy-induced peripheral neuropathy (CIPN) presents a significant challenge in various chemotherapy treatments. CIPN manifests with symptoms such as numbness, tingling sensations, persistent shooting or burning pain, loss of sensation, muscle weakness, and impaired balance in the extremities. Its incidence is reported to be as high as 68% within the first month of chemotherapy and remains at 60% after three months. Current management strategies lack a universally accepted gold standard, with approaches like physical therapy, anticonvulsants, and other non-pharmacological therapies showing limited efficacy. Consequently, there is an urgent need for an effective non-pharmacological treatment option for CIPN, which would significantly benefit patients undergoing cancer treatment. There have been limited investigations into the potential of spinal cord stimulation (SCS) to enhance neuropathy and neurological function in patients with chemotherapy-induced peripheral neuropathy (CIPN), and there is a scarcity of studies examining the effects of SCS specifically on CIPN. Therefore, this proposed study aims to evaluate the effectiveness of burst versus tonic spinal cord stimulation in addressing chemotherapy-induced peripheral neuropathy. The study will assess changes in pain scores, pain medication consumption, sensory and physical function, patient-reported outcomes, and the composition of peripheral nerves and mechanoreceptors before and after spinal cord stimulation. The research holds promise in reducing the reliance on opioids in CIPN patients, making it a crucial endeavor for affected individuals and society at large. Ultimately, this will mark the first randomized, controlled trial to investigate the efficacy of tonic versus burst SCS waveforms for managing CIPN, with a focus on improving pain, sensory function, and reducing pain medication consumption. Trial registration : ClinicalTrials.gov, NCT06121232. Registered 2 November 2024, https://clinicaltrials.gov/study/NCT06121232?term=saba%20javed&rank=4 Chemotherapy-induced peripheral neuropathy (CIPN) Spinal cord stimulation (SCS) Burst stimulation Tonic stimulation Neuromodulation Pain management Quantitative sensory testing (QST) Gait analysis Epidermal nerve fiber density (ENF) Meissner’s corpuscles 1 INTRODUCTION 1.1 Study Rationale and Justification Chemotherapy-induced peripheral neuropathy (CIPN) is a challenging complication of many chemotherapeutic regimens (vinca alkaloid, taxanes, bortezomib), characterized by numbness, tingling sensations, persistent shooting, stabbing, burning pain or loss of cutaneous sensation, extremity muscle weakness, and impaired balance in the extremities [1]. The incidence of CIPN is reported in up to 68% within the first month (of chemotherapy), 60% at three months, and 40% at six months after chemotherapy [2]. Mechanism is thought to be due to microtubule disruption, impairing axonal transport leading to Wallerian degeneration, and causing hyperexcitability of peripheral neurons. CIPN is conventionally managed with antidepressants, antiepileptics, and adjuvants. Unfortunately, CIPN can be refractory to medications, and patients who fail conservative therapies may consider alternative options such a spinal cord stimulation (SCS). The role of spinal cord stimulation has previously been reported scarcely for improvement of neuropathy and neurologic function for CIPN [3, 4]. Tonic and burst stimulation are two subliminal waveforms used for SCS [5]. Although a commonly proposed mechanism is the gate control theory, new mechanisms proposed may indicate some association with unique waveform paradigms. While stimulation of the dorsal column is widely acceptable for tonic stimulation, burst stimulation has shown to activate both the lateral and medial aspects of the spinothalamic tract [5]. Besides the gate control theory, analgesia from SCS may also be explained by its modulation of neurotransmitters (cholinergic, serotonergic, and opioidergic pathways), depression of wide dynamic range neurons, and activation of supraspinal levels from orthodromic dorsal column action potentials [4]. Although burst stimulation has shown to be superior to tonic for patients with back pain, there is no reported data available for CIPN [5]. The challenge of studying SCS or any interventional pain therapies is placebo effect and having limited objective measures to measure improvement. Additionally, there are very limited mechanistic studies available looking at the impact of neuromodulation on peripheral nerve density. For the first time, we propose using subliminal tonic stimulation with burst stimulation and comparing with sham group to account for placebo. Additionally, we propose using functional assessment tools (gait and QST) to measure and correlate subjective pain scores with objective improvement in functional status. Lastly, we propose taking skin biopsy samples before and after spinal cord stimulation to study changes in epidermal nerve fibers (ENFs) and Meissner’s corpuscles (MC) using immunohistochemistry (IHC). This study will advance the field of interventional pain medicine research by providing insight into (1) which subliminal waveform is more beneficial for CIPN, (2) how the pain scores compare to functional improvement, and (3) provide mechanistic understanding of change in nerve density and recovery after SCS in CIPN. Our long-term goal is to understand the mechanism of CIPN at the neuronal level and use psychophysical studies (quantitative sensory testing and gait testing) to objectively assess the effects and applications of different neuromodulation techniques (dorsal root ganglion stimulation and peripheral nerve stimulation) on CIPN. We hypothesize that burst spinal cord stimulation will be superior to tonic stimulation as measured by pain improvement and functional improvement (gait and QST). Figure 1 shows the conceptual framework of this proposal. AIM 1: Compare the effect of burst versus tonic spinal cord stimulation on the primary endpoint, short-term changes in pain scores (i.e., pain changes between baseline and 30-days post treatment), for chemotherapy induced peripheral neuropathy. Hypothesis : We hypothesize burst SCS to be superior to tonic by resulting in significant decrease in pain score. This hypothesis is based on our preliminary findings (discussed in prelim results) suggesting burst stimulation results in better pain relief. AIM 2: Compare the effect of burst versus tonic spinal cord stimulation on secondary endpoints, including long-term changes in pain scores (i.e., pain changes between baseline and 90-days post treatment), as well as short-term and long-term changes in morphine equivalent daily dose (MEDD), NIH-PROMIS, functional status using gait and QST, and nerve density using skin biopsy samples to analyze epidermal nerve fibers and Meissner’s corpuscle density for chemotherapy induced peripheral neuropathy. Hypothesis : We hypothesize there to be greater improvement in functional status (gait testing and QST) and regrowth of peripheral nerve density after burst than tonic stimulation. AIM 3: Compare the effect of spinal cord stimulation versus sham stimulation on the short-term primary and secondary endpoints for chemotherapy induced peripheral neuropathy. Hypothesis : We hypothesize SCS to be superior to sham stimulation. Completion of these studies will provide first ever comprehensive analysis of the benefit of SCS for CIPN and provide tangible data on functional benefit (QST and gait), which may be used as tools for purposes of diagnoses or disease progression. Nerve fiber analyses can elucidate CIPN mechanism. Finally, this proposal will provide me with the opportunity to gain valuable, mentored experience in clinical research and will help me to cultivate a career as a successful, independent investigator. 1.2 Background Chemotherapy-induced peripheral neuropathy (CIPN) is a challenging complication of many chemotherapeutic regimens. It is most commonly associated with three types of cancer treatment: vinca alkaloid, taxanes and bortezomib. CIPN is characterized by numbness, tingling sensations, persistent shooting, stabbing, burning pain or loss of cutaneous sensation, extremity muscle weakness, and impaired balance. The incidence of CIPN is reported up to 68% within the first month (of chemotherapy), 60% at three months, and 40% at six months after chemotherapy [2]. Onset of CIPN may require chemotherapy dose reduction or cessation, which can increase cancer-related morbidity and mortality [6]. Additionally, average healthcare costs were $17,344 higher for CIPN patients than their non-CIPN counterparts annually [6]. There is no Food and Drug Administration (FDA) approved therapy management of CIPN; however, CIPN is conventionally managed with antidepressants, antiepileptics, and adjuvants. Quality evidence is lacking regarding management of CIPN. Most conventional neuropathic treatment are not supported by clinical trials and are often unsuccessful. Spinal cord stimulation (SCS)) is FDA approved for treatment of failed back surgery syndrome, lumbar radiculopathy or complex regional pain syndrome and is emerging as a potential treatment for CIPN [3]. A few case reports and series have reported the use of SCS in management of CIPN [4, 7]. While these case reports relied mostly on patient-reported outcomes, there has not been any objective, functional improvement outcomes reported. Additionally, data on use of tonic versus burst SCS for CIPN is completely lacking. Scientific premise: The underlying principle supporting this proposal is to explore the benefit of tonic versus burst SCS in CIPN is based on our preliminary findings (discussed below) and on premise that burst stimulation has shown superiority for complex regional pain syndrome and other neuropathic pain syndromes [5]. We hypothesize that burst SCS will be superior to tonic SCS, both of which will be superior to sham stimulation, based on the following premise: a) Use of SCS stimulation for treatment of lower extremity CIPN We recently submitted a case series of patient with painful CIPN who underwent SCS for lower extremity painful CIPN revealing significant improvement in numerical rating scores (NRS) pain scores. Previously our similar study on successful outcomes of dorsal root ganglion stimulation (DRG-S) for lower extremity CIPN exhibited similar findings ( Figure 2 ) [8]. Different waveforms of stimulation and their mechanism was not the scope of the article, which is what we intend to study now. [INSERT FIGURE 2 HERE] b) Psychophysical testing to elicit mechanism. Recently, quantitative sensory testing (QST) has shown some feasibility in sorting between specific fiber type and differentiate between light touch/vibration (large myelinated A-beta fibers), vs. pin-prink/warm/cool (small myelinated A-delta fibers) fibers [9, 10]. Furthermore, gait assessment has shown some feasibility in CIPN, as gait testing revealed slower gait velocity, shorter step time, longer timed walking tests compared to matched controls [11, 12], as well as increased patient-reported response times [13]. In my current proposal, we propose using this premise of QST and gait testing and incorporating it to objectively measure functional outcome and further elicit mechanism of CIPN and impact of spinal cord stimulation on neuropathy. c) Meissner’s corpuscle (MC) and epidermal nerve fibers (ENFs) are potential neural targets to elucidate mechanism of CIPN associated neuropathic pain. The use of immunohistochemistry (IHC) and microscopy for evaluation of changes in MC and ENF density can be useful in neuropathic states. Morphological and quantitative changes in peripheral nerves have proven useful for serial monitoring, progression, and recovery in neuropathy due to diabetes, HIV, and idiopathic disease [14, 15]. Measurement of changes in nerve density (MC and ENF) using immunohistochemistry has shown promise as a tool to measure disease progression for CIPN. Our current proposal will continue to collect data on patients with lower extremity CIPN and measure changes in nerve density before and after SCS to measure its impact. INNOVATION: Our study has several innovative aspects. This study will advance the field of interventional pain medicine by providing insight into (1) which subliminal waveform is more beneficial for CIPN, (2) how the pain scores compare to functional improvement, and (3) provide mechanistic understanding of change in nerve density and recovery after SCS in CIPN. Our long-term goal is to understand the mechanism of CIPN at the neuronal level and use psychophysical studies (QST and gait) to objectively assess the impact of different neuromodulation techniques (dorsal root ganglion stimulation and peripheral nerve stimulation) on CIPN. 2 OBJECTIVES 2.1 Objective Compare the effect of burst versus tonic spinal cord stimulation on the primary endpoint, short-term changes in pain scores (i.e., pain changes between baseline and 30-days post treatment), for chemotherapy induced peripheral neuropathy. 2.2 Secondary Objectives Compare the effect of burst versus tonic spinal cord stimulation on secondary endpoints, including long-term changes in pain scores (i.e., pain changes between baseline and 90-days post treatment), as well as short-term and long-term changes in morphine equivalent daily dose (MEDD), NIH-PROMIS, functional status using gait and QST, and nerve density using skin biopsy samples to analyze epidermal nerve fibers and Meissner’s corpuscle density for chemotherapy induced peripheral neuropathy. Compare the effect of spinal cord stimulation versus sham stimulation on the short-term primary and secondary endpoints for chemotherapy induced peripheral neuropathy. 2.3 Study Type In this prospective study, 33 patients with CIPN of lower extremity will be randomly assigned using block randomization to one of the three study arms: tonic stimulation, burst stimulation or sham stimulation. After 30-days, the sham group will be randomly assigned to one of the two stimulation groups and followed for 90-days for assessment. The allocation sequence for randomization will be generated by the research coordinator using the OnCore system. Participants will be enrolled by the research coordinator and allocation details will be communicated to them via telephone to ensure allocation concealment. All three groups will undergo spinal cord stimulator (SCS) implantation, so patients will remain blinded to the type of stimulation they are receiving (tonic, burst, or sham). Since all three stimulation techniques are subparesthesia, patients will not know whether they are receiving tonic, burst, or sham stimulation. Patients will be unblinded at the end of the study (90 days). Hypothesis : We hypothesize burst SCS to be superior to tonic by resulting in significant decrease in pain score. This hypothesis is based on our preliminary findings (discussed in prelim results) suggesting burst stimulation results in better pain relief. Hypothesis: We hypothesize there to be greater improvement in functional status (gait testing and QST) and regrowth of peripheral nerve density after burst than tonic stimulation. Hypothesis : We hypothesize SCS to be superior to sham stimulation. 3 STUDY METHODS 3.1 Study Methods From patients meeting the inclusion criteria, we will recruit total 33 participants; planning for a 5% attrition rate (Figure 1). We anticipate 10 patients per group will complete the study to be evaluable. Thirty-three patients will be randomized to one of the 3 groups (tonic stimulation, burst stimulation, sham stimulation). Patients are permitted to continue certain concomitant interventions during the study, including physical therapy, over-the-counter medications, neuropathic pain medications (e.g., gabapentin, pregabalin, tricyclic antidepressants), anti-inflammatory pain medications, and muscle relaxants. Steroid injections are prohibited throughout the study duration. They will complete NRS pain score, MEDD, NIH-PROMIS, gait, QST testing as well as skin biopsy at baseline. Thereafter, patients with successful SCS trial (>50% improvement in pain) will undergo SCS implantation. Within the therapeutic stimulation group, repeat assessment (NRS pains score, MEDD, NIH-PROMIS-29, gait, QST, and skin biopsy) will be performed at 30 days post-implantation stimulation and 90 days post-implantation stimulation. Within the sham stimulation group, after 30-days post sham stimulation, patients will be randomized to either tonic or burst and followed for 90 days for assessment. Standard tonic stimulation settings are as follows: range of frequency is 30 to 120Hz, with a pulse width ranging from 200 microseconds up to 500 microseconds. Standard burst stimulation settings as follows: frequency is set at 40Hz, intra-burst rate is 500Hz, pulse width at 1000 microseconds. With sham stimulation, the stimulation parameters will be set to null. All 3 groups are subliminal. Note: the procedure steps for SCS trial and implant are discussed in the appendix. Dr. Javed will be performing SCS trial and implant. Additionally, Dr. Matthew Chung will be collaborating in this project and will be performing his own procedures. Spinal cord stimulator Trial Procedure C-arm fluoroscopy is used to take anterior posterior views. T12-L1 interspace is identified. The skin and subcutaneous tissue overlying the proposed trajectory was anesthetized with a 1-1/2 inch, 25-gauge needle with a 1:1 mixture of 1% lidocaine and 0.25% bupivacaine. Then, a 14-gauge epidural Tuohy needle was advanced in the anesthetized tract until reaching the lamina at the inferior portion of the T12-L1 interspace. The needle is then walked off the lamina using a loss of resistance technique to saline until the epidural space is reached using intermittent AP and lateral fluoroscopic guidance. Then, an 8-contact trial lead is advanced in the midline of the vertebral column. Under lateral imaging, we verified correct placement of the lead in the posterior epidural space. Then, under pulsed fluoroscopy in AP view, the stimulator is advanced to the superior endplate of the T7 vertebra and placed the tip of the lead just left of midline. The second lead is inserted in a similar fashion. Ensuring both leads are in posterior epidural space under lateral imaging, under fluoroscopic guidance, the Touhy needles are carefully removed. The impulse generator is implanted in adipose tissue above iliac crest. Entire procedure is done in sterile fashion in the operating room. Typical description of SCS implant is extensively described in literature [8]. Testing for peripheral neuropathy markers 1. Skin Punch Biopsy for presence of epidermal nerve fibers and Meissner’s corpuscles Skin biopsies will be collected according to a published methods [18]. The skin is anesthetized with 1% lidocaine (0.3-0.5 ml) and cleaned using betadine and an alcohol swab. Once anesthetized, as indicated by loss of pinprick sensation, biopsies are collected using a sterile 3 mm punch tool (Acupunch; Acuderm, Fort Lauderdale, FL). Only very superficial skin will be removed. After removal of the biopsy, the skin will be wiped with a sterile gauze, antibiotic ointment will be applied to the biopsy site, and it will be covered with a band aid. Subjects will be given antibiotic ointment and band aids and will be instructed to clean the skin with soap and water twice each day and to apply the ointment and band aid. This biopsy does not require any sutures and heals within a few days. Once removed, the biopsy is stored in Zamboni fixative and later processed by immunohistochemistry for the presence of nerve fiber groups. Sensory Testing 1. Quantitative Sensory Testing (QST) – performed by trained study team members as delegated by the Principal Investigator. QST testing elements listed as follows: A) Heat pain threshold and cold threshold The threshold for heat pain will be determined using the Marstok technique 4. Starting at a baseline temperature of 35° C for 3 sec, the heat stimulus is increased at 0.85° C/s. Subjects are instructed to push a button when the stimulus is perceived as painful. The computer automatically returns the temperature to the baseline temperature of 30° C when the button is pushed or when the cutoff temperature of 51.5° C is reached. Heat pain threshold is defined as the temperature of the stimulus at the time that the button is pushed. No correction will be made for reaction time artifact. If a subject fails to reach a threshold before the cutoff temperature, then 51.5° C is recorded as the heat pain threshold. The threshold for cold detection is determined in a similar manner, except that the base temperature is started at 30° C, decreasing at a rate of 0.85° C/sec to a 5° C cutoff temperature. B) Mechanical Testing 1. Touch detection thresholds. Touch detection thresholds are determined using the up/down method of Dixon 1 with 6 von Frey monofilaments that are calibrated to administer a force of 0.l, 0.5, 0.9, 3.2, 6.1 or 8.0 mN. Starting with 0.5 mN, the von Frey monofilament is applied for approximately 1 sec. If the subject fails to detect the stimulus, then the next higher force von Frey monofilament is applied. When the subject detects the presence of the stimulus, the next lower von Frey is administered. The up/down test sequence continues for four additional von Frey applications after the initial detection. The 50% mechanical detection threshold is calculated using the procedure described in Dixon 1. If there is no detection to the highest force von Frey monofilament, then the 50% detection threshold is assigned the value of 19 mN. 2. Sharpness threshold and pain to needle probes Sharpness detection is determined using a weighted needle device. The tip of 30 gauge needle (200 ìm diameter) is filed to produce a flat, cylindrical end. A cotton tip applicator is inserted into the Luer connection of the needle, and washers were placed on the shaft of the cotton tip applicator to achieve the desired force level for the stimulus. The entire assembly is then placed inside a 30 cc syringe so that the needle came out of the tip of the syringe and the assembly moved freely within the syringe. When the needle is applied to the skin surface, a reliable and consistent force is applied. Three forces will be used: 100, 200 and 400 mN. Each stimulus is applied for about 1 sec. Each force is applied 10 times within each area of interest in a pseudorandom order. The subjects are instructed to indicate if the stimulus is sharp. If a stimulus is sharp, the subject then indicates if the stimulus is painful. 3. Skin Temperature Skin temperature is collected using a radiometer. 2. Gait testing Timed Up and Go (TUG) Test was originally developed in frail elderly adults to assess a person’s risk of falling. It has also been adopted for use in conditions such as arthritis, strokes, and vertigo. It is easily administered with a single tester and takes less than 15 minutes to perform. The equipment needed includes an armchair with seat height approximately 46cm and arm height of 65cm, a 3 meter walkway, and a stopwatch or wrist watch with a second hand. The measurement is the time in seconds for a person to stand from sitting from an armchair, walk 3 meters, turn around, walk back to the chair, and sit down. The person can wear their regular footwear and assistive walking device as needed. Gait analysis will also include objective measures using an open access smartphone app data analyzer (CMMotionMannager) that acts as an accelerometer and pedometer by leveraging the smartphone’s IOS sensor fusion algorithm. During the timed walking/TUG test, the patient will carry their smartphone in their pocket or bag. Using the motion sensing app, both vertical and horizontal acceleration data will be collected. Knowing the total distanced walked, and total step count, step lengths will be calculated. Gait velocity, step length, step time, swing time, and stance time. Walking forward and walking back to the chair will be counted as two separate distances. Sample Data Collection The NRS pain score, MEDD, nerve density (Meissner’s Corpuscle and ENF), and functional testing (QST and Gait testing), will be performed at baseline, 30 days and 90 days post intervention (as shown in Table 1 ). Research coordinator will assist in performing these tests. 3.2 Setting This study is a single site study to be conducted at the University of Texas MD Anderson Cancer Center, pain management clinic. The study will take place in person. 3.3 Source Documents Electronic medical records such as H&P note, follow-up notes, operative notes, etc. will be used as source documents. 3.4 Data Monitoring The PI will oversee archiving and sharing of the analysis codes generated from this project upon publication or at the end of the project period, whichever comes first. The final project report will summarize adherence to this data management and sharing plan. All accessible data will be de-identified and in the case of HIPAA conflicts, a limited data set will be created. The institution will determine whether the de-identified individual-level data are subject to the NIH Certificate of Confidentiality policy, and if so, will protect accordingly and ensure that recipients of the data are aware of the protection. Prior to release of individual-level data, researchers will be required to complete data sharing and confidentiality agreements as established by CDS. Researchers must commit to 1) not attempting to re-identify participants, 2) secure the data with appropriate technology and enforce strict access rules, 3) destroy data after analyses are completed, 4) meet any requirements as stipulated by the health system involved in the study, and 5) if research is conducted within a covered entity, HIPAA requirements must be met prior to use. Research findings will be disseminated to key decision makers, including the medical, academic, and research communities (which will be reached directly through traditional means of dissemination—publication in peer-reviewed journals and presentations at national and international conferences), as well as insurers and policymakers who have an interest in the health of cancer patients. Data and metadata will be deposited into the repository at the time of publication or by the end of the project period, whichever comes first. Data will be preserved for at least five years following the end of the grant period. Researchers may request controlled-access data using standard processes at CDS. 3.5 Data Analysis This pilot is projected to finish accrual in 12 months, and given the low risk to patients, a DSMB waiver will be requested. Descriptive analyses will be conducted for the outcomes of interest (e.g., pain scores, MEDD) at each time point (baseline, 30 days, 90 days post treatment) for each group (i.e., sham, burst, tonic spinal cord simulation). Descriptive statistics, such as mean, standard deviation (SD), median, quartiles, range, frequencies and proportions, and confidence intervals (CI), will be assessed. Graphical presentations, such as box plot, scatter plot, will be used to visually assess the outcomes. Potential normalizing transformation for the outcome variables will be conducted where appropriate. Bivariate associations between the outcomes and demographic variables will be evaluated using the Pearson or Spearman correlation coefficient. The t- test, ANOVA, or chi-squared test will be used to compare the outcome variables between different patient groups (e.g., gender). Non-parametric approaches, such as Mann-Whitney, Kruskal-Wallis, or Fisher’s exact test, will be used when appropriate. All analyses will be performed at a two-sided significance level of 0.05 unless otherwise specified. Multiple comparisons will be adjusted where appropriate. 3.6 Sample Size Justification and Power Analysis The primary endpoint is the short-term change in pain score between baseline and 30-days post treatment. The power calculation is conducted based on the primary analysis, comparing the effect of burst versus tonic spinal cord stimulation on the primary endpoint. Based on the previous study, we assume that the difference in the mean change of pain score would be approximately 1.7 points [16]. We will need 10 evaluable patients per arm to detect such a mean difference in change of pain score between the burst and tonic spinal cord stimulation arms, using a two-sided two-group t-test at a 0.05 significance level and 80% power, assuming a standard deviation of 1.3. This requires a total sample size of evaluable patients of 30. With approximate 5% attrition rate, we need a total of 33 patients. Aim 1: The primary analysis is to compare the effects of burst versus tonic spinal cord stimulation, based on the primary endpoint of the short-term improvement of pain score from baseline to 30-days post treatment. The primary analysis will be conducted on an intent-to-treat basis, in which all patients will be included in the group they were allocated to by randomization. We will use t-test to compare the change in pain score from baseline to 30 days between burst and tonic stimulation groups. If the distributional assumption is not met, we will use its nonparametric counterpart, the Mann-Whitney test. Linear regression model will be used to adjust for relevant covariates (e.g., age, gender, disease stage etc.). As secondary analysis, we will also fit the generalized linear mixed models using pain score as the dependent variable and group assignment (burst vs tonic), time, group by time interaction and other important covariates (e.g., age, stage) as independent variables. These models are for hypothesis generating rather than for hypothesis testing. Aim 2: This aim is to compare the effects of burst versus tonic spinal cord stimulation on multiple secondary endpoints for chemotherapy induced peripheral neuropathy, including long-term changes in pain scores (i.e., pain changes between baseline and 90-days post treatment), as well as short-term and long-term changes in morphine equivalent daily dose (MEDD), functional status using gait and QST, and nerve density using skin biopsy samples to analyze epidermal nerve fibers and Meissner’s corpuscle density. Similarly, we will use the t-test (or Mann-Whitney test), as well as linear regression models, to compare the secondary endpoints of interest between burst and tonic spinal cord stimulation arms. For long-term changes in pain scores and other secondary endpoints (i.e., between baseline and 90-days post treatment), we will further include the patients, who are initially assigned to the sham arm and then cross-overed to stimulation arms, as exploratory analysis. In this analysis, there will be 15 evaluable patients per group. Given such a sample size, we will have at least 80% power to detect an effect size of 1.06 for the secondary endpoints between burst and tonic stimulation groups with a significance level of 0.05. We will also use the generalized linear mixed models to analyze the repeated measures for these endpoints collected over multiple time points to account for the correlation within patients. The analyses for secondary endpoints are conducted to generate hypothesis rather than to test hypothesis. Aim 3: This aim is to compare the effect of spinal cord stimulation (combining burst and tonic stimulation) versus sham stimulation on the short-term primary and secondary endpoints (i.e., between baseline and 30-days post treatment) for chemotherapy induced peripheral neuropathy. Similar statistical approaches, such as t-test and linear regression, will be employed. Given 20 patients in the stimulation arm and 10 patients in the sham arm, we will have 80% power to detect an effect size of 1.12 between the stimulation and sham groups with a 0.05 significance level. We will use the generalized linear mixed effects model to correlate the longitudinal measures over time to account for the correlation within patients. Relevant covariates (e.g., age, disease stage) will be adjusted for in the mixed effects model. Sub-group analysis for each treatment might be conducted. These analyses are conducted for hypothesis generating purposes. Missing data: If missing data become an issue, we will assess the mixed model assumption by examining predictors of missingness. We will examine whether patients who drop out differ from those who remain and adjust for potentially relevant covariates found to be related to missingness. Additional techniques such as pattern mixture models will be explored if missingness is assumed to be nonignorable. Sensitivity analyses under various missing data mechanisms will be conducted. 4 STUDY POPULATION We will recruit a total of 33 patients. - Gender non-specific - Enroll 2-3 patients/month 4.1 Eligibility Criteria Inclusion Criteria: · Ability to understand and the willingness to sign a written informed consent document · Patients diagnosed with CIPN lower extremity due to either vinca alkaloids, taxanes, bortezomib, thalidomide, platinum-based compounds · Patients seen at Pain Management Center at MD Anderson Cancer Center · Patient ages greater or equal to 18 years but less than or equal to 85 years 4.2 Exclusion Criteria Exclusion Criteria: · Patients with cognitive dysfunction · Patient with recent history (<6 months) of drug or alcohol abuse · Patients with open skin lesion or undergoing antibiotic therapy for local for systemic infection · Patients with painful diabetic peripheral neuropathy or preexisting peripheral neuropathy 4.3 Children Children ( 18 years), non-English speaking persons, and military personnel will only be excluded if meeting exclusion criteria. For non-English speaking persons, language appropriate translation services will be employed. - Patients without capacity to consent will be excluded as it is unethical to impose a therapy for which they cannot give consent. Pregnant women and prisoners will also be excluded. 4.5 Recruitment Methods Patients will be recruited from MD Anderson Pain Management Clinic as they are assessed for CIPN. Based on the chart review of patients with diagnosis of CIPN, pain management clinic sees upwards of 10 patients with CIPN a month. To improve adherence to intervention protocols, patients will receive appointment reminder phone calls, follow-up calls, and their parking fees for study visits will be reimbursed. 5 STUDY ASSESSMENTS AND PROCEDURES 5.1 Consent Process If interested, patients will have the informed consent (IC) explained to them by a PI before entering the study. The study will use the electronic informed consent in EPIC to consent each participant; however, if an electronic consent cannot be obtained, then the patient will sign, date, and put the time on the IC hard copy. The PI or research team member authorized to obtain consent will also sign, date and put time on the IC. A copy of the IC will be made and given to the patient for their records. The original copy will be sent to Health Information Management for storage and another copy will be locked in secure location by the principal investigator. We will follow OCR SOP 04: Informed Consent Process. 6 ADVERSE EVENTS & RISKS 6.1 Adverse Events Adverse Event Definition Spinal cord stimulation – risk inherent to the procedure - Adverse event – (1) irritation around the percutaneous trial electrode, (2) battery pocket site pain, (3) wound dehiscence, (4) lead migration. Management – (1) irritation resolves transiently in most cases; sometimes ice packs or non-steroidal anti-inflammatories may be needed to reduce swelling or for pain control. (2) Battery pocket site pain can be managed with anti-inflammatories, or pain medications and possible steroid injection around the cluneal nerves. In rare cases, the pocket site may need to be moved to the opposite site. (3) Wound dehiscence may be managed with steri-strips and antibiotics, or many need to be taken back to the OR for a washout closure. (4) Lead migration may result in loss of therapy and the leads may need to be repositioned. - Risks are minimized to the lowest possible level by ensuring sterile procedural techniques, reviewing patient’s allergy list, and appropriate usage of the device (as approved by FDA). - While we do not anticipate or expect any adverse events from the proposed intervention, any adverse events will be promptly recorded in electric medical record and reported to the IRB. - Participants may choose to withdraw from the study at any time upon their request. Serious Adverse Events While we do not anticipate or expect any Serious Adverse Events from the proposed intervention, SAEs will be reported according to institution’s standards. An adverse event or suspected adverse event is considered “serious” if in the view of either the investigator or the sponsor, it results in any of the following outcomes: · Death · Life-threatening adverse event · Results in persistent or significant disability/incapacity · In-patient hospitalization or prolongation of existing hospitalization · Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions · Congenital anomaly/birth defect 6.2 Participant Compensation Patients will not be compensated for their participation in this study. Since these procedures are approved treatments for neuropathic pain, insurance providers may be financially responsible for the cost of Study procedures and for care and treatment of any complications resulting from these procedures. Standard medical care received under this research study will be billed in an ordinary manner. 7 POTENTIAL BENEFITS Patients enrolled in treatment group have a potential to receive benefit (i.e. pain relief) from the procedure. 8 DATA MANAGEMENT AND SHARING PLAN Subject data will be identified in the research data set using random sequential numbering. Study data will be collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at MD Anderson. REDCap (www.projectredcap.org) is a secure, web-based application with controlled access designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless downloads to common statistical packages; and 4) procedures for importing data from external sources. REDCap (https://redcap.mdanderson.org) is hosted on a secure server by MD Anderson Cancer Center’s Department of Research Information Systems & Technology Services. REDCap has undergone a Governance Risk & Compliance Assessment (May 2014) by MD Anderson's Information Security Office and found to be compliant with HIPAA, Texas Administrative Codes 202-203, University of Texas Policy 165, federal regulations outlined in 21CFR Part 11, and UTMDACC Institutional Policy #ADM0335. The Department’s Data Manager will assist us in creating the database in REDCap, building the necessary queries and coordinating data entry. We will collect data from EPIC. Collected data per medical record will be assigned a unique identifier in the database and access will be limited to those who are directly working on the project and are part of the Institutional Review Board (IRB) approved protocol. Password protected computers will also be used to secure the database and prevent improper use of Protected Health Information (PHI). Following publication study data will be archived in REDCap. PHI will not be shared with any other persons or entities except as required by law. Identifiers will be destroyed at the earliest opportunity and the study team will not disclose PHI to any other person or entity except as required by law. Abbreviations SCS Spinal cord stimulation DRG Dorsal root ganglion PNS Peripheral nerve stimulation MC Meissner’s corpuscle CIPN Chemotherapy induced peripheral neuropathy ENF Epidermal nerve fiber Declarations 9 DISSEMINATION POLICY: AUTHORSHIP To qualify as an author individuals must have: 1. Contributed to the conception or design of the work, statistical analyses, or data interpretation 2. Drafted and revised the work critically for intellectual content 3. Provided final approval of the version to be published 4. Agreed to be accountable for all aspects of the work Trial Status NCT06121232 Version 2.0 was registered on November 2 nd , 2024. Recruitment began January, 2025 and is expected to complete in April, 2026. IRB (#2023-0041) was approved on May, 1 st , 2024 (OHRP IRB Registration #: IRB00000121). 9.1 Ethics approval and consent to participate The study was approved by the MD Anderson IRB (2023-0041), UT MD Anderson Cancer Center Institutional Review Board, 7007 Bertner Avenue, Unit 1637, Houston, TX 77030. An informed consent form will be collected from participants in the study. 9.2 Consent for publication Not Applicable. 9.3 Availability of data and material Data and materials will be available on ClinicalTrials.gov (NCT06121232). 9.4 Funding This study is funded by the MD Anderson Junior Faculty Division to provide salary support for the research coordinator. The study sponsor, MD Anderson Junior Faculty Division, is not involved in designing the study, collecting, managing, analyzing, or interpreting the data, drafting the report, or determining whether the report will be submitted for publication. 9.5 Competing Interests The authors declare that they have no competing interests. 9.6 Authors’ contributions SJ conceived of the trial, designed the interventions, and developed the plans for statistical analyses. SJ and SJK drafted and refined the manuscript. All authors read and approved the manuscript. 9.7 Acknowledgements Thanks to the MD Anderson Junior Faculty Division ( [email protected] ) for providing funding. CONFIDENTIALITY STATEMENT Thisdocument is confidential communication. Acceptance of this document constitutes agreement by the recipient that no unpublished information contained herein will be published or disclosed without prior approval of the Principal Investigator References Tanner, K.D., D.B. Reichling, and J.D. Levine, Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat. J Neurosci, 1998. 18 (16): p. 6480-91. Koeppen, S., Treatment of multiple myeloma: thalidomide-, bortezomib-, and lenalidomide-induced peripheral neuropathy. Oncol Res Treat, 2014. 37 (9): p. 506-13. D'Souza, R.S., et al., Neuromodulation Therapy for Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review. Biomedicines, 2022. 10 (8). Abd-Elsayed, A., N. Schiavoni, and H. Sachdeva, Efficacy of spinal cord stimulators in treating peripheral neuropathy: a case series. J Clin Anesth, 2016. 28 : p. 74-7. Slavin, K.V., et al., Tonic and burst spinal cord stimulation waveforms for the treatment of chronic, intractable pain: study protocol for a randomized controlled trial. Trials, 2016. 17 (1): p. 569. Pike, C.T., et al., Healthcare costs and workloss burden of patients with chemotherapy-associated peripheral neuropathy in breast, ovarian, head and neck, and nonsmall cell lung cancer. Chemother Res Pract, 2012. 2012 : p. 913848. Groenen, P.S., N. van Helmond, and K.B. Chapman, Chemotherapy-Induced Peripheral Neuropathy Treated with Dorsal Root Ganglion Stimulation. Pain Med, 2019. 20 (4): p. 857-859. Ege, E., et al., Risk factors for surgical site infection in advanced neuromodulation pain procedures: a retrospective study. Pain Manag, 2023. 13 (7): p. 397-404. Tanner, K.D., J.D. Levine, and K.S. Topp, Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat. J Comp Neurol, 1998. 395 (4): p. 481-92. Seretny, M., et al., Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain, 2014. 155 (12): p. 2461-2470. Teran-Wodzinski, P., et al., Assessing gait, balance, and muscle strength among breast cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN): study protocol for a randomized controlled clinical trial. Trials, 2022. 23 (1): p. 363. Menant, J.C., et al., Evidence of slow and variable choice-stepping reaction time in cancer survivors with chemotherapy-induced peripheral neuropathy. Gait Posture, 2021. 89 : p. 178-185. Winters-Stone, K.M., et al., Falls, Functioning, and Disability Among Women With Persistent Symptoms of Chemotherapy-Induced Peripheral Neuropathy. J Clin Oncol, 2017. 35 (23): p. 2604-2612. Koskinen, M.J., et al., Intraepidermal nerve fibre density in cancer patients receiving adjuvant chemotherapy. Anticancer Res, 2011. 31 (12): p. 4413-6. Boyette-Davis, J.A., et al., Follow-up psychophysical studies in bortezomib-related chemoneuropathy patients. J Pain, 2011. 12 (9): p. 1017-24. De Ridder, D., et al., A 2-center comparative study on tonic versus burst spinal cord stimulation: amount of responders and amount of pain suppression. Clin J Pain, 2015. 31 (5): p. 433-7. Tables Table 2. The schedule of enrollment, interventions, and assessments Table 2. All items from the World Health Organization Trial Registration Data Set Primary registry and trial identifying number ClinicalTrials.gov NCT06121232 Date of registration in primary registry November 2 nd , 2024 Secondary identifying numbers NCI-2023-09269 Source(s) of monetary or material support MD Anderson Junior Faculty Division Primary sponsor MD Anderson Junior Faculty Division Contact for public queries Saba Javed, M D Email: [email protected] Contact for scientific queries Saba Javed, M D Email: [email protected] Public title Benefit of tonic versus burst spinal cord stimulation for chemo-induced peripheral neuropathy using psychophysical testing Scientific title Exploring the Benefit of Neuromodulation in Treating Chemo-induced Peripheral Neuropathy Using Peripheral Neuropathy Markers (Meissner's Corpuscles and Epidermal Nerve Fiber Density) and Sensory Testing (Quantitative Sensory and Gait Testing): A Single Center Feasibility Study Countries of recruitment USA Health condition(s) or problem(s) studied Chemotherapy induced peripheral neuropathy Intervention(s) Neuromodulation Key inclusion and exclusion criteria Inclusion Criteria: Ability to understand and the willingness to sign a written informed consent document Patients diagnosed with CIPN lower extremity due to either vinca alkaloids, taxanes, bortezomib, thalidomide, platinum-based compounds Patients seen at Pain Management Center at MD Anderson Cancer Center Patient ages greater or equal to 18 years but less than or equal to 85 years Exclusion Criteria Patients with cognitive dysfunction Patient with recent history (<6 months) of drug or alcohol abuse Patients with open skin lesion or undergoing antibiotic therapy for local for systemic infection Patients with painful diabetic peripheral neuropathy or preexisting peripheral neuropathy Study type A Single Center Feasibility Study Date of first enrolment 01/2025 Target sample size 33 Recruitment status Active Primary outcome(s) The NRS pain score, MEDD, nerve density (Meissner’s Corpuscle and ENF), and functional testing (QST and Gait testing) Supplementary Files AdditionalFile1figures.docx ADDITIONAL FILES Additional File 1: · Doc · Figures 1 and 2 · STUDY SCHEMA and NRS scores after DRG AdditionalFile4Doc.docx TABLEOFCONTENTS.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5915887","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":437835749,"identity":"6aac1a99-9a34-4598-b57f-ec431f0058bc","order_by":0,"name":"Saba Javed","email":"","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Saba","middleName":"","lastName":"Javed","suffix":""},{"id":437835750,"identity":"703c7ba9-8213-4926-93ee-fc01fb24400a","order_by":1,"name":"Serena Jiyeon Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBADAzYG5mMQ5gHitbClkaiFgYHHjDgt8u29Dx8X1DAY84md+fbgZw6DHN+NBAKmnzlubDzjGIMZm3TudsPebQzGkgS1SKSxSfOwMdgAtWyTZtzGkLiBkBb5+c/Yf/P8A2nJeQbSUk9QC8MNNjZm3jaQw3LYQFoSDAj7JY1ZmrdPwphNOs0c6BcJw5lnHhBwWPsxxs8832wM589Ofvbg5zYbeb7jhBwGARIYjFEwCkbBKBgFlAAArLw6q5ALYqwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0000-7251-0374","institution":"Baylor College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Serena","middleName":"Jiyeon","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2025-01-28 03:45:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5915887/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5915887/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87513782,"identity":"c3beb725-7b94-4a81-a21d-173ec63db4ad","added_by":"auto","created_at":"2025-07-24 16:04:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1025293,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5915887/v1/c660c2c4-09bd-4565-9298-67ed6ac091e7.pdf"},{"id":80078122,"identity":"ebaf4446-18cc-47d4-8d6a-05b9d4393bc0","added_by":"auto","created_at":"2025-04-07 15:13:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":80255,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eADDITIONAL FILES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional File 1:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· Doc\u003c/p\u003e\n\u003cp\u003e· Figures 1 and 2\u003c/p\u003e\n\u003cp\u003e· STUDY SCHEMA and NRS scores after DRG\u003c/p\u003e","description":"","filename":"AdditionalFile1figures.docx","url":"https://assets-eu.researchsquare.com/files/rs-5915887/v1/42778cf39aa203024595b07b.docx"},{"id":80078125,"identity":"d0c630a1-5396-478d-9391-8250e3bf364b","added_by":"auto","created_at":"2025-04-07 15:13:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":40416,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile4Doc.docx","url":"https://assets-eu.researchsquare.com/files/rs-5915887/v1/7d3920ca610d2845322ae18d.docx"},{"id":80078120,"identity":"da8cb46c-f461-4d2d-9d1c-b06d9c236ada","added_by":"auto","created_at":"2025-04-07 15:13:57","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":15538,"visible":true,"origin":"","legend":"","description":"","filename":"TABLEOFCONTENTS.docx","url":"https://assets-eu.researchsquare.com/files/rs-5915887/v1/82cb54d7d535b43e9e433f40.docx"}],"financialInterests":"","formattedTitle":"Benefit of Tonic Versus Burst Spinal Cord Stimulation for Chemo-Induced Peripheral Neuropathy Using Psychophysical Testing","fulltext":[{"header":"1\tINTRODUCTION","content":"\u003ch2\u003e1.1 Study Rationale and Justification\u003c/h2\u003e\n\u003cp\u003eChemotherapy-induced peripheral neuropathy (CIPN) is a challenging complication of many chemotherapeutic regimens (vinca alkaloid, taxanes, bortezomib), characterized by numbness, tingling sensations, persistent shooting, stabbing, burning pain or loss of cutaneous sensation, extremity muscle weakness, and impaired balance in the extremities [1]. The incidence of CIPN is reported in up to 68% within the first month (of chemotherapy), 60% at three months, and 40% at six months after chemotherapy [2]. Mechanism is thought to be due to microtubule disruption, impairing axonal transport leading to Wallerian degeneration, and causing hyperexcitability of peripheral neurons. CIPN is conventionally managed with antidepressants, antiepileptics, and adjuvants. Unfortunately, CIPN can be refractory to medications, and patients who fail conservative therapies may consider alternative options such a spinal cord stimulation (SCS). \u003c/p\u003e\n\u003cp\u003eThe role of spinal cord stimulation has previously been reported scarcely for improvement of neuropathy and neurologic function for CIPN [3, 4]. Tonic and burst stimulation are two subliminal waveforms used for SCS [5]. Although a commonly proposed mechanism is the gate control theory, new mechanisms proposed may indicate some association with unique waveform paradigms. While stimulation of the dorsal column is widely acceptable for tonic stimulation, burst stimulation has shown to activate both the lateral and medial aspects of the spinothalamic tract [5]. Besides the gate control theory, analgesia from SCS may also be explained by its modulation of neurotransmitters (cholinergic, serotonergic, and opioidergic pathways), depression of wide dynamic range neurons, and activation of supraspinal levels from orthodromic dorsal column action potentials [4]. Although burst stimulation has shown to be superior to tonic for patients with back pain, there is no reported data available for CIPN [5].\u003c/p\u003e\n\u003cp\u003eThe challenge of studying SCS or any interventional pain therapies is placebo effect and having limited objective measures to measure improvement. Additionally, there are very limited mechanistic studies available looking at the impact of neuromodulation on peripheral nerve density. For the first time, we propose using subliminal tonic stimulation with burst stimulation and comparing with sham group to account for placebo. Additionally, we propose using functional assessment tools (gait and QST) to measure and correlate subjective pain scores with objective improvement in functional status. Lastly, we propose taking skin biopsy samples before and after spinal cord stimulation to study changes in epidermal nerve fibers (ENFs) and Meissner\u0026rsquo;s corpuscles (MC) using immunohistochemistry (IHC). This study will advance the field of interventional pain medicine research by providing insight into (1) which subliminal waveform is more beneficial for CIPN, (2) how the pain scores compare to functional improvement, and (3) provide mechanistic understanding of change in nerve density and recovery after SCS in CIPN. Our long-term goal is to understand the mechanism of CIPN at the neuronal level and use psychophysical studies (quantitative sensory testing and gait testing) to objectively assess the effects and applications of different neuromodulation techniques (dorsal root ganglion stimulation and peripheral nerve stimulation) on CIPN.\u003c/p\u003e\n\u003cp\u003eWe \u003cu\u003ehypothesize\u003c/u\u003e that burst spinal cord stimulation will be superior to tonic stimulation as measured by pain improvement and functional improvement (gait and QST). \u003cstrong\u003eFigure 1\u003c/strong\u003e shows the conceptual framework of this proposal. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAIM 1: \u003c/strong\u003eCompare the effect of burst versus tonic spinal cord stimulation on the primary endpoint, short-term changes in pain scores (i.e., pain changes between baseline and 30-days post treatment), for chemotherapy induced peripheral neuropathy.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHypothesis\u003c/u\u003e: We hypothesize burst SCS to be superior to tonic by resulting in significant decrease in pain score. This hypothesis is based on our preliminary findings (discussed in prelim results) suggesting burst stimulation results in better pain relief. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAIM 2: \u003c/strong\u003eCompare the effect of burst versus tonic spinal cord stimulation on secondary endpoints, including long-term changes in pain scores (i.e., pain changes between baseline and 90-days post treatment), as well as short-term and long-term changes in morphine equivalent daily dose (MEDD), NIH-PROMIS, functional status using gait and QST, and nerve density using skin biopsy samples to analyze epidermal nerve fibers and Meissner\u0026rsquo;s corpuscle density for chemotherapy induced peripheral neuropathy.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHypothesis\u003c/u\u003e: We hypothesize there to be greater improvement in functional status (gait testing and QST) and regrowth of peripheral nerve density after burst than tonic stimulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAIM 3: \u003c/strong\u003eCompare the effect of spinal cord stimulation versus sham stimulation on the short-term primary and secondary endpoints for chemotherapy induced peripheral neuropathy. \u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHypothesis\u003c/u\u003e: We hypothesize SCS to be superior to sham stimulation.\u003c/p\u003e\n\u003cp\u003eCompletion of these studies will provide first ever comprehensive analysis of the benefit of SCS for CIPN and provide tangible data on functional benefit (QST and gait), which may be used as tools for purposes of diagnoses or disease progression. Nerve fiber analyses can elucidate CIPN mechanism. Finally, this proposal will provide me with the opportunity to gain valuable, mentored experience in clinical research and will help me to cultivate a career as a successful, independent investigator. \u003c/p\u003e\n\u003ch2 id=\"_Toc121997249\"\u003e1.2 Background\u003c/h2\u003e\n\u003cp\u003eChemotherapy-induced peripheral neuropathy (CIPN) is a challenging complication of many chemotherapeutic regimens. It is most commonly associated with three types of cancer treatment: vinca alkaloid, taxanes and bortezomib. CIPN is characterized by numbness, tingling sensations, persistent shooting, stabbing, burning pain or loss of cutaneous sensation, extremity muscle weakness, and impaired balance. The incidence of CIPN is reported up to 68% within the first month (of chemotherapy), 60% at three months, and 40% at six months after chemotherapy [2]. Onset of CIPN may require chemotherapy dose reduction or cessation, which can increase cancer-related morbidity and mortality [6]. Additionally, average healthcare costs were $17,344 higher for CIPN patients than their non-CIPN counterparts annually [6].\u003c/p\u003e\n\u003cp\u003eThere is no Food and Drug Administration (FDA) approved therapy management of CIPN; however, CIPN is conventionally managed with antidepressants, antiepileptics, and adjuvants. Quality evidence is lacking regarding management of CIPN. Most conventional neuropathic treatment are not supported by clinical trials and are often unsuccessful. Spinal cord stimulation (SCS)) is FDA approved for treatment of failed back surgery syndrome, lumbar radiculopathy or complex regional pain syndrome and is emerging as a potential treatment for CIPN [3]. A few case reports and series have reported the use of SCS in management of CIPN [4, 7]. While these case reports relied mostly on patient-reported outcomes, there has not been any objective, functional improvement outcomes reported. Additionally, data on use of tonic versus burst SCS for CIPN is completely lacking. \u003c/p\u003e\n\u003cp\u003e\u003cu\u003eScientific premise:\u003c/u\u003e The underlying principle supporting this proposal is to explore the benefit of tonic versus burst SCS in CIPN is based on our preliminary findings (discussed below) and on premise that burst stimulation has shown superiority for complex regional pain syndrome and other neuropathic pain syndromes [5]. We hypothesize that burst SCS will be superior to tonic SCS, both of which will be superior to sham stimulation, based on the following premise:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea) Use of SCS stimulation for treatment of lower extremity CIPN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe recently submitted a case series of patient with painful CIPN who underwent SCS for lower extremity painful CIPN revealing significant improvement in numerical rating scores (NRS) pain scores. Previously our similar study on successful outcomes of dorsal root ganglion stimulation (DRG-S) for lower extremity CIPN exhibited similar findings (\u003cstrong\u003eFigure 2\u003c/strong\u003e) [8]. Different waveforms of stimulation and their mechanism was not the scope of the article, which is what we intend to study now.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e[INSERT FIGURE 2 HERE]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb) Psychophysical testing to elicit mechanism. \u003c/strong\u003eRecently, quantitative sensory testing (QST) has shown some feasibility in sorting between specific fiber type and differentiate between light touch/vibration (large myelinated A-beta fibers), vs. pin-prink/warm/cool (small myelinated A-delta fibers) fibers [9, 10]. Furthermore, gait assessment has shown some feasibility in CIPN, as gait testing revealed slower gait velocity, shorter step time, longer timed walking tests compared to matched controls [11, 12], as well as increased patient-reported response times [13]. In my current proposal, we propose using this premise of QST and gait testing and incorporating it to objectively measure functional outcome and further elicit mechanism of CIPN and impact of spinal cord stimulation on neuropathy. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec) Meissner\u0026rsquo;s corpuscle (MC) and epidermal nerve fibers (ENFs) are potential neural targets to elucidate mechanism of CIPN associated neuropathic pain.\u003c/strong\u003e The use of immunohistochemistry (IHC) and microscopy for evaluation of changes in MC and ENF density can be useful in neuropathic states. Morphological and quantitative changes in peripheral nerves have proven useful for serial monitoring, progression, and recovery in neuropathy due to diabetes, HIV, and idiopathic disease [14, 15]. Measurement of changes in nerve density (MC and ENF) using immunohistochemistry has shown promise as a tool to measure disease progression for CIPN. Our current proposal will continue to collect data on patients with lower extremity CIPN and measure changes in nerve density before and after SCS to measure its impact. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eINNOVATION:\u003c/u\u003e \u003c/strong\u003eOur study has several innovative aspects. This study will advance the field of interventional pain medicine by providing insight into (1) which subliminal waveform is more beneficial for CIPN, (2) how the pain scores compare to functional improvement, and (3) provide mechanistic understanding of change in nerve density and recovery after SCS in CIPN. Our long-term goal is to understand the mechanism of CIPN at the neuronal level and use psychophysical studies (QST and gait) to objectively assess the impact of different neuromodulation techniques (dorsal root ganglion stimulation and peripheral nerve stimulation) on CIPN.\u003c/p\u003e"},{"header":"2 OBJECTIVES","content":"\u003ch2\u003e2.1 Objective\u003c/h2\u003e\n\u003cp\u003eCompare the effect of burst versus tonic spinal cord stimulation on the primary endpoint, short-term changes in pain scores (i.e., pain changes between baseline and 30-days post treatment), for chemotherapy induced peripheral neuropathy.\u003c/p\u003e\n\u003ch2 id=\"_Toc395019463\"\u003e2.2 Secondary Objectives\u003c/h2\u003e\n\u003cul\u003e\n \u003cli\u003eCompare the effect of burst versus tonic spinal cord stimulation on secondary endpoints, including long-term changes in pain scores (i.e., pain changes between baseline and 90-days post treatment), as well as short-term and long-term changes in morphine equivalent daily dose (MEDD), NIH-PROMIS, functional status using gait and QST, and nerve density using skin biopsy samples to analyze epidermal nerve fibers and Meissner\u0026rsquo;s corpuscle density for chemotherapy induced peripheral neuropathy.\u003c/li\u003e\n \u003cli\u003eCompare the effect of spinal cord stimulation versus sham stimulation on the short-term primary and secondary endpoints for chemotherapy induced peripheral neuropathy.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch2 id=\"_Toc121997255\"\u003e2.3 Study Type\u003c/h2\u003e\n\u003cp\u003eIn this prospective study, 33 patients with CIPN of lower extremity will be randomly assigned using block randomization to one of the three study arms: tonic stimulation, burst stimulation or sham stimulation. After 30-days, the sham group will be randomly assigned to one of the two stimulation groups and followed for 90-days for assessment.\u003c/p\u003e\n\u003cp\u003eThe allocation sequence for randomization will be generated by the research coordinator using the OnCore system. Participants will be enrolled by the research coordinator and allocation details will be communicated to them via telephone to ensure allocation concealment.\u003c/p\u003e\n\u003cp\u003eAll three groups will undergo spinal cord stimulator (SCS) implantation, so patients will remain blinded to the type of stimulation they are receiving (tonic, burst, or sham). Since all three stimulation techniques are subparesthesia, patients will not know whether they are receiving tonic, burst, or sham stimulation. Patients will be unblinded at the end of the study (90 days).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHypothesis\u003c/u\u003e: We hypothesize burst SCS to be superior to tonic by resulting in significant decrease in pain score. This hypothesis is based on our preliminary findings (discussed in prelim results) suggesting burst stimulation results in better pain relief.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHypothesis:\u003c/u\u003e We hypothesize there to be greater improvement in functional status (gait testing and QST) and regrowth of peripheral nerve density after burst than tonic stimulation.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHypothesis\u003c/u\u003e: We hypothesize SCS to be superior to sham stimulation.\u003c/p\u003e"},{"header":"3 STUDY METHODS","content":"\u003ch2\u003e3.1 Study Methods \u003c/h2\u003e\n\u003cp\u003eFrom patients meeting the inclusion criteria, we will recruit total 33 participants; planning for a 5% attrition rate (Figure 1). We anticipate 10 patients per group will complete the study to be evaluable. Thirty-three patients will be randomized to one of the 3 groups (tonic stimulation, burst stimulation, sham stimulation). Patients are permitted to continue certain concomitant interventions during the study, including physical therapy, over-the-counter medications, neuropathic pain medications (e.g., gabapentin, pregabalin, tricyclic antidepressants), anti-inflammatory pain medications, and muscle relaxants. Steroid injections are prohibited throughout the study duration. They will complete NRS pain score, MEDD, NIH-PROMIS, gait, QST testing as well as skin biopsy at baseline. Thereafter, patients with successful SCS trial (\u0026gt;50% improvement in pain) will undergo SCS implantation. Within the therapeutic stimulation group, repeat assessment (NRS pains score, MEDD, NIH-PROMIS-29, gait, QST, and skin biopsy) will be performed at 30 days post-implantation stimulation and 90 days post-implantation stimulation. Within the sham stimulation group, after 30-days post sham stimulation, patients will be randomized to either tonic or burst and followed for 90 days for assessment. Standard tonic stimulation settings are as follows: range of frequency is 30 to 120Hz, with a pulse width ranging from 200 microseconds up to 500 microseconds. Standard burst stimulation settings as follows: frequency is set at 40Hz, intra-burst rate is 500Hz, pulse width at 1000 microseconds. With sham stimulation, the stimulation parameters will be set to null. All 3 groups are subliminal. Note: the procedure steps for SCS trial and implant are discussed in the appendix. Dr. Javed will be performing SCS trial and implant. Additionally, Dr. Matthew Chung will be collaborating in this project and will be performing his own procedures. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSpinal cord stimulator Trial Procedure\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC-arm fluoroscopy is used to take anterior posterior views. T12-L1 interspace is identified. The skin and subcutaneous tissue overlying the proposed trajectory was anesthetized with a 1-1/2 inch, 25-gauge needle with a 1:1 mixture of 1% lidocaine and 0.25% bupivacaine. Then, a 14-gauge epidural Tuohy needle was advanced in the anesthetized tract until reaching the lamina at the inferior portion of the T12-L1 interspace. The needle is then walked off the lamina using a loss of resistance technique to saline until the epidural space is reached using intermittent AP and lateral fluoroscopic guidance.\u003c/p\u003e\n\u003cp\u003eThen, an 8-contact trial lead is advanced in the midline of the vertebral column. Under lateral imaging, we verified correct placement of the lead in the posterior epidural space. Then, under pulsed fluoroscopy in AP view, the stimulator is advanced to the superior endplate of the T7 vertebra and placed the tip of the lead just left of midline. The second lead is inserted in a similar fashion.\u003c/p\u003e\n\u003cp\u003eEnsuring both leads are in posterior epidural space under lateral imaging, under fluoroscopic guidance, the Touhy needles are carefully removed.\u003c/p\u003e\n\u003cp\u003eThe impulse generator is implanted in adipose tissue above iliac crest. Entire procedure is done in sterile fashion in the operating room.\u003c/p\u003e\n\u003cp\u003eTypical description of SCS implant is extensively described in literature [8]. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTesting\u003c/strong\u003e\u003cstrong\u003e for peripheral neuropathy markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1. Skin Punch Biopsy for presence of epidermal nerve fibers and Meissner\u0026rsquo;s corpuscles\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSkin biopsies will be collected according to a published methods [18]. The skin is anesthetized with 1% lidocaine (0.3-0.5 ml) and cleaned using betadine and an alcohol swab. Once anesthetized, as indicated by loss of pinprick sensation, biopsies are collected using a sterile 3 mm punch tool (Acupunch; Acuderm, Fort Lauderdale, FL). Only very superficial skin will be removed. After removal of the biopsy, the skin will be wiped with a sterile gauze, antibiotic ointment will be applied to the biopsy site, and it will be covered with a band aid. Subjects will be given antibiotic ointment and band aids and will be instructed to clean the skin with soap and water twice each day and to apply the ointment and band aid. This biopsy does not require any sutures and heals within a few days. Once removed, the biopsy is stored in Zamboni fixative and later processed by immunohistochemistry for the presence of nerve fiber groups. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSensory Testing\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1. \u003c/em\u003e\u003cem\u003eQuantitative Sensory Testing (QST)\u003c/em\u003e\u0026ndash; performed by trained study team members as delegated by the Principal Investigator. QST testing elements listed as follows:\u003c/p\u003e\n\u003cp\u003eA) \u003cu\u003eHeat pain threshold and cold threshold \u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe threshold for heat pain will be determined using the Marstok technique 4. Starting at a baseline temperature of 35\u0026deg; C for 3 sec, the heat stimulus is increased at 0.85\u0026deg; C/s. Subjects are instructed to push a button when the stimulus is perceived as painful. The computer automatically returns the temperature to the baseline temperature of 30\u0026deg; C when the button is pushed or when the cutoff temperature of 51.5\u0026deg; C is reached. Heat pain threshold is defined as the temperature of the stimulus at the time that the button is pushed. No correction will be made for reaction time artifact. If a subject fails to reach a threshold before the cutoff temperature, then 51.5\u0026deg; C is recorded as the heat pain threshold. The threshold for cold detection is determined in a similar manner, except that the base temperature is started at 30\u0026deg; C, decreasing at a rate of 0.85\u0026deg; C/sec to a 5\u0026deg; C cutoff temperature. \u003c/p\u003e\n\u003cp\u003eB) \u003cu\u003eMechanical Testing \u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e1. \u003cem\u003eTouch detection thresholds. \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTouch detection thresholds are determined using the up/down method of Dixon 1 with 6 von Frey monofilaments that are calibrated to administer a force of 0.l, 0.5, 0.9, 3.2, 6.1 or 8.0 mN. Starting with 0.5 mN, the von Frey monofilament is applied for approximately 1 sec. If the subject fails to detect the stimulus, then the next higher force von Frey monofilament is applied. When the subject detects the presence of the stimulus, the next lower von Frey is administered. The up/down test sequence continues for four additional von Frey applications after the initial detection. The 50% mechanical detection threshold is calculated using the procedure described in Dixon 1. If there is no detection to the highest force von Frey monofilament, then the 50% detection threshold is assigned the value of 19 mN. \u003c/p\u003e\n\u003cp\u003e2. \u003cem\u003eSharpness threshold and pain to needle probes \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSharpness detection is determined using a weighted needle device. The tip of 30 gauge needle (200 \u0026igrave;m diameter) is filed to produce a flat, cylindrical end. A cotton tip applicator is inserted into the Luer connection of the needle, and washers were placed on the shaft of the cotton tip applicator to achieve the desired force level for the stimulus. The entire assembly is then placed inside a 30 cc syringe so that the needle came out of the tip of the syringe and the assembly moved freely within the syringe. When the needle is applied to the skin surface, a reliable and consistent force is applied. Three forces will be used: 100, 200 and 400 mN. Each stimulus is applied for about 1 sec. Each force is applied 10 times within each area of interest in a pseudorandom order. The subjects are instructed to indicate if the stimulus is sharp. If a stimulus is sharp, the subject then indicates if the stimulus is painful. \u003c/p\u003e\n\u003cp\u003e3. \u003cem\u003eSkin Temperature \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSkin temperature is collected using a radiometer. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2. \u003c/em\u003e\u003cem\u003eGait testing\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTimed Up and Go (TUG) Test was originally developed in frail elderly adults to assess a person\u0026rsquo;s risk of falling. It has also been adopted for use in conditions such as arthritis, strokes, and vertigo. It is easily administered with a single tester and takes less than 15 minutes to perform. The equipment needed includes an armchair with seat height approximately 46cm and arm height of 65cm, a 3 meter walkway, and a stopwatch or wrist watch with a second hand. The measurement is the time in seconds for a person to stand from sitting from an armchair, walk 3 meters, turn around, walk back to the chair, and sit down. The person can wear their regular footwear and assistive walking device as needed. \u003c/p\u003e\n\u003cp\u003eGait analysis will also include objective measures using an open access smartphone app data analyzer (CMMotionMannager) that acts as an accelerometer and pedometer by leveraging the smartphone\u0026rsquo;s IOS sensor fusion algorithm. During the timed walking/TUG test, the patient will carry their smartphone in their pocket or bag. Using the motion sensing app, both vertical and horizontal acceleration data will be collected. Knowing the total distanced walked, and total step count, step lengths will be calculated. Gait velocity, step length, step time, swing time, and stance time. Walking forward and walking back to the chair will be counted as two separate distances.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSample Data Collection \u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NRS pain score, MEDD, nerve density (Meissner\u0026rsquo;s Corpuscle and ENF), and functional testing (QST and Gait testing), will be performed at baseline, 30 days and 90 days post intervention (as shown in \u003cstrong\u003eTable 1\u003c/strong\u003e). Research coordinator will assist in performing these tests. \u003c/p\u003e\n\u003ch2 id=\"_Toc121997258\"\u003e3.2 Setting\u003c/h2\u003e\n\u003cp\u003eThis study is a single site study to be conducted at the University of Texas MD Anderson Cancer Center, pain management clinic. The study will take place in person. \u003c/p\u003e\n\u003ch2\u003e3.3 Source Documents\u003c/h2\u003e\n\u003cp\u003eElectronic medical records such as H\u0026amp;P note, follow-up notes, operative notes, etc. will be used as source documents.\u003c/p\u003e\n\u003ch2\u003e3.4 Data Monitoring \u003c/h2\u003e\n\u003cp\u003eThe PI will oversee archiving and sharing of the analysis codes generated from this project upon publication or at the end of the project period, whichever comes first. The final project report will summarize adherence to this data management and sharing plan.\u003c/p\u003e\n\u003cp\u003eAll accessible data will be de-identified and in the case of HIPAA conflicts, a limited data set will be created. The institution will determine whether the de-identified individual-level data are subject to the NIH Certificate of Confidentiality policy, and if so, will protect accordingly and ensure that recipients of the data are aware of the protection.\u003c/p\u003e\n\u003cp\u003ePrior to release of individual-level data, researchers will be required to complete data sharing and confidentiality agreements as established by CDS. Researchers must commit to 1) not attempting to re-identify participants, 2) secure the data with appropriate technology and enforce strict access rules, 3) destroy data after analyses are completed, 4) meet any requirements as stipulated by the health system involved in the study, and 5) if research is conducted within a covered entity, HIPAA requirements must be met prior to use.\u003c/p\u003e\n\u003cp\u003eResearch findings will be disseminated to key decision makers, including the medical, academic, and research communities (which will be reached directly through traditional means of dissemination\u0026mdash;publication in peer-reviewed journals and presentations at national and international conferences), as well as insurers and policymakers who have an interest in the health of cancer patients.\u003c/p\u003e\n\u003cp\u003eData and metadata will be deposited into the repository at the time of publication or by the end of the project period, whichever comes first. Data will be preserved for at least five years following the end of the grant period. Researchers may request controlled-access data using standard processes at CDS.\u003c/p\u003e\n\u003ch2 id=\"_Toc121997261\"\u003e3.5 Data Analysis\u003c/h2\u003e\n\u003cp\u003eThis pilot is projected to finish accrual in 12 months, and given the low risk to patients, a DSMB waiver will be requested. \u003c/p\u003e\n\u003cp\u003eDescriptive analyses will be conducted for the outcomes of interest (e.g., pain scores, MEDD) at each time point (baseline, 30 days, 90 days post treatment) for each group (i.e., sham, burst, tonic spinal cord simulation). Descriptive statistics, such as mean, standard deviation (SD), median, quartiles, range, frequencies and proportions, and confidence intervals (CI), will be assessed. Graphical presentations, such as box plot, scatter plot, will be used to visually assess the outcomes. Potential normalizing transformation for the outcome variables will be conducted where appropriate. Bivariate associations between the outcomes and demographic variables will be evaluated using the Pearson or Spearman correlation coefficient. The \u003cem\u003et-\u003c/em\u003etest, ANOVA, or chi-squared test will be used to compare the outcome variables between different patient groups (e.g., gender). Non-parametric approaches, such as Mann-Whitney, Kruskal-Wallis, or Fisher\u0026rsquo;s exact test, will be used when appropriate. All analyses will be performed at a two-sided significance level of 0.05 unless otherwise specified. Multiple comparisons will be adjusted where appropriate. \u003c/p\u003e\n\u003ch2\u003e3.6 Sample Size Justification and Power Analysis\u003c/h2\u003e\n\u003cp\u003eThe primary endpoint is the short-term change in pain score between baseline and 30-days post treatment. The power calculation is conducted based on the primary analysis, comparing the effect of burst versus tonic spinal cord stimulation on the primary endpoint. Based on the previous study, we assume that the difference in the mean change of pain score would be approximately 1.7 points [16]. We will need 10 evaluable patients per arm to detect such a mean difference in change of pain score between the burst and tonic spinal cord stimulation arms, using a two-sided two-group t-test at a 0.05 significance level and 80% power, assuming a standard deviation of 1.3. This requires a total sample size of evaluable patients of 30. With approximate 5% attrition rate, we need a total of 33 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim 1:\u003c/strong\u003e The primary analysis is to compare the effects of burst versus tonic spinal cord stimulation, based on the primary endpoint of the short-term improvement of pain score from baseline to 30-days post treatment. The primary analysis will be conducted on an intent-to-treat basis, in which all patients will be included in the group they were allocated to by randomization. We will use t-test to compare the change in pain score from baseline to 30 days between burst and tonic stimulation groups. If the distributional assumption is not met, we will use its nonparametric counterpart, the Mann-Whitney test. Linear regression model will be used to adjust for relevant covariates (e.g., age, gender, disease stage etc.). As secondary analysis, we will also fit the generalized linear mixed models using pain score as the dependent variable and group assignment (burst vs tonic), time, group by time interaction and other important covariates (e.g., age, stage) as independent variables. These models are for hypothesis generating rather than for hypothesis testing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim 2: \u003c/strong\u003eThis aim is to compare the effects of burst versus tonic spinal cord stimulation on multiple secondary endpoints for chemotherapy induced peripheral neuropathy, including long-term changes in pain scores (i.e., pain changes between baseline and 90-days post treatment), as well as short-term and long-term changes in morphine equivalent daily dose (MEDD), functional status using gait and QST, and nerve density using skin biopsy samples to analyze epidermal nerve fibers and Meissner\u0026rsquo;s corpuscle density. Similarly, we will use the t-test (or Mann-Whitney test), as well as linear regression models, to compare the secondary endpoints of interest between burst and tonic spinal cord stimulation arms. For long-term changes in pain scores and other secondary endpoints (i.e., between baseline and 90-days post treatment), we will further include the patients, who are initially assigned to the sham arm and then cross-overed to stimulation arms, as exploratory analysis. In this analysis, there will be 15 evaluable patients per group. Given such a sample size, we will have at least 80% power to detect an effect size of 1.06 for the secondary endpoints between burst and tonic stimulation groups with a significance level of 0.05. We will also use the generalized linear mixed models to analyze the repeated measures for these endpoints collected over multiple time points to account for the correlation within patients. The analyses for secondary endpoints are conducted to generate hypothesis rather than to test hypothesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim 3:\u003c/strong\u003eThis aim is to compare the effect of spinal cord stimulation (combining burst and tonic stimulation) versus sham stimulation on the short-term primary and secondary endpoints (i.e., between baseline and 30-days post treatment) for chemotherapy induced peripheral neuropathy. Similar statistical approaches, such as t-test and linear regression, will be employed. Given 20 patients in the stimulation arm and 10 patients in the sham arm, we will have 80% power to detect an effect size of 1.12 between the stimulation and sham groups with a 0.05 significance level. We will use the generalized linear mixed effects model to correlate the longitudinal measures over time to account for the correlation within patients. Relevant covariates (e.g., age, disease stage) will be adjusted for in the mixed effects model. Sub-group analysis for each treatment might be conducted. These analyses are conducted for hypothesis generating purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMissing data: \u003c/strong\u003eIf missing data become an issue, we will assess the mixed model assumption by examining predictors of missingness. We will examine whether patients who drop out differ from those who remain and adjust for potentially relevant covariates found to be related to missingness. Additional techniques such as pattern mixture models will be explored if missingness is assumed to be nonignorable. Sensitivity analyses under various missing data mechanisms will be conducted. \u003c/p\u003e"},{"header":"4\tSTUDY POPULATION","content":"\u003cp\u003eWe will recruit a total of 33 patients.\u003c/p\u003e\n\u003cp\u003e- Gender non-specific\u003c/p\u003e\n\u003cp\u003e- Enroll 2-3 patients/month\u003c/p\u003e\n\u003ch2 id=\"_Toc121997263\"\u003e4.1 Eligibility Criteria\u003c/h2\u003e\n\u003ch2\u003eInclusion Criteria: \u0026nbsp;\u003c/h2\u003e\n\u003cp\u003e\u0026middot; Ability to understand and the willingness to sign a written informed consent document\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients diagnosed with CIPN lower extremity due to either vinca alkaloids, taxanes, bortezomib, thalidomide, platinum-based compounds\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients seen at Pain Management Center at MD Anderson Cancer Center\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patient ages greater or equal to 18 years but less than or equal to 85 years\u003c/p\u003e\n\u003ch2 id=\"_Toc121997264\"\u003e4.2 Exclusion Criteria\u003c/h2\u003e\n\u003cp\u003e\u003cu\u003eExclusion Criteria:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients with cognitive dysfunction\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patient with recent history (\u0026lt;6 months) of drug or alcohol abuse\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients with open skin lesion or undergoing antibiotic therapy for local for systemic infection\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients with painful diabetic peripheral neuropathy or preexisting peripheral neuropathy\u003c/p\u003e\n\u003ch2 id=\"_Toc121997265\"\u003e4.3 Children\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eChildren (\u0026lt;18 years) will be excluded \u0026ndash; we do not have the expertise to perform SCS or DRG stimulation in children.\u003c/p\u003e\n\u003ch2 id=\"_Toc121997266\"\u003e4.4 Special Populations\u003c/h2\u003e\n\u003cp\u003e- Employees, students (\u0026gt; 18 years), non-English speaking persons, and military personnel will only be excluded if meeting exclusion criteria. For non-English speaking persons, language appropriate translation services will be employed.\u003c/p\u003e\n\u003cp\u003e- Patients without capacity to consent will be excluded as it is unethical to impose a therapy for which they cannot give consent. Pregnant women and prisoners will also be excluded.\u003c/p\u003e\n\u003ch2 id=\"_Toc121997267\"\u003e4.5 Recruitment Methods\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003ePatients will be recruited from MD Anderson Pain Management Clinic as they are assessed for CIPN. Based on the chart review of patients with diagnosis of CIPN, pain management clinic sees upwards of 10 patients with CIPN a month.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo improve adherence to intervention protocols, patients will receive appointment reminder phone calls, follow-up calls, and their parking fees for study visits will be reimbursed.\u0026nbsp;\u003c/p\u003e"},{"header":"5\tSTUDY ASSESSMENTS AND PROCEDURES","content":"\u003ch2\u003e5.1 Consent Process\u003c/h2\u003e\n\u003cp\u003eIf interested, patients will have the informed consent (IC) explained to them by a PI before entering the study. The study will use the electronic informed consent in EPIC to consent each participant; however, if an electronic consent cannot be obtained, then the patient will sign, date, and put the time on the IC hard copy. The PI or research team member authorized to obtain consent will also sign, date and put time on the IC. A copy of the IC will be made and given to the patient for their records. \u0026nbsp;The original copy will be sent to Health Information Management for storage and another copy will be locked in secure location by the principal investigator.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe will follow OCR SOP 04: Informed Consent Process.\u0026nbsp;\u003c/p\u003e"},{"header":"6\tADVERSE EVENTS \u0026 RISKS ","content":"\u003ch2\u003e6.1 Adverse Events\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAdverse Event Definition\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSpinal cord stimulation\u003c/em\u003e\u0026ndash; risk inherent to the procedure\u003c/p\u003e\n\u003cp\u003e- Adverse event \u0026ndash; (1) irritation around the percutaneous trial electrode, (2) battery pocket site pain, (3) wound dehiscence, (4) lead migration.\u003c/p\u003e\n\u003cp\u003eManagement \u0026ndash; (1) irritation resolves transiently in most cases; sometimes ice packs or non-steroidal anti-inflammatories may be needed to reduce swelling or for pain control. (2) Battery pocket site pain can be managed with anti-inflammatories, or pain medications and possible steroid injection around the cluneal nerves. In rare cases, the pocket site may need to be moved to the opposite site. (3) Wound dehiscence may be managed with steri-strips and antibiotics, or many need to be taken back to the OR for a washout closure. (4) Lead migration may result in loss of therapy and the leads may need to be repositioned.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- Risks are minimized to the lowest possible level by ensuring sterile procedural techniques, reviewing patient\u0026rsquo;s allergy list, and appropriate usage of the device (as approved by FDA).\u003c/p\u003e\n\u003cp\u003e- While we do not anticipate or expect any adverse events from the proposed intervention, any adverse events will be promptly recorded in electric medical record and reported to the IRB.\u003c/p\u003e\n\u003cp\u003e- Participants may choose to withdraw from the study at any time upon their request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSerious Adverse Events\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhile we do not anticipate or expect any Serious Adverse Events from the proposed intervention, SAEs will be reported according to institution\u0026rsquo;s standards. An adverse event or suspected adverse event is considered \u0026ldquo;serious\u0026rdquo; if in the view of either the investigator or the sponsor, it results in any of the following outcomes:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Death\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026middot; Life-threatening adverse event\u003c/p\u003e\n\u003cp\u003e\u0026middot; Results in persistent or significant disability/incapacity\u003c/p\u003e\n\u003cp\u003e\u0026middot; In-patient hospitalization or prolongation of existing hospitalization\u003c/p\u003e\n\u003cp\u003e\u0026middot; Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions\u003c/p\u003e\n\u003cp\u003e\u0026middot; Congenital anomaly/birth defect\u003c/p\u003e\n\u003ch2\u003e6.2\u0026nbsp; Participant Compensation\u003c/h2\u003e\n\u003cp\u003ePatients will not be compensated for their participation in this study. Since these procedures are approved treatments for neuropathic pain, insurance providers may be financially responsible for the cost of Study procedures and for care and treatment of any complications resulting from these procedures. Standard medical care received under this research study will be billed in an ordinary manner.\u0026nbsp;\u003c/p\u003e"},{"header":"7\tPOTENTIAL BENEFITS","content":"\u003cp\u003ePatients enrolled in treatment group have a potential to receive benefit (i.e. pain relief) from the procedure.\u0026nbsp;\u003c/p\u003e"},{"header":"8\tDATA MANAGEMENT AND SHARING PLAN ","content":"\u003cp\u003eSubject data will be identified in the research data set using random sequential numbering.\u003c/p\u003e\n\u003cp\u003eStudy data will be collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at MD Anderson. REDCap (www.projectredcap.org) is a secure, web-based application with controlled access designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless downloads to common statistical packages; and 4) procedures for importing data from external sources. REDCap (https://redcap.mdanderson.org) is hosted on a secure server by MD Anderson Cancer Center’s Department of Research Information Systems \u0026amp; Technology Services. REDCap has undergone a Governance Risk \u0026amp; Compliance Assessment (May 2014) by MD Anderson's Information Security Office and found to be compliant with HIPAA, Texas Administrative Codes 202-203, University of Texas Policy 165, federal regulations outlined in 21CFR Part 11, and UTMDACC Institutional Policy #ADM0335.\u003c/p\u003e\n\u003cp\u003eThe Department’s Data Manager will assist us in creating the database in REDCap, building the necessary queries and coordinating data entry. We will collect data from EPIC. Collected data per medical record will be assigned a unique identifier in the database and access will be limited to those who are directly working on the project and are part of the Institutional Review Board (IRB) approved protocol. Password protected computers will also be used to secure the database and prevent improper use of Protected Health Information (PHI). Following publication study data will be archived in REDCap. PHI will not be shared with any other persons or entities except as required by law. Identifiers will be destroyed at the earliest opportunity and the study team will not disclose PHI to any other person or entity except as required by law.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSpinal cord stimulation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDRG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDorsal root ganglion\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePeripheral nerve stimulation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMeissner\u0026rsquo;s corpuscle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCIPN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChemotherapy induced peripheral neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eENF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEpidermal nerve fiber\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e9 DISSEMINATION POLICY: AUTHORSHIP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo qualify as an author individuals must have: \u003c/p\u003e\n\u003cp\u003e1. Contributed to the conception or design of the work, statistical analyses, or data interpretation \u003c/p\u003e\n\u003cp\u003e2. Drafted and revised the work critically for intellectual content\u003c/p\u003e\n\u003cp\u003e3. Provided final approval of the version to be published \u003c/p\u003e\n\u003cp\u003e4. Agreed to be accountable for all aspects of the work \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Status \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNCT06121232 Version 2.0 was registered on November 2\u003csup\u003end\u003c/sup\u003e, 2024. Recruitment began January, 2025 and is expected to complete in April, 2026. IRB (#2023-0041) was approved on May, 1\u003csup\u003est\u003c/sup\u003e, 2024 (OHRP IRB Registration #: IRB00000121). \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.1 Ethics approval and consent to participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the MD Anderson IRB (2023-0041), UT MD Anderson Cancer Center\u003cbr\u003e Institutional Review Board, 7007 Bertner Avenue, Unit 1637, Houston, TX 77030. An informed consent form will be collected from participants in the study. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.2 Consent for publication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.3 Availability of data and material \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData and materials will be available on ClinicalTrials.gov (NCT06121232).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.4 Funding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by the MD Anderson Junior Faculty Division to provide salary support for the research coordinator. The study sponsor, MD Anderson Junior Faculty Division, is not involved in designing the study, collecting, managing, analyzing, or interpreting the data, drafting the report, or determining whether the report will be submitted for publication. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.5 Competing Interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.6 Authors\u0026rsquo; contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSJ conceived of the trial, designed the interventions, and developed the plans for statistical analyses. SJ and SJK drafted and refined the manuscript. All authors read and approved the manuscript. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.7 Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThanks to the MD Anderson Junior Faculty Division ([email protected]) for providing funding. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCONFIDENTIALITY STATEMENT\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThisdocument is confidential communication. Acceptance of this document constitutes agreement by the recipient that no unpublished information contained herein will be published or disclosed without prior approval of the Principal Investigator\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTanner, K.D., D.B. Reichling, and J.D. Levine, \u003cem\u003eNociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat.\u003c/em\u003e J Neurosci, 1998. \u003cstrong\u003e18\u003c/strong\u003e(16): p. 6480-91.\u003c/li\u003e\n\u003cli\u003eKoeppen, S., \u003cem\u003eTreatment of multiple myeloma: thalidomide-, bortezomib-, and lenalidomide-induced peripheral neuropathy.\u003c/em\u003e Oncol Res Treat, 2014. \u003cstrong\u003e37\u003c/strong\u003e(9): p. 506-13.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Souza, R.S., et al., \u003cem\u003eNeuromodulation Therapy for Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review.\u003c/em\u003e Biomedicines, 2022. \u003cstrong\u003e10\u003c/strong\u003e(8).\u003c/li\u003e\n\u003cli\u003eAbd-Elsayed, A., N. Schiavoni, and H. Sachdeva, \u003cem\u003eEfficacy of spinal cord stimulators in treating peripheral neuropathy: a case series.\u003c/em\u003e J Clin Anesth, 2016. \u003cstrong\u003e28\u003c/strong\u003e: p. 74-7.\u003c/li\u003e\n\u003cli\u003eSlavin, K.V., et al., \u003cem\u003eTonic and burst spinal cord stimulation waveforms for the treatment of chronic, intractable pain: study protocol for a randomized controlled trial.\u003c/em\u003e Trials, 2016. \u003cstrong\u003e17\u003c/strong\u003e(1): p. 569.\u003c/li\u003e\n\u003cli\u003ePike, C.T., et al., \u003cem\u003eHealthcare costs and workloss burden of patients with chemotherapy-associated peripheral neuropathy in breast, ovarian, head and neck, and nonsmall cell lung cancer.\u003c/em\u003e Chemother Res Pract, 2012. \u003cstrong\u003e2012\u003c/strong\u003e: p. 913848.\u003c/li\u003e\n\u003cli\u003eGroenen, P.S., N. van Helmond, and K.B. Chapman, \u003cem\u003eChemotherapy-Induced Peripheral Neuropathy Treated with Dorsal Root Ganglion Stimulation.\u003c/em\u003e Pain Med, 2019. \u003cstrong\u003e20\u003c/strong\u003e(4): p. 857-859.\u003c/li\u003e\n\u003cli\u003eEge, E., et al., \u003cem\u003eRisk factors for surgical site infection in advanced neuromodulation pain procedures: a retrospective study.\u003c/em\u003e Pain Manag, 2023. \u003cstrong\u003e13\u003c/strong\u003e(7): p. 397-404.\u003c/li\u003e\n\u003cli\u003eTanner, K.D., J.D. Levine, and K.S. Topp, \u003cem\u003eMicrotubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat.\u003c/em\u003e J Comp Neurol, 1998. \u003cstrong\u003e395\u003c/strong\u003e(4): p. 481-92.\u003c/li\u003e\n\u003cli\u003eSeretny, M., et al., \u003cem\u003eIncidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.\u003c/em\u003e Pain, 2014. \u003cstrong\u003e155\u003c/strong\u003e(12): p. 2461-2470.\u003c/li\u003e\n\u003cli\u003eTeran-Wodzinski, P., et al., \u003cem\u003eAssessing gait, balance, and muscle strength among breast cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN): study protocol for a randomized controlled clinical trial.\u003c/em\u003e Trials, 2022. \u003cstrong\u003e23\u003c/strong\u003e(1): p. 363.\u003c/li\u003e\n\u003cli\u003eMenant, J.C., et al., \u003cem\u003eEvidence of slow and variable choice-stepping reaction time in cancer survivors with chemotherapy-induced peripheral neuropathy.\u003c/em\u003e Gait Posture, 2021. \u003cstrong\u003e89\u003c/strong\u003e: p. 178-185.\u003c/li\u003e\n\u003cli\u003eWinters-Stone, K.M., et al., \u003cem\u003eFalls, Functioning, and Disability Among Women With Persistent Symptoms of Chemotherapy-Induced Peripheral Neuropathy.\u003c/em\u003e J Clin Oncol, 2017. \u003cstrong\u003e35\u003c/strong\u003e(23): p. 2604-2612.\u003c/li\u003e\n\u003cli\u003eKoskinen, M.J., et al., \u003cem\u003eIntraepidermal nerve fibre density in cancer patients receiving adjuvant chemotherapy.\u003c/em\u003e Anticancer Res, 2011. \u003cstrong\u003e31\u003c/strong\u003e(12): p. 4413-6.\u003c/li\u003e\n\u003cli\u003eBoyette-Davis, J.A., et al., \u003cem\u003eFollow-up psychophysical studies in bortezomib-related chemoneuropathy patients.\u003c/em\u003e J Pain, 2011. \u003cstrong\u003e12\u003c/strong\u003e(9): p. 1017-24.\u003c/li\u003e\n\u003cli\u003eDe Ridder, D., et al., \u003cem\u003eA 2-center comparative study on tonic versus burst spinal cord stimulation: amount of responders and amount of pain suppression.\u003c/em\u003e Clin J Pain, 2015. \u003cstrong\u003e31\u003c/strong\u003e(5): p. 433-7.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 2. \u0026nbsp;The schedule of enrollment, interventions, and assessments\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" style=\"width: 687px; height: 768.807px;\" width=\"687\" height=\"768.807\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e All items from the World Health Organization Trial Registration Data Set\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePrimary registry and trial identifying number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eClinicalTrials.gov\u003c/p\u003e\n \u003cp\u003eNCT06121232\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eDate of registration in primary registry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eNovember 2\u003csup\u003end\u003c/sup\u003e, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eSecondary identifying numbers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eNCI-2023-09269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eSource(s) of monetary or material support\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eMD Anderson Junior Faculty Division\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePrimary sponsor\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eMD Anderson Junior Faculty Division\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eContact for public queries\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eSaba\u0026nbsp;Javed, M D\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEmail:\u0026nbsp;\u003c/strong\[email protected]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eContact for scientific queries\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eSaba\u0026nbsp;Javed, M D\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEmail:\u0026nbsp;\u003c/strong\[email protected]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePublic title\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eBenefit of tonic versus burst spinal cord stimulation for chemo-induced peripheral neuropathy using psychophysical testing\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eScientific title\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eExploring the Benefit of Neuromodulation in Treating Chemo-induced Peripheral Neuropathy Using Peripheral Neuropathy Markers (Meissner\u0026apos;s Corpuscles and Epidermal Nerve Fiber Density) and Sensory Testing (Quantitative Sensory and Gait Testing): A Single Center Feasibility Study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eCountries of recruitment\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eHealth condition(s) or problem(s) studied\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eChemotherapy induced peripheral neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eIntervention(s)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eNeuromodulation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eKey inclusion and exclusion criteria\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eInclusion Criteria:\u003c/p\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eAbility to understand and the willingness to sign a written informed consent document\u003c/li\u003e\n \u003cli\u003ePatients diagnosed with CIPN lower extremity due to either vinca alkaloids, taxanes, bortezomib, thalidomide, platinum-based compounds\u003c/li\u003e\n \u003cli\u003ePatients seen at Pain Management Center at MD Anderson Cancer Center\u003c/li\u003e\n \u003cli\u003ePatient ages greater or equal to 18 years but less than or equal to 85 years\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003eExclusion Criteria\u003c/p\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003ePatients with cognitive dysfunction\u003c/li\u003e\n \u003cli\u003ePatient with recent history (\u0026lt;6 months) of drug or alcohol abuse\u003c/li\u003e\n \u003cli\u003ePatients with open skin lesion or undergoing antibiotic therapy for local for systemic infection\u003c/li\u003e\n \u003cli\u003ePatients with painful diabetic peripheral neuropathy or preexisting peripheral neuropathy\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eA Single Center Feasibility Study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eDate of first enrolment\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003e01/2025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eTarget sample size\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eRecruitment status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePrimary outcome(s)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003eThe NRS pain score, MEDD, nerve density (Meissner\u0026rsquo;s Corpuscle and ENF), and functional testing (QST and Gait testing)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chemotherapy-induced peripheral neuropathy (CIPN), Spinal cord stimulation (SCS), Burst stimulation, Tonic stimulation, Neuromodulation, Pain management, Quantitative sensory testing (QST), Gait analysis, Epidermal nerve fiber density (ENF), Meissner’s corpuscles","lastPublishedDoi":"10.21203/rs.3.rs-5915887/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5915887/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChemotherapy-induced peripheral neuropathy (CIPN) presents a significant challenge in various chemotherapy treatments. CIPN manifests with symptoms such as numbness, tingling sensations, persistent shooting or burning pain, loss of sensation, muscle weakness, and impaired balance in the extremities. Its incidence is reported to be as high as 68% within the first month of chemotherapy and remains at 60% after three months. Current management strategies lack a universally accepted gold standard, with approaches like physical therapy, anticonvulsants, and other non-pharmacological therapies showing limited efficacy. Consequently, there is an urgent need for an effective non-pharmacological treatment option for CIPN, which would significantly benefit patients undergoing cancer treatment.\u003c/p\u003e\n\u003cp\u003eThere have been limited investigations into the potential of spinal cord stimulation (SCS) to enhance neuropathy and neurological function in patients with chemotherapy-induced peripheral neuropathy (CIPN), and there is a scarcity of studies examining the effects of SCS specifically on CIPN. Therefore, this proposed study aims to evaluate the effectiveness of burst versus tonic spinal cord stimulation in addressing chemotherapy-induced peripheral neuropathy. The study will assess changes in pain scores, pain medication consumption, sensory and physical function, patient-reported outcomes, and the composition of peripheral nerves and mechanoreceptors before and after spinal cord stimulation.\u003c/p\u003e\n\u003cp\u003eThe research holds promise in reducing the reliance on opioids in CIPN patients, making it a crucial endeavor for affected individuals and society at large. Ultimately, this will mark the first randomized, controlled trial to investigate the efficacy of tonic versus burst SCS waveforms for managing CIPN, with a focus on improving pain, sensory function, and reducing pain medication consumption.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: ClinicalTrials.gov, NCT06121232. Registered 2 November 2024, https://clinicaltrials.gov/study/NCT06121232?term=saba%20javed\u0026amp;rank=4\u003c/p\u003e","manuscriptTitle":"Benefit of Tonic Versus Burst Spinal Cord Stimulation for Chemo-Induced Peripheral Neuropathy Using Psychophysical Testing","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-07 15:13:52","doi":"10.21203/rs.3.rs-5915887/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5c5ca169-bc6c-45b7-8810-75d7d922d409","owner":[],"postedDate":"April 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-24T15:56:50+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-07 15:13:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5915887","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5915887","identity":"rs-5915887","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}