The Fibromyalgia Transcutaneous Electrical Nerve Stimulation in Physical Therapy Study Protocol: A Multisite Embedded Pragmatic Trial

Abstract

Objectives

Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention that provides an electrical current through the skin to produce analgesia. The primary purpose of this study is to examine if the addition of TENS to routine physical therapy improves movement-evoked pain in individuals with fibromyalgia in a physical therapy clinical setting.

Methods

Fibromyalgia TENS in Physical Therapy Study is a phase III embedded pragmatic clinical trial funded through the National Institutes of Health Helping to End Addiction Long-Term Initiative. This trial will utilize a randomized cluster design that includes more than 110 physical therapists in 24 to 30 physical therapy clinics within 6 health care systems and 7 states. Clinics will be randomized to TENS or No-TENS, stratified by health care system and clinic size. The plan is to enroll 600 participants, with all participants completing physical therapy as prescribed by their physical therapist. Participants at TENS clinics will utilize TENS for a minimum of 2-hour per day while at the physical therapy clinic and at home when active. The primary outcome is reduction in movement-evoked pain from baseline to day 60 on an 11-point numeric rating scale when participants sit and stand 5 times (Sit and Stand Test). Secondary outcomes include resting pain and fatigue, pain interference, fibromyalgia disease activity, movement-evoked fatigue, multidimensional assessment of fatigue, rapid assessment of physical activity, patient global impression of change, and common data elements shared across studies supported through the Helping to End Addiction Long-Term Initiative.

Impact

The findings from this study will provide effectiveness data on TENS for individuals with fibromyalgia for health care policymakers, clinicians, and insurers. Data from this study will also inform future pragmatic trials for nonpharmacological interventions and chronic musculoskeletal pain conditions.

Introduction

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain, tenderness, and stiffness and is associated with fatigue and sleep disturbance. A recent meta-analysis of 65 studies including more than 3 million people worldwide showed FM prevalence is approximately 2% overall and 4% in women.¹ Pharmacological interventions are modestly effective for FM, with most individuals continuing to experience activity-limiting pain and fatigue despite use of multiple drugs.^2,3 It has become increasingly recognized that nonpharmacological interventions should be considered first-line treatments for chronic pain^4–6 and can be used as initial treatments or added to pharmacological approaches. Despite clinical recommendations, nonpharmacological treatments are underutilized for chronic pain, including FM.⁷

FM is associated with altered central processing manifested as increased central excitability and loss of central inhibition.^8,9 Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention that delivers electrical current through the skin for pain control. Prior research shows TENS activates endogenous inhibitory mechanisms, including release of endogenous opioids, in the central nervous system to reduce central excitability.^10,11 Our recent randomized controlled clinical trial (RCT), the Fibromyalgia Activity Study with TENS (FAST), showed that TENS significantly reduced movement-evoked pain and fatigue in individuals with FM compared with Placebo-TENS or No-TENS.¹² Although there is strong evidence that exercise is an effective treatment for chronic pain, including FM,^13,14 individuals with chronic pain often report movement-evoked pain that limits activity participation.^15,16 Thus, use of a nonpharmacological treatment that reduces movement-evoked pain could enhance activity and adherence to exercise recommendations.

Although physical therapists are trained in the use and prescription of TENS, it is an underutilized and often underdosed intervention in routine physical therapy practice.^17–20 The Fibromyalgia TENS in Physical Therapy Study (FM-TIPS, NCT 04683042) is a phase III, embedded pragmatic trial assessing the effectiveness of TENS for FM when implemented in a physical therapy practice setting. The primary objective of FM-TIPS is to determine if the addition of TENS to routine physical therapy improves movement-evoked pain in individuals with FM. Secondary aims will determine if the addition of TENS to physical therapy improves disease activity and symptoms, increases adherence to physical therapy, improves likelihood of achieving patient-specific functional goals, and reduces medication use. We also plan to examine the feasibility of implementing TENS into routine physical therapy care for FM.

Methods

Multidisciplinary Study Team

The study team includes the Clinical Trials Statistical and Data Management Center at the University of Iowa that serves as the data coordinating center and pain researchers in physical therapy and rheumatology that serve as clinical coordinators (Fig. 1). The study team also includes more than 110 physical therapists from 24 to 30 clinics across 6 health care systems in 7 states. In addition, as part of the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing funding mechanism, the team worked closely with the National Institutes of Health (NIH) Collaboratory to design and implement this pragmatic trial. The NIH Collaboratory is supported by the Common Fund at the NIH, serving as a resource coordinating center for large-scale embedded pragmatic clinical trials.

Figure 1.

Study organizational chart. The study was led by Dr Sluka and Dr Crofford, the principal investigators (PIs), who are responsible for the oversight of study activities, communication with health care systems, research study staff, National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Data and Safety Monitoring Board. An executive committee is the decision-making body and includes PIs, National Institute of Health representatives, and study team leaders. A weekly operations meeting that includes all team members, reviews and discusses high-priority initiatives for collaborative decision-making and reviews study activities, including enrollment and retention. Four groups are responsible for different aspects of the study. The Regulatory Group manages the central institutional review board and maintains the study protocol and the site contracts. The Data and Safety Management Group manages REDCap, electronic health record (EHR) extraction, reports, statistical design, and analysis. The Clinic Direct Communication group is responsible for site training and clinic enrollment and retention, whereas the Patient Direct Communication group is responsible for recruitment and retention of participants and issues related to the transcutaneous electrical nerve stimulation (TENS) intervention.

Study Design

This study is a cluster-randomized, embedded pragmatic trial that began recruitment in January 2021 and will enroll 600 individuals with FM. Physical therapy clinics are randomized to TENS or No-TENS and stratified by health care system and clinic size (large: >3 physical therapists vs small: ≤3 physical therapists). Twenty-four clinics were originally randomized. However, due to COVID-19, participating clinics and health care systems were adversely affected and therefore limited their ability to recruit and enroll participants. Further, several clinics chose to discontinue participation in the study due to a variety of reasons, including burdens from the pandemic or a loss of interest. To achieve the study target enrollment goal of 600 participants, an additional health care system and 10 clinics were added and randomized to TENS or No-TENS utilizing the same stratification strategy. Currently, we have randomized 34 clinics and 28 clinics are activated to enroll.

Participants

Eligible participants will be starting an episode of land-based physical therapy for FM, neck pain with FM, or back pain with FM. All participants will complete physical therapy as prescribed by their physical therapist. Participants will be included if they have been previously told by a clinician that they have FM (Fig. 2). When a participant enrolls, they will complete a series of baseline self-report outcome measures that will include the 2016 American College of Rheumatology FM diagnostic criteria.²¹ We will record the percentage of participants who fulfill the American College of Rheumatology FM diagnostic criteria. Exclusion criteria are limited to contraindications for TENS and serious mental or health conditions that preclude participation. All participants receive financial compensation for their time and efforts and will receive 2 TENS units and electrodes.

Figure 2.

Shown are the inclusion and exclusion criteria, which are subject to change throughout the course of study to assist with enrollment. Alterations in inclusion and exclusion criteria will be determined with input from the National Institutes of Health, the Study Team, and the Data and Safety Monitoring Board. TENS = transcutaneous electrical nerve stimulation.

Study Intervention: TENS

TENS is a nonpharmacological intervention for pain control available without a prescription. The TENS device is purchased from NeuroMetrix Inc (Woburn, MA, USA) and was designed for this study to use similar parameters as our prior RCT¹² and to record usage data. The device is controlled by both a single button on the device and with the QuellFlex application (app) (Quell Wearable Pain Relief Technology, Woburn, MA, USA). The custom device uses an asymmetric, biphasic, rectangular, pulsed waveform with a modulating frequency (2–125 pps), where the first phase is 100 microseconds and the second phase is 180 microseconds, including a 100-microsecond inter-phase interval, similar to parameters used in our prior RCT.¹² Placement of electrodes and dosing will follow the same protocol as our prior RCT. Participants will apply TENS with butterfly electrodes on both the upper back and lower back at a strong but comfortable intensity for a minimum of 2 h/d during physical therapy and routine activities or exercises at home.¹²

Outcomes

All participants will complete home-based outcome measures at days 1, 30, 60, 90, and 180 (termed “Research Homework”) (Table). The primary outcome will be collected on day 60.

Table.

Outcome Measures^a

Instrument	Timepoint	Construct and General Information	Reliability	Validity	Study
Numeric rating scale	Day 1, 30, 60, 90, 180 (65 for No-TENS group)	Self-report of pain and fatigue on 0–10 scale at rest and movement	ICC = 0.71–0.99	0.710.78	Kahl and Cleland37
Patient Specific Functional Scale	Day 1, 30, 60, 90, 180	Patient-reported difficulty with self-selected activities; 0–10 scale	ICC = 0.91	r = 0.53	Maughan et al38 Gross et al39
2016 Fibromyalgia diagnostic criteria	Day 1	WPI ≥ 7, SSS ≥ 5, OR WPI of 4–6, and SSS ≥ 9	Kappa = 0.73	NA	Wolfe et al21 Shresher et al40
Fibromyalgia Impact Questionnaire Revised	Day 1, 30, 60, 90, 180	Fibromyalgia-specific questionnaire on function, impact, and symptoms; 21 items	r = 0.88	r = 0.69-0.88	Bennett et al41
Multidimensional Assessment of Fatigue	Day 1, 30, 60, 90, 180	Measure fatigue with 4 dimensions; 16 items	0.89–93	r = 0.62–0.84	Belza et al42 Hughes43
Brief Pain Inventory	Day 1, 30, 60, 90, 180	Pain severity and interference; 11 items	Cronbach alpha = .85–0.88	r = 0.57	Tan et al44
PROMIS-Physical Functionb	Day 1, 30, 60, 90, 180	Physical function, NIH patient-reported outcome measure system	Cronbach alpha = .58–0.94	r = 0.73	Merriwether et al45
PROMIS-Sleepb	Day 1, 30, 60, 90, 180	Quality and quantity of sleep; 8 items	Test–retest: ICC = 0.62–0.71	r = 0.71	Chimenti et al46
Pain Catastrophizing Scaleb	Day 1, 30, 60, 90, 180	Pain magnification, rumination, and helplessness; 13 items	Total Cronbach alpha = .95	0.42	Osman et al47
Personal Health Questionnaire Depression Scaleb	Day 1, 30, 60, 90, 180	Depressive disorder; 8 items	Cronbach alpha = .89	r = 0.61	Shin et al48
Generalized Anxiety Disorder -7b	Day 1, 30, 60, 90, 180	Severity of various signs of generalized anxiety disorder; 7 items	Cronbach alpha = .85–0.93	Spearman rho = 0.45–0.65	Byrd-Bredbenner et al49
Rapid Assessment of Physical Activity	Day 1, 30, 60, 90, 180	Current level of physical activity; 9 items	NA	r = 0.54	Topolski et al50
Patient Global Impression of changeb	Day 1, 30, 60, 90, 180	Patient evaluation of health and improvement, 1 item	N/A	r = 0.43	Rampakakis et al51
Tobacco, alcohol, prescription medication, and other substance useb	Day 1, 60, 180	Substance abuse, 4 items	N/A	N/A	N/A
Concomitant medications	Day 1, 180	N/A	N/A	N/A	N/A
Adverse events	Days 30, 60, 90, 180	N/A	N/A	N/A	N/A
Barriers to TENS	Day 180	N/A	N/A	N/A	N/A

^a ICC = intraclass correlation coefficient; SSS = Symptom Severity Scale; TENS = transcutaneous electrical nerve stimulation; WPI = Widespread Pain Index.

^b HEAL Initiative Core Data Element.

The primary outcome measure will be reduction of movement-evoked pain measured on an 11-point Numeric Rating Scale (NRS) from day 1 to day 60 (change score). Movement-evoked pain will be assessed during a Sit and Stand Test (Fig. 3) based on results from our prior RCT that showed a clinically significant reduction using this test.¹² The study team piloted the procedures with test participants at home to develop instructions and ensure proper execution. Secondary outcome measures include (1) resting pain (NRS), (2) pain interference (Brief Pain Inventory), (3) FM disease activity (Revised Fibromyalgia Impact Questionnaire), (4) movement-evoked fatigue (NRS), (5) resting fatigue (NRS), (6) Multidimensional Assessment of Fatigue, (7) Rapid Assessment of Physical Activity, (8) Patient Global Impression of Change, and (9) HEAL common data elements.

Figure 3.

Sit and Stand Test. Movement-evoked pain is our primary outcome and is measured as the maximum pain that occurs when the participant sits and stands 5 times (Sit and Stand Test). Participants will be asked to measure their pain and fatigue before starting the assessment on REDCap. Participants will then complete the Sit and Stand Test. The participant will be asked to wear comfortable shoes and place a chair against a wall. They will then sit and stand from the chair for a total of 5 repetitions with their feet shoulder width apart. Participants will be asked to not utilize arm rests unless necessary to complete the assessment. Following the test, participants will rate their pain and fatigue during the task on REDCap. We will therefore collect resting pain as well as pain during a movement activity.

We will also examine effects of TENS use from day 1 to day 180 within the TENS group and day 65 to day 180 in the no-TENS group. We will look for changes in primary and secondary outcomes listed above to assess for long-term symptom profiles following early and delayed TENS use within each group.

Study Flow

Figure 4 provides details for the study flow. In brief, participants are screened on physical therapy visit (PT Visit) #1, sign an electronic informed consent (eConsent) after successful screening before PT Visit #2, and receive TENS (or no-TENS) instruction on PT Visit #2. Participants in the TENS group will receive TENS units at PT Visit #2 and will be expected to use TENS for the duration of their enrollment. All participants complete physical therapy as prescribed by their physical therapist. Participants will complete assessments at home on day 1 after PT Visit #2, and days 30, 60, 90, and 180. The Patient Specific Functional Scale will be completed with at least 2 patient-selected activities. Participants in the no-TENS group will receive TENS units following completion of their Research Homework on day 60, the primary outcome, and will instructed on use of TENS virtually by a licensed physical therapist on the study team. On day 65, the no-TENS group completes Research Homework for the Sit and Stand Test with TENS and will utilize TENS in the same manner as TENS participants until the end of their enrollment.

Figure 4.

Study flow diagram. At the initial physical therapy visit (PT Visit #1), physical therapists will identify and provide potential participants information about the study. If interested, the potential participant will complete an eligibility screen on a tablet through a secure, online data management system (REDCap). Potential participants will receive additional information on the study through education from their physical therapist, study brochures and flyers, and links to web-based study information. Participants who pass the eligibility screening will immediately be sent an electronic informed consent form (eConsent) that reviews the purpose of the study, procedures, risk and benefits, participant information data storage, and contact information of the study team for questions. Once the participant signs the eConsent, a member of the study team will review the eConsent and provide a second signature. On the second visit (PT Visit #2), physical therapists will verify completion of the eConsent prior to initiation of study procedures. Physical therapists at TENS and No-TENS clinics will review the process for completing Research Homework (outcome measures) with participants. For participants at TENS clinics, their physical therapist will complete TENS instruction. The participant’s day 1 (baseline) Research Homework must be completed prior to their third visit (PT Visit #3) to continue in the study, with the third visit scheduled within 10 days of the second visit. Participants will then complete Research Homework at 30, 60, 90, and 180 days. After completion of day 60 Research Homework, participants in the No-TENS clinics will be sent 2 TENS units and will complete a virtual TENS instruction session with a member of the study team. They will then complete the Sit and Stand Test at day 65 with the use of TENS and will utilize TENS similar to the TENS group for the duration of their enrollment.

Research Homework will be completed by participants utilizing a patient-facing portal in REDCap (REDcap, https://www.project-redcap.org/software). Participants are sent a REDCap link to their email that takes them directly to the surveys with no log-in required. Participants will complete data collection at home with the use of a personal electronic device (eg, computer, laptop, tablet, or phone). During PT Visit #2, the physical therapist will instruct the participant on the use of REDCap to access survey forms. Participants will receive a reminder email with a link to their REDCap surveys and a text message reminder 5 and 3 days prior to each Research Homework timepoint. The link remains open for ±5 days from each timepoint. An additional reminder email and text message are sent 2 days after the timepoint. If a participant does not complete their Research Homework at days 60 or 180 within 2 to 4 days of the due date, a study team member will contact the participant by phone and/or email to encourage completion. To help with accessing and navigating the surveys and to answer general questions regarding the Research Homework throughout the study, a study-specific email address and phone contact is provided to all participants. The physical therapists are also provided a study team contact number for immediate help to assist with eConsent on PT Visit #2.

Physical Therapist Study Training

We developed a comprehensive training plan that includes virtual and onsite training with each physical therapist using written and video materials. All physical therapists complete Human Subjects Protection training through the Collaborative Institutional Training Initiative or virtually through the University of Iowa Institutional Review Board (IRB)/Human Subjects Office. TENS and No-TENS clinics are provided with individualized manuals with study organizational overview charts and diagrams, instructions on study procedures, scripts, and study team contact information. Study-related information is also published on a private clinician page on the study website. New physical therapists joining a clinic will be required to complete training with the study team and obtain IRB approval prior to recruiting and enrolling participants. Physical therapists are instructed on identifying patients with FM, screening and enrollment procedures, mechanisms and clinical effectiveness of TENS, operating TENS devices, and participant Research Homework requirements. Study staff are unblinded to allow for appropriate clinician training and to answer clinic-specific questions regarding study protocol and procedures. The physical therapists and participants are also unblinded to clinic randomization. The Safety Officer will remain blinded.

Our clinician engagement plan includes regular communication with clinicians and clinic owners or managers. Each health care system has a study team representative who communicates with individual clinics to answer questions and discuss enrollment. Each clinic has a physical therapist who serves as a site champion and contact. Clinics are provided monetary and nonmonetary incentives to facilitate recruitment and enrollment (Fig. 5). Additional strategies to assist recruitment include posting flyers and brochures in public areas, contacting referring providers about the study, and developing materials for clinic websites and social media.

Figure 5.

Clinician engagement plan and clinic incentives for recruitment. PT = physical therapy.

Data Management

A data management plan was developed utilizing the REDCap platform and managed by the Institute for Clinical and Translational Science at the University of Iowa to collect patient-level data. In addition to study-specific outcome measures, case report forms (CRFs) include Common Data Elements from the HEAL Initiative for a total of 21 survey CRFs and 2 study CRFs developed by the study team. The electronic versions of each instrument were pilot tested prior to moving the project into production and with each update to ensure data capture is functioning according to specifications.

To measure adherence to physical therapy, data are collected from the electronic health records (EHRs) from each health care system, including number of physical therapy visits scheduled and attended. Additional EHR data extraction includes ICD-10 codes, treatment codes (Current Procedural Terminology coding), and start-and-stop dates for the episode of care.

Reports are generated from the REDCap database to monitor recruitment and enrollment and to develop reports for internal team meetings, clinics, the study sponsor, and the NIH Collaboratory. Study reports for data completeness are created by the study team and reviewed regularly to determine if participants should be prompted to complete eConsent or Research Homework.

TENS usage is captured using the QuellFlex smart phone app by having the participant open the app once per week. The number of TENS sessions, minutes used per week, and TENS intensity will be collected.

Adverse Event Reporting

Due to the pragmatic nature of the trial, all adverse events (AEs), serious adverse events (SAEs), and unanticipated problems will be self-reported by participants through a CRF titled Participant Experiences at 30, 60, 90, and 180 days following enrollment. An AE in this study is defined as any unfavorable and unintended sign or symptom temporally associated with the use of the TENS units or with study procedures. An unanticipated problem will be defined as unexpected adverse clinical symptoms related to TENS or electrode use.

In our FAST RCT with 300 individuals with TENS, we had no SAEs related to the study procedures or intervention.¹² We did report some minor AEs related to the intervention and used these to develop our Participant Experiences CRF. The experiences from using TENS or electrodes that are specifically queried include anxiety with TENS, itchiness with TENS, nausea with TENS, skin irritation with electrodes, and pain with TENS. The participants have the opportunity to report other experiences as well. The experiences we specifically ask regarding study procedures are falls during the Sit and Stand Test and fall or injury during therapeutic exercises at home. In addition, we specifically query the participant regarding changes in health that would exclude participants from TENS use, including pacemaker, implanted neurostimulator or any other implanted device, new diagnosis of epilepsy, new diagnosis of cancer, or pregnancy. Should these changes to health be reported, the participant will be withdrawn from TENS treatment.

Finally, we ask if participants have been hospitalized or have been to the emergency room and ask for the reason. We specifically ask the participant if the event was related to TENS or study procedures. If not, they are not considered an AE or SAE.

If a participant reports a change in health status excluding them from TENS, visit to the emergency room, or hospitalization, a Participant Experience follow-up form is completed. If relatedness to TENS or study procedures is unclear, the study team will follow-up with the participant to clarify the event. The medical monitor then assigns relatedness and severity of the AE, along with information regarding the onset and stop date of the AE and whether any action was taken.

Any SAEs or unanticipated problems that are reported as related to TENS use will be reviewed within 1 working day of the time of report. If any event meets expedited reporting criteria, the event will be reported to the University of Iowa central IRB (cIRB) within 5 working days and according to their policies.

Sample Size

We will recruit 600 participants over the course of 3 years. The study sample size was calculated to assess the effect of TENS versus No-TENS for change from baseline to day 60 in movement-evoked pain using 2-independent samples t test with inflation factor of [1 + (m−1)*ICC] applied to account for average cluster size (m) and intraclass correlation coefficient (ICC). From our previous RCT with TENS,¹² there was a decrease in pain with Active-TENS compared with No-TENS of 1.8 (95% CI = 1.0 to 2.8), with an associated SD of 2 units for change in movement-evoked pain during the Sit and Stand Test. For FM-TIPS, sample size was determined so that statistical tests at the .05 significance level will be able to detect a difference of at least 1.0 in mean change in pain with a SD of 2 units (NRS = 0−10) and ICC of 0.14. Complete data from 19 patients per clinic from 24 clinics for 456 patients total will provide 80% power. To account for a 24% drop-out rate, which includes those who are lost to follow-up, we will enroll 600 participants (300 per group).

Statistical Analysis

Descriptive statistics will be computed for demographic and baseline variables for each treatment group and evaluated for normality. If data are not normally distributed, appropriate transformation will be applied or non-parametric methods will be used. Variables found to significantly differ between groups will be used as covariates in the comparison of outcome measures between groups.

For the primary outcome and all secondary outcomes during the 6-month follow-up period, we will utilize a modified intention-to-treat for all analyses. Signing eConsent automatically assigns a participant to the treatment arm based on clinic randomization (TENS or No-TENS). However, it is possible that after signing eConsent, an enrolled participant will not return to physical therapy or will not complete Research Homework at day 1. Therefore, such a participant will have no baseline data and will be a “no-show” for the rest of the study. Thus, we will employ a modified intention-to-treat approach that will include all participants who have completed baseline Research Homework.

Reduction in movement-evoked pain from baseline to day 60 between the TENS and No-TENS groups will be tested using linear mixed-model analysis for repeated measures with treatment group, time, and treatment*time interaction as fixed effects. Random effects include facilities (within treatment) and participants (within facility, within treatment). In fitting the mixed model, appropriate covariance structures for longitudinal measures within participant will be considered. From this fitted model, differences in mean change between treatment groups will be assessed by testing for treatment*time interaction effect. In the event that adjusted analyses are necessary, a secondary comparison of the primary endpoint between groups will be made by expanding the linear mixed model to include additional fixed effects for covariates. In addition, opioid use at baseline as a possible effect moderator of TENS will be examined by including an opioid*treatment*time interaction in the model. Statistical significance for effectiveness of TENS versus No-TENS will be based on a 2-tailed test at .05 significance level with treatment effect summarized as mean difference with 95% CI. Similar analyses will be performed for secondary outcome measures.

Ethics

Central Institutional Review Board

This study uses the University of Iowa (UI) cIRB that approved the research protocol for each health care system. All institutions signed agreements to rely on the UI cIRB.

Informed Consent

The study uses the electronic informed consent module in REDCap. Participants who pass the eligibility screen at their PT Visit #1 will immediately be sent an eConsent that reviews the purpose of the study, procedures, risk and benefits, participant information data storage, and contact information of the study team for questions. Once the participant signs eConsent, a member of the study team reviews the eConsent and provides a second signature. Participants will be required to complete eConsent prior to initiating study activities at their PT Visit #2.

Role of the Funding Source

The funders played no role in the design, conduct, or reporting of this study.

Discussion

Pragmatic trials are increasingly used in rehabilitation research for a variety of interventions and may provide enhanced information to providers, patients, funders, and policy makers.^22,23 Using an RCT design, we previously showed efficacy and safety of TENS for movement-evoked pain in individuals with FM.^12,24 The RCT was designed to control for sources of bias at the patient level, such as inclusion and exclusion criteria, and at the experimenter level, such as blinding and randomization. The current pragmatic trial, on the other hand, tests whether TENS works for nearly all individuals when implemented in a real-world practice setting. The only exclusion criteria proposed in this study are related to TENS contraindication or unstable physical or mental health conditions. Pragmatic trials therefore assess generalizability of the results, but inherently they have greater variability and thus require a larger sample size.²³

Exercise is recommended as a first line treatment for FM.¹⁴ However, individuals with FM report movement-evoked pain as the primary reason that limits participation in physical activity.^15,16 Non-pharmacological treatments that reduce movement-evoked pain are expected to enhance engagement in exercise and daily activity. Prior studies show that TENS reduces pain and fatigue during movement^25–27 and thus may enhance patient adherence to exercise programs prescribed by the physical therapist. The current pragmatic trial aims to examine the effectiveness of TENS for movement-evoked pain for individuals with FM when added to routine physical therapy. This trial will add to existing literature of pragmatic studies in outpatient physical therapy^22,28,29 by examining the feasibility of implementing TENS into physical therapy practice.

The effectiveness for TENS in reducing chronic pain is controversial. Whereas our previous multisite RCT shows TENS reduces pain and fatigue at rest and during movement in women with FM compared with Placebo-TENS or No-TENS,¹² recent Cochrane systematic reviews for FM or chronic pain show low-quality or insufficient evidence to support that TENS is effective for pain reduction.^30,31 Significant limitations of currently published TENS research include insufficient sample sizes, no long-term follow-up, and insufficient TENS dosing.^32–34 A recent comprehensive appraisal of systematic reviews on TENS for pain relief that included 169 studies reported standardized mean differences (range = −4.32 to 1.27) and absolute mean differences (range = −44.4 to 6.1 on 100-mm scale) that were generally in favor of TENS, but overall pooled sample sizes were low.³⁵ FM-TIPS will extend prior literature on TENS by examining if TENS produces analgesia in a real-world setting in a large sample population.

The FAST study showed TENS produced a significant reduction in pain and fatigue after a single application that increased after 1 month of home use and continued to be effective through 2 months,¹² showing our TENS parameters prevented analgesic tolerance with repeated application. We also show that TENS at a strong comfortable intensity is well tolerated, with no SAEs and few (<5%) AEs. AEs reported were minor (eg, skin irritation with electrode, nausea, anxiety), with the number needed to harm for these minor AEs ranging from 20 to 100.²⁴ Even though our primary outcome variable will be collected at 2 months, FM-TIPS will extend assessments through 6 months and similarly examine for TENS-related AEs.

The pragmatic design of FM-TIPS presents unique potential limitations. The results obtained during pragmatic trials may potentially have greater variability, thus requiring a larger sample size and ultimately requiring greater participant enrollment from each clinic. An additional limitation is the unknown long-term effect of TENS (>60 days) in individuals with FM. Our prior clinical trial shows continued efficacy of TENS for at least 60 days,¹² the time of our primary outcome measure. The follow-up assessment at 6 months in FM-TIPS will assist in extending prior TENS study design to examine for the effect of TENS in a real-world setting beyond 60 days. Another barrier for our pragmatic clinical trial was the patient enrollment as a result of the pandemic, which resulted in lower-than-expected enrollment at all sites. Some sites after training and activation chose to discontinue participation in the study for a variety of reason, including loss of interest in the study and the increased burden of the pandemic. Thus, some of the originally randomized physical therapy clinics were deactivated before enrolling participants. The potential impact on the study design from low enrollment and reduced clinic numbers was quickly mitigated by activating and randomizing 10 additional clinics. Finally, barriers to implementation of nonpharmacological treatments into clinical practice include lack of patient support and inadequate clinician and patient familiarity with the interventions.³⁶ Currently, the feasibility of TENS implementation into routine physical therapy practice is unknown. However, FM-TIPS will allow for physical therapists who are knowledgeable in TENS to propose an adjunct nonpharmacological treatment to regular care, educate patients on TENS, and assist adherence through frequent contact with participants. FM-TIPS will also provide generalizable effectiveness data for referring providers, clinicians, and insurers. Lastly, our work will inform future pragmatic trials of nonpharmacologic treatments conducted in physical therapy practices for individuals with chronic pain conditions.

Author Contributions

Concept/idea/research design: D.L. Dailey, R.L. Chimenti, C. Franck, E. Johnson, C.G.T. Vance, B. Van Gorp, B.M. Zimmerman, D. Ecklund, L.J. Crofford, K.A. Sluka

Writing: A.A. Post, D.L. Dailey, E.O. Bayman, R.L. Chimenti, E. Johnson, C.G.T. Vance, T. Neill-Hudson, M. Costigan, L.J. Crofford, K.A. Sluka

Data collection: D.L. Dailey, C. Franck, E.O. Bayman, M. Costigan, T. Huff, M.E. McCabe, D. Ecklund, D.E Lafontant

Data analysis: E.O. Bayman, D.E Lafontant, M.E. McCabe, B.M. Zimmerman

Project management: D.L. Dailey, E.O. Bayman, M. Costigan, E. Johnson, M. Koepp, T. Neill-Hudson, A.A. Post, C.G.T. Vance, D. Ecklund, L.J. Crofford, K.A. Sluka

Fund procurement: K.A. Sluka, L.J. Crofford

Providing facilities/equipment: C. Franck, D. Ecklund, E.O. Bayman, K.A. Sluka, Advanced Physical Therapy and Sports Medicine, Big Stone Therapies, Genesis Physical Therapy, Kepros Physical Therapy, Rock Valley Physical Therapy, University of Illinois Hospital and Health Sciences System

Providing institutional liaisons: A.A. Post, D.L. Dailey, B. Van Gorp, C.G.T. Vance, E. Johnson

Consultation (including review of manuscript before submitting): A.A. Post, D.L. Dailey, E.O. Bayman, R.L. Chimenti, M. Costigan, C. Franck, T. Huff, E. Johnson, M. Koepp, D.E. Lafontant, M.E. McCabe, T. Neill-Hudson, C.G.T. Vance, B. Van Gorp, B.M. Zimmerman, D. Ecklund, L.J. Crofford, K.A. Sluka

Acknowledgments

The authors thank Advanced Physical Therapy and Sports Medicine, Big Stone Therapies, Genesis Physical Therapy, Kepros Physical Therapy, Rock Valley Physical Therapy, University of Illinois Hospital and Health Sciences System.

Ethics Approval

This study uses the UI cIRB that approved the research protocol for each health care system. All institutions signed agreements to rely on the UI cIRB.

Funding

This work was supported by the National Institutes of Health (NIH) through the NIH Helping to End Addiction Long-Term (HEAL) Initiative (award no.: UG3AR076387) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. This work also received logistical and technical support from the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing Resource Coordinating Center (award no.: U24AT010961) from the NIH through the NIH HEAL Initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or its HEAL Initiative.

Clinical Trial Review Registration

This study is registered at ClinicalTrials.gov (NCT 04683042).

Disclosures

The authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.