Combined aerobic exercise and photobiomodulation for pain and other symptoms in fibromyalgia: study protocol

ABSTRACT

This study describes a protocol to evaluate the effects of combining aerobic exercise (AE) and systemic photobiomodulation (PBM) via transcutaneous intravascular laser irradiation of blood (TILIB) on pain, fatigue, functional performance, and quality of life in women with fibromyalgia (FM). Ninety-two women aged 18–60 years with FM will be randomly assigned to one of four groups: AE and active TILIB, AE and sham TILIB, active TILIB alone and, sham TILIB alone. The AE will be performed on a stationary bike, with gradual load progression, twice a week for 12 weeks, while the TILIB will be applied at the same frequency. Assessments will include pain intensity measured by a visual analogue scale, pressure pain threshold determined using an algometer, and evaluations of quality of life, functionality and perceived fatigue using validated questionnaires. Performance fatigue will be assessed with an isokinetic dynamometer, and physical function will be analyzed through performance-based tests. These measurements will be conducted before the first intervention session, after the last session, and during follow-ups at 16, 26, and 52 weeks. The results of this trial could enhance the management of symptoms in women with FM. Additionally, follow-ups will provide insights into the short- and medium-term effectiveness of the intervention.

Trial registration

RBR-3pxmycv. This study protocol was registered in ensaiosclinicos.gov.br (Brazilian Registry of Clinical Trials), published on 19 December 2023, https://ensaiosclinicos.gov.br/rg/RBR-3pxmycv.

Plain Language Summary

What is this article about?

This study looks at a new way to help people with fibromyalgia feel better. Fibromyalgia is a condition that causes long-lasting pain and fatigue. It can make everyday life difficult. The study is testing whether two treatments – light therapy and aerobic exercise – can help reduce pain and fatigue. Light therapy shines a gentle light on the skin to help the body function better. When used with exercise, it can help people move more easily and feel less tired. This treatment does not use drugs and could become a new option for people living with fibromyalgia.

What do the results of the study mean?

If the treatment works, it may become a new way to help people with fibromyalgia feel better – without using medicine. This could mean fewer side effects. The study may also help scientists learn more about how light therapy can support the body. It could lead to better ways to manage long-term conditions like fibromyalgia. In the future, combining light therapy and exercise might be a safe and helpful option to improve daily life for people with this condition.

1. Introduction

Fibromyalgia (FM) is a chronic disease characterized by generalized pain and sensitivity in soft tissues [1,2]. FM is estimated to affect up to 7% of the general population and is more prevalent in women, with a rate of nearly 4%, whereas the prevalence among men is estimated at 0.01% [3,4]. Among women, the condition is more prevalent in those between 20 and 55 years of age [3]. Thus, FM affects individuals in peak productive years, resulting in an increase in the occurrence of absenteeism and the loss of productivity [5]. Moreover, the cost of treatment is high. For instance, annual health costs related to FM reach U$ 9573 per patient in the USA [6].

The symptoms are often associated with somatic complaints, such as depressive episodes, sleep disturbances, functional intestinal disorders, anxiety, chronic headache and cognitive complaints [7–9]. Individuals with FM experience greater perceived fatigue and performance fatigue after exercise [10–12]. Such symptoms affect quality of life due to the negative impact on physical and psychosocial aspects [5]. Individuals with FM also tend to have a sedentary lifestyle and are generally intolerant to physical exercise due mainly to the pain symptom [13]. This leads to several consequences, such as a reduction in global muscle strength, a significant reduction in cardiorespiratory capacity and an increased risk of additional morbidities [14], which, in turn, can aggravate the pain, thus establishing a vicious cycle.

The combination of pharmacological and non-pharmacological treatments is currently recommended for symptom management as well as the increase or maintenance of functional abilities at home or work, with a reduction in other manifestations that cause suffering and exert a direct impact on the quality of life of this population [15–19]. Among non-pharmacological approaches, exercise is strongly recommended for the treatment of FM, according to the guidelines of the European Alliance of Associations for Rheumatology (EULAR) [19]. Systematic reviews and meta-analyses show that physical exercise is beneficial for individuals with FM and should be an integral part of treatment [20–24].

The benefits of physical exercise in FM have been reported in various systematic reviews and meta-analyses, which describe a reduction in pain as well as improvements in symptoms and physical fitness [16,20–29]. In a literature review of studies involving individuals with FM, Bidonde et al. [29] concluded that aerobic exercise was capable of reducing physical inactivity, which is common in this population due to chronic pain, improving cardiorespiratory fitness and lowering the level of fatigue, with a consequent improvement in quality of life.

Despite the potential therapeutic role of exercise, patients affected by FM tend to have low tolerance to physical effort due to the symptoms of pain and fatigue, which can result in low adherence to physical exercise programs [30–33]. This low adherence can be explained by the fact that individuals with FM have different pain modulation immediately after exercise compared to healthy individuals. Healthy individuals experience an increase in the pain threshold following physical exercise, whereas this change does not necessarily occur in individuals with FM [34–38]. Thus, other therapies, such as acupuncture [39] and electrophysical agents [40,41], have been used concomitantly with physical exercise programs with the aim of enhancing the beneficial effects in this population. Photobiomodulation (PBM) is among the most promising modalities for such cases.

PBM is a therapeutic modality with analgesic, regenerative and anti-inflammatory effects and it also assists in reducing muscle fatigue and accelerating the healing process [42–48]. When PBM is administered to biological tissues, light is absorbed by the mitochondria (specifically cytochrome C oxidase, which is the 4th unit in the mitochondrial respiratory chain), leading to a set of changes in cellular metabolism. Moreover, PBM enhances the pain reduction mechanism due to increases in the production of serotonin and synthesis of β–endorphin (neurotransmitters related to pain relief), and acetylcholinesterase activity in the synapses (acetylcholinesterase degrades the nociceptive neurotransmitter acetylcholine) and temporarily inhibits action potentials evoked by bradykinin (substance present in inflammatory processes) [49–53]. As consequence of all these modifications, PBM produces many positive therapeutical effects such as the regenerative effects of the tissue repair process, modulation of the inflammatory process and analgesia [42,47].

A systematic review with meta-analysis showed that individuals with FM who received local PBM had significantly greater improvements in pain intensity, fatigue, stiffness, quality of life, depression and anxiety as well as a reduction in tender points compared to those in the sham group [40]. Studies have also investigated the effects of the combination of physical exercise and PBM in the treatment of FM [54,55]. Da Silva et al. [55] assessed the effect of PBM using a cluster device and physical training as well as combined treatment on general symptoms, pain and quality of life in women with FM. The cluster device (infrared 905-nm emitter with four light-emitting diodes [LEDs] of 640 nm, four LEDs of 875 nm and 39.3 J per point) was used on 10 points, each of which was irradiated for 300 seconds. The exercise protocol consisted of stretching and aerobic training on treadmill with the load established at 75% of maximum heart rate at a frequency of twice per week for 10 weeks. The authors found a more substantial effect using the combined protocol (PBM + exercise) with regards to analgesia, reductions in symptoms, anxiety, depression, fatigue and difficulty sleeping as well as an improvement in quality of life.

PBM can be administered in different forms: local application, the projection of internal organ, laser acupuncture, reflexology, intracavity, transdermal illumination and intravascular (denominated intravascular laser irradiation of blood [ILIB]) as well as combined methods [56]. ILIB has recently attracted particular attention. This method was originally developed for the treatment of cardiovascular diseases through the insertion of an intravenous catheter in one of the upper limbs (generally in the radial artery of the chosen upper limb) coupled to an optical fiber that irradiated the blood with laser at a wavelength of 630–640 nm with a power of 3 to 5 mW for 20 to 30 minutes. The aim of ILIB is to achieve a systemic effect, which is a considerable innovation.

Clinical and laboratory studies have since investigated the therapeutic effects of ILIB on systemic conditions, such as cardiovascular diseases, nerve disorders, mental disorders, metabolic endocrine disease, acute cholecystitis as well as acute and chronic diseases, such as bronchitis, pneumonia, pancreatitis, rheumatoid arthritis and juvenile idiopathic arthritis [57–62]. The mechanisms of action include the influence on the cell membrane, activation of the immune system, better oxygenation of the blood, cellular biostimulation and the activation of antioxidant enzymes [60,63–70]. However, ILIB is a limited technique due to its invasive nature, which restricts is use. A way to overcome this restriction was the adaptation to noninvasive administration, such as intranasal laser irradiation and transcutaneous laser or LED irradiation administered over the wrist [71,72]. This modification of the irradiation technique enables more frequent use, broadens the applicability to at-home treatment, and avoids problems related to sterilization and venipuncture [69,73]. Thus, for patients without adequate conditions for venipuncture and the insertion of the catheter with the laser and those who do not accept invasive treatment, PBM of the blood can be performed using noninvasive/transcutaneous (TLIB or modified ILIB), transmucosal or sublingual systemic irradiation.

The effects of ILIB via noninvasive irradiation (TLIB/modified ILIB) are considered systemic, favoring the physiological dynamics of the organism, such as a reduction in blood viscosity, improvement in the viscoelasticity of erythrocytes and osmotic resistance. Animal and human studies indicate benefits such as a reduction in the inflammatory response and the control of blood pressure, glucose and cholesterol [73–76].

The systemic effects of ILIB are underpinned by well-established PBM mechanisms. Upon absorption of red or near-infrared light by cytochrome c oxidase (CCO) in mitochondria, ILIB enhances mitochondrial membrane potential and ATP synthesis, and generates reactive oxygen species (ROS) that act as signaling molecules [77–79]. These redox signals activate transcription factors such as NF-κB and AP-1, leading to modulation of inflammatory, antioxidant, and regenerative gene expression [80]. Additionally, ILIB stimulates intracellular signaling cascades, including the PI3K/Akt/mTOR and MAPK/ERK pathways, which contribute to immunomodulation, angiogenesis, and tissue repair [80]. Clinically, ILIB has been shown to downregulate pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) while increasing anti-inflammatory mediators like IL-10 and TGF-β [80]. This molecular framework supports ILIB’s systemic action in modulating inflammation and alleviating chronic pain across various clinical conditions

A study with an animal model showed that transcutaneous systemic PBM with a red LED (660 nm; power: 100 mW; energy density: 5 J/cm; total energy: 15 J; time: 150 seconds) reduced the number of neutrophils recruited for bronchoalveolar lavage and myeloperoxidase activity and also reduced interleukins (IL) 1β, IL-6 and IL-17 in the lung of rats with lipopolysaccharide-induced acute lung injury [81]. A pilot study on the effects of transcutaneous systemic PBM (modified ILIB) on blood pressure, glucose and cholesterol in women demonstrated that PBM (660 nm; power: 100 mW; total energy: 180 J; time: 30 minutes; 2x/week for eight weeks) can be safely used as an adjunct method for regulating systolic and diastolic blood pressure, glucose, triglycerides and cholesterol (total, LDL and HDL) [76].

Oliveira de Lima et al. [75] investigated the effects of transcutaneous ILIB over the radial artery (660 nm; power: 100 mW; energy: 60 J; dose: 63.7 J/cm²) for 30 and 60 minutes on the side effects of intravenous antineoplastic chemotherapeutic agents in hematopoietic tissue in adults. The authors found that both protocols were effective at controlling the side effects for the maintenance or increase in blood components: hemoglobin (85% and 86%, respectively), platelets (100% and 100%) and neutrophils (95% and 92%). Da Silva Leal et al. [74] demonstrated that transcutaneous systemic PBM administered over the radial artery (660 nm; power: 100 mW; application time: 30 minutes) was effective at reducing pain and improving quality of life in patients with diabetic neuropathy. Thus, promising results are reported for transcutaneous systemic PBM in various conditions. However, the benefits have not yet been explored in individuals with FM.

The aim of the present study was to present the design of a randomized trial to determine the effects of the combination of aerobic exercise and systemic PBM (transcutaneous ILIB) on pain, fatigue, physical functioning and health-related quality of life in individuals with FM. The hypothesis is that transcutaneous ILIB combined with an aerobic exercise program will be effective in reducing pain, perceived fatigue, and performance fatigue in individuals with fibromyalgia. These clinical improvements are expected to result from the modulation of central and peripheral pain mechanisms, including enhanced mitochondrial function and redox signaling induced by ILIB, and exercise-induced neuroplastic adaptations related to pain processing. Consequently, improvements in physical functioning and quality of life are also anticipated. The proposed randomized controlled trial will contribute new evidence to the field of physical therapy in the treatment of fibromyalgia by concentrating on interventions aimed at rehabilitation and improvements in pain, physical functioning and quality of life in this population.

2. Methods

2.1. Type of study and registration

This paper describes a protocol for a randomized, single-blind, controlled, parallel-group clinical trial with an allocation ratio of 1:1:1:1 across four intervention groups. The trial is designed within a superiority framework, aiming to determine whether the combination of aerobic exercise and systemic PBM (transcutaneous ILIB) is superior to aerobic exercise combined with sham transcutaneous ILIB, active transcutaneous ILIB alone, or sham transcutaneous ILIB alone in improving pain, fatigue, physical functioning, and quality of life in individuals with FM.

The clinical trial will follow the guidelines of the Consolidated Standards of Reporting Trials (CONSORT statement) [82] and was registered in the Brazilian Registry of Clinical Trials (RBR-3pxmycv). The protocol version is 1, dated December 19,2023, and has not been modified since registration.

2.2. Ethical aspects, patient, and public involvement

The project received approval from the authors’ institution Human Research Ethics Committee (certificate number: 66837323.6.0000.5505). All volunteers will receive clarifications regarding the objectives and procedures and those who agree to participate will sign a statement of informed consent. Although patients or the public were not involved in the initial design and conduct of this trial, plans are in place to involve patient representatives in reviewing and advising on dissemination strategies to enhance the accessibility of study results.

This study will not have a Data Monitoring Committee, as it involves minimal risk to participants and does not include invasive or medicinal interventions that require continuous and independent data monitoring. Additionally, the protocol includes regular monitoring of study conduct and participant safety by the research team through monthly meetings to evaluate the trial progress, review data, ensure participant safety, and assess adherence to the protocol, as well as oversight by the appropriate ethics committees, ensuring the integrity and safety of the study. Monitoring activities will include data reviews and adverse event reporting.

Any significant amendments to the protocol will be promptly submitted to the Institutional Ethics Committee for review and approval. Furthermore, corresponding updates will be made to the ReBec to ensure transparency and regulatory compliance.

2.3. Sample calculation

The sample size was calculated a priori with the aid of the G*Power software program (version 3.1.9.4, Heinrich-Heine-Universität, Düsseldorf, Germany) using one-way repeated-measures analysis of variance (ANOVA) of the interaction within and between groups, adopting a significance level of α = 0.05, power (β) of 0.80 and an effect size of 0.2, which corresponds to a small-to-medium effect The primary outcome considered for this estimation was pain intensity, assessed using the Numerical Pain Rating Scale (NPRS). The calculation determined the need for 76 participants. However, considering a 20% sample loss, 92 participants are needed, who will be randomly allocated to four groups:

• Aerobic exercise + active transcutaneous ILIB (AE+AI) group (n = 23);

• Aerobic exercise + sham transcutaneous ILIB (AE+SI) group (n = 23);

• Active transcutaneous ILIB (AI) group (n = 23);

• Sham transcutaneous ILIB (SI) group (n = 23).

2.4. Sample and eligibility criteria

Women 18 to 60 years of age with a diagnosis of FM (International Classification of Diseases – ICD-11, code MG30.01), will be included in the study. The diagnosis will be performed by the participant’s own physician and will be confirmed by a physiotherapist with a PhD and ten years of experience in rheumatology considering the diagnostic criteria for FM of the American College of Rheumatology [83]: widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) ≥ 5 or WPI of 4–6 and SSS ≥ 9, widespread pain (defined as pain in at least four of the five regions [chest, mandibular and abdominal pain are not included in the definition of widespread pain]) and symptoms for at least three months. Other inclusion criteria will be adequate cognitive capacity to understand the procedures (based on the results of the Mini Mental State Examination with the cutoff points based on educational level), and interest to participate in the entire experimental protocol.

The following will be the non-inclusion criteria: (1) uncontrolled systemic disease (e.g., diabetes mellitus and systemic arterial hypertension); (2) neurological and musculoskeletal conditions that could directly interfere with the assessments, such as paralysis, substantial sensitivity abnormalities, joint diseases in an advanced state (e.g., osteoarthritis); (3) absolute contraindication for PBM (e.g., neoplasms); (4) undernourished individuals (body mass index [BMI] < 18.5 kg/m²) and those with morbid obesity (BMI ≥40 kg/m²); (5) participants with cognitive impairments identified through clinical history or a score below 24 on the Mini-Mental State Examination who are unable to understand all the procedures carried out during the evaluation.

Participants may discontinue or have their allocated intervention modified if they experience adverse events or side effects related to the intervention, as determined by the study physiotherapist or medical team. Additionally, participants have the right to withdraw from the intervention at any time without any penalty or loss of benefits. The intervention may also be modified or stopped if there is significant worsening of clinical symptoms or other safety concerns arise during the trial, in accordance with the study’s safety monitoring procedures.

2.5. Randomization and blinding

The participants will be divided into four groups (AE+AI, AE+SI, AI and SI). Randomization will be performed with the aid of a computer program (Microsoft Excel 2019) and the random.org site in a simple table with four columns (A, B, C and D) and random numbers to determine to which group the participants will be allocated [84]. Each participant will receive a random code corresponding to the treatment group. The participants will be allocated to the different groups based on their codes using sequentially numbered sealed opaque envelopes to ensure allocation concealment. A researcher will perform the randomization without informing the participants to which they will belong. Thus, the participants will be blinded to allocation.

Unblinding will only be permissible in exceptional circumstances when knowledge of the allocated intervention is deemed essential for the clinical management or safety of the participant (e.g., in the event of a serious adverse event potentially related to the intervention). In such cases, the decision to unblind will be made by the principal investigator, who will have access to the randomization list. The procedure for unblinding involves opening a sealed envelope corresponding to the participant’s identification number, which will reveal the assigned group. Any case of unblinding will be fully documented, including the reason and the individuals involved, and will be reported in the final trial results.

The researcher in charge of the statistical analysis will also be blinded to the allocation of the participants. Once the intervention is concluded, the statistician will receive a table in Excel with all necessary data and with no identification of the individuals or groups.

2.6. Aerobic exercise protocol

Both the AE+AI and AE+SI groups with undergo the same exercise protocol, which will involve supervised aerobic exercises on a stationary bike (Bicicleta Profissional Horizontal RTR Movement, Brudden Equipamentos Ltda., Pompeia SP, Brazil) under the supervision of a physiotherapist. Sessions will be held at a frequency of twice per week for 12 consecutive weeks. The frequency and duration are based on the findings of a systematic review reporting improvements in general symptoms, pain and quality of life in women with FM [20].

The exercise program will be conducted at the laboratory. The room has ample space and is air conditioned to ensure the comfort of the participants. Each session will last approximately 30 minutes (five minutes of warmup on a stationary bike, 20 minutes of exercise on the stationary bike and five minutes of cooldown) and will be supervised by a physiotherapist. Table 1 shows the progression of the exercises over time.

Table 1.

Aerobic exercise protocol.

Phases	Week	Speed (RPM)	Intensity
Warmup (5 min)	1 to 12	40–50	Without load
Protocol on stationary bike (20 min)	1 and 2	50–60	60% of peak heart rate, without load.
	3 and 4	50–60	Increase in load that increases heart rate by approximately 5% in relation to previous week.
	5 and 6	50–60	Increase in load that increases heart rate by approximately 5% in relation to previous week.
	7 and 8	50–60	Increase in load that increases heart rate by approximately 5% in relation to previous week.
	9 and 10	50–60	Increase in load that increases heart rate by approximately 5% in relation to previous week.
	11 and 12	50–60	Increase in load that increases heart rate by approximately 5% in relation to previous week.
Cooldown (5 min)	1 to 12	40–50	Without load.

RPM: repetitions per minute.

Participants in the exercise group will perform a cardiopulmonary exercise test (CPET) on a stationary bike using a rapidly incremental “ramp” protocol. The test consists of four phases: (I) a 3-minute resting phase, (II) a 3-minute warm-up period at zero load, (III) an 8–12-minute incremental period, and (IV) a 3-minute active recovery period at zero load. Throughout the test, heart rate (HR) will be monitored using a 12-lead electrocardiogram (C12x, COSMED, Italy). Oxygen consumption (VO2), carbon dioxide production (VCO2), and pulmonary ventilation (VE) will be continuously measured during breathing and then filtered every 15 seconds using an arithmetic mean. The VO2 corresponding to the anaerobic threshold will be visually determined using the gas exchange method at the inflection point of the VCO2/VO2 ratio [85]. The maximum VO2 is obtained from the highest VO2 achieved by the participant during the test. Blood pressure and subjective responses to effort (Borg scale) will be measured every two minutes throughout the test. All CPETs will be supervised by an experienced cardiologist, as well as by highly trained physiotherapists qualified to conduct the tests. We will use the maximum HR obtained as a reference to adjust the target load, with increments of 5% every two weeks, starting at 60% and progressing to 85% of the maximum HR.

2.7. Transcutaneous systemic PBM protocol

Systemic PBM will be performed in the AE+AI and AI groups with transcutaneous ILIB using low-level laser equipment: Therapy EC (DMC Importação e Exportação de Equipamentos Ltda., São Carlos, SP, Brazil). The blood will be irradiated with red laser administered transcutaneously. The participant will wear a bracelet to which the laser tip will be coupled and positioned in a specific space over the radial artery [72]. The following irradiation parameters will be used: red laser (660 nm); energy: 144 J; continuous emission mode; output power: 80 mW; dose: 286.5 J/cm². The laser will be administered for 30 minutes at a frequency of two sessions per week for 12 consecutive weeks. During the intervention, the participant and therapist will use protective eyewear.

The procedure will be identical in the AE+SI and SI groups, but with sham laser radiation. For such, the equipment will be programmed with the same parameters used in AE+AI and AI groups and will emit a red light (no therapeutic) and sound (beep).

2.8. Procedure

The trial will be conducted by the Laboratory of Biomaterials and Tissue Engineering of the Department of Biosciences, located at the Federal University of São Paulo (Universidade Federal de São Paulo), in the city of Santos, Brazil. All interventions and assessments will take place at this facility.

The study will be disclosed through the university website, flyers, social media, radio, newspapers and local magazines, with information provided on the project as well as benefits and risks. An initial interview will be scheduled with individuals interested in participating. During the interview, the diagnostic criteria of the American College of Rheumatology [83] and eligibility criteria will be assessed and the clinical/medical history of the volunteers will be collected.

Volunteers who met the eligibility criteria and agree to participate will be asked to come for the initial assessment scheduled for one week after the interview. The collected data will be entered and managed using Microsoft Excel 365. Assessment forms will be securely stored in locked cabinets within the laboratory, with access restricted exclusively to the research team. To ensure confidentiality, each participant will be assigned a unique identification code, and only coded data will be tabulated and analyzed.

The participants will then initiate treatment in accordance to the group to which they are allocated. Treatment sessions will last 12 consecutive weeks, followed by the post-intervention assessment. Follow-up assessments will be performed 16, 26 and 52 weeks after the initial assessment. Figure 1 presents the CONSORT 2010 flow diagram summarizing the process of participant screening, randomization, group allocation, and follow-up.

Figure 1.

Flow diagram of participant progression through the study, including eligibility assessment, randomization, allocation to the four intervention arms, follow-up, and analysis, according to the CONSORT 2010 guidelines.

The participants in the AE+AI and AE+SI groups will be submitted to the aerobic exercise program and systemic PBM (transcutaneous ILIB) at a frequency of two sessions per week for 12 consecutive weeks. The participants in the AI and SI group will be submitted only to systemic PBM at a frequency of two sessions per week for 12 consecutive weeks. The participants in the active and sham transcutaneous ILIB groups will also receive orientations and will be offered the physical exercise protocol after the last follow-up assessment (52 weeks). All participants will undergo clinical assessments, which will be performed at the laboratory. The procedures of the clinical assessment will be repeated at the post-intervention assessment and all follow-up assessments (16, 26 and 52 weeks after the initial assessment). Table 2 presents the timeframe of the study protocol in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. The table outlines the four intervention groups, the duration of the intervention period (12 weeks), the scheduled follow-up assessments (at 16, 26, and 52 weeks), and the outcome measures to be collected at baseline, post-intervention, and throughout the follow-up period.

Table 2.

SPIRIT checklist. Timeframe of the study protocol in accordance with the SPIRIT (standard protocol items: recommendations for interventional trials) checklist, including the four intervention groups, duration of the intervention period, scheduled follow-up assessments (at 16, 26, and 52 weeks), and outcome measures assessed at baseline, post-intervention, and during follow-up.

STUDY PERIOD
	Enrolment	Allocation		Post-allocation			Follow-up
TIMEPOINT	-t1	0	Baseline	Week 4 t4	Week 8 t8	Week 12* t12	Week 16 t16	Week 26 t26	Week 52 t52
ENROLMENT:
Elegibility screen	X
Informed consent	X
Alocation		X
INTERVENTIONS:
Aerobic exercise + active transcutaneous ILIB				X	X	X
Aerobic exercise + sham transcutaneous ILIB				X	X	X
Active transcutaneous ILIB				X	X	X
Sham transcutaneous ILIB				X	X	X
ASSESSMENTS
Pain Intensity			X			X	X	X	X
Pressure-pain threshold			X			X
Quality of life and funcionality			X			X	X	X	X
Level of perceived fatigue			X			X	X	X	X
Performance Fatigue			X			X
Performance based-tests			X			X	X	X	X

* Week 12 marks the end of the intervention period and the completion of the post-intervention assessment.

During the trial, participants will be allowed to continue their usual medical care and use of medications prescribed prior to enrollment. However, the initiation of new treatments specifically targeting FM symptoms, such as new physical therapy programs, exercise regimens outside the study protocol, or other PBM therapies, will be prohibited during the intervention period to avoid confounding effects. Participants will be instructed to report any changes in medication or therapies during the trial.

Harms will be defined as any adverse events or unintended effects potentially related to the interventions, including but not limited to musculoskeletal pain (e.g., joint or muscle soreness beyond expected post-exercise discomfort), cardiovascular symptoms (e.g., dizziness, palpitations, shortness of breath), skin reactions at the ILIB application site (e.g., erythema, irritation), or systemic symptoms such as headache, nausea, or fatigue beyond typical levels reported by individuals with FM. These events will be assessed systematically at each session through direct questioning by the supervising physiotherapist and through spontaneous participant reporting. All adverse events will be documented in standardized forms, monitored throughout the intervention period, and reported in accordance with institutional ethical guidelines and regulatory requirements Participants who experience any adverse effects or harm related to trial participation will receive appropriate medical care and support during and after the trial period. The research team and the sponsoring institution will ensure access to necessary ancillary care as needed. In the event of trial-related injury or harm, participants will be compensated in accordance with applicable institutional policies and local regulations. Details regarding the procedures for reporting and managing such events are outlined in the trial’s ethical approval documents.

To improve adherence to the intervention protocols, participants will receive clear verbal and written instructions about the importance of attending all scheduled sessions. The exercise sessions and systemic PBM treatments will be supervised by a physiotherapist to ensure proper execution and engagement. Attendance will be recorded at each session, and participants who miss sessions will be contacted to encourage continued participation and rescheduling when possible. Additionally, regular follow-up calls or messages will be used to maintain motivation and address any barriers to adherence.

Pain intensity will be measured using the numerical pain rating scale [86,87]. The pressure-pain threshold will be determined using a digital algometer [84]. The impact of FM on functionality will be measured using Revised Fibromyalgia Impact Questionnaire (FIQ-R) [88]. Quality of life will be assessed using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) [89]. Level of perceived fatigue will be assessed using the Fatigue Severity Scale [90]. Performance fatigue will be measured using an isokinetic dynamometer. Physical functioning will be assessed using the Timed Up and Go (TUG) test and Six-Minute Walk Test (6MWT) [91]. The participants must also have a medical certificate attesting to the capacity to perform physical exercise. Physical activity level will be determined using the International Physical Activity Questionnaire (IPAQ), which has been translated and validated for use in Brazil [92]. The IPAQ is easy to administer and has satisfactory precision.

2.8.1. Outcomes

The primary outcomes of this study were pain intensity, and functionality and health-related quality of life. These variables were chosen to reflect the core symptoms and overall impact of FM on daily functioning. The secondary outcomes included perceived fatigue, performance fatigue and functional performance aiming to capture additional dimensions of symptom burden and the participants’ ability to perform daily activities. Below, each outcome is described in detail along with the instruments and procedures used for its assessment.

2.8.1.1. Assessment of pain and pressure-pain threshold

The numerical pain rating scale will be used to quantify self-reported pain on a scale of 0 (absence of pain) to 10 (worst pain imaginable) [86,87]. The scores will be recorded and the mean of each group before and after the intervention will be used for data analysis. Pain will be assessed in four ways: current pain at rest and during movement, worst pain in previous week and lowest pain intensity in previous week.

The pressure-pain threshold will be determined using a digital algometer (Mod. DD-2000, Instrutherm Instrumentos de Medição Ltda., São Paulo, Brazil) applied bilaterally to the upper/descending trapezius (proximal third between spinous process of the C7 vertebra and the acromion), biceps (middle third between the coracoid process and cubital fossa/tuberosity of the radius), quadriceps (middle third between anteroinferior iliac spine and base of patella), hamstrings (middle third between gluteal fold/ischial tuberosity and popliteal fossa) and gastrocnemius (proximal third between popliteal fossa/femoral condyle and calcaneal tuberosity) [84]. The device has a rubber disk connected to a pressure gauge, which will be positioned perpendicular to the point being analyzed, generating pressure at an application rate of 1 kgf/cm². A switch is connected to the algometer that sends a signal and immediately records the value. The instant at which the sensation of pressure becomes pain, the participant will press a button so that the pressure is quantified in kgf/cm². Pain intensity will be quantified using the numerical pain rating scale. Thus, two values will be obtained – the pressure necessary to generate pain (in kgf/cm²) and the intensity of this pain on a scale from 0 to 10. Three repetitions will be performed with a 30-second rest period between readings. The reliability of the algometer is high (intraclass correlation coefficient = 0.91 [95% confidence interval: 0.82–0.97]).

2.8.1.2. Assessment of quality of life and impact of fibromyalgia on functionality

Quality of life will be assess using the SF-36 questionnaire, which has been translated and validated for use in Brazil [89]. The SF-36 is a multidimensional instrument that addresses eight components of quality of life: physical functioning, physical role limitations, bodily pain, general health state, vitality, social functioning, emotional role limitations and mental health [93]. The total score of each domain ranges from 0 to 100, with higher scores denoting better health-related quality of life [93].

The FIQ-R will be used to measure the impact of FM on functionality [88]. This questionnaire was developed as an updated version of the Fibromyalgia Impact Questionnaire. The FIQ-R is composed of 21 items distributed among three domains (function, general impact and symptoms), with higher scores denoting a greater impact of FM on quality of life [88]. The first domain (function) has nine items addressing the effect of FM on activities of daily living [88]. The second domain has only two items addressing the general impact of FM on a scale ranging from ‘never’ to ‘always’ [88]. The third domain (symptoms) has 10 items addressing pain, energy, fatigue, sleep quality, depression, mental problems, anxiety, sensitivity to touch, balance and sensitivity to light, sound and odors [88].

All items are scored on an 11-point numerical scale (0 a 10), with 10 denoting the worst possible condition. The FIQ-R is the sum of the three domains: function score (0 to 90) divided by three, general impact score (0 to 20) and symptoms score (0 to 100) divided by 2 [94]. Total score is 100, with greater scores meaning greater impact. The translated version will be used, which has been validated for use in Brazil [94].

2.8.1.3. Assessment of perceived fatigue and performance fatigue

Perceived fatigue will be assessed using the Fatigue Severity Scale [90], which is composed of nine items that address daily situations. Each item is scored on a seven-point Likert scale ranging from ‘I strongly disagree’ to ‘I strongly agree’ [90]. The sum of all items ranges from 9 to 63. The total is obtained by the sum of all items divided by the number of statements (nine), with higher scores denoting greater fatigue severity [90].

Performance fatigue of the knee extensors and flexors will be measured using the Biodex Multi-Joint System 3 isokinetic dynamometer (Biodex Medical Inc, Shirley, NY, USA) in the concentric mode and recording with a sampling frequency of 100 Hz. This equipment is considered the ‘gold standard’ for the measurement of muscle performance [95] and will be calibrated prior to the assessments and all procedures, including the correction for the effect of gravity. The readings will be performed following the manufacturer’s instruction manual [96].

Prior to the evaluation, the participant will be familiarized with the procedure using an activity that will consist of three submaximal and two maximal contractions [97]. After a three-minute rest period, data collection will begin, which will consist of a one-minute protocol at a velocity of 240º/s. During the readings, the participants will receive verbal encouragement in a vigorous, standardized manner to stimulate greater production of force during the contractions [98]. However, the participants will not receive visual feedback from the equipment at any time.

The participants will be positioned sitting with the hips and knees flexed at 90º. The trunk, pelvis and thigh will be stabilized with straps [99]. The rotation axis of the dynamometer will be aligned with the lateral epicondyle of the femur and the lever will be attached distally to the ankle 5 cm above the medial malleolus [99]. The range of motion for the assessments will be from 20° to 90º of knee flexion (complete extension of the knee = 0º) [100]. The reading will be performed using only the dominant lower limb, which will be determined based on the answer to the following question: “Which leg would you use to kick a soccer ball as far as possible?” [101]. The participants will be instructed not to perform any physical activity beyond habitual activity in the 48 h prior to the readings [102]. Cumulative work and the fatigue index of the extensors and flexors of the knee at 240º/s will be used in the statistical analysis.

2.8.1.4. Assessment of physical functioning

Physical functioning will be assessed using the TUG test and 6MWT. Familiarization will first be performed to ensure the participant’s understanding of the test.

2.8.1.4.1. Timed up-and-go test

This test consists of the quantification (in seconds) of functional mobility based on the time required to stand up from a chair, walk three meters, turn around walk back to the chair and sit back down [91].

2.8.1.4.2. Six-minute walk test

The 6MWT is a safe, low-cost measure for assessing physical functioning in patients with heart, lung or musculoskeletal disease as well as asymptomatic older people. The test will be performed along a straight 30-meter track on a flat surface and always administered by the same examiner, with verbal encouragement at one-minute intervals [91]. The maximum distance traveled in a period of six minutes will be recorded.

2.9. Follow-up data collection

The participants will be followed up after finishing 12 weeks of treatment. Follow-up assessments will be performed 16, 26 and 52 weeks after the initial assessment. During these follow-up periods, outcomes including pain intensity, perceived fatigue, health-related quality of life, functionality, and physical performance will be reassessed. The participants will be expected to maintain the same level of weekly physical activity. Those who experience severe adverse events in the follow-up period will be excluded from the study.

To promote participant retention and ensure complete follow-up, several strategies will be implemented, including regular contact through phone calls and messaging apps, appointment reminders, and scheduling flexibility to accommodate participants’ availability. Participants will be reminded of the importance of their involvement and the contribution of their data to the study’s goals. In cases where participants discontinue or deviate from the intervention protocols, efforts will be made to collect primary and secondary outcome data at all scheduled follow-up points, whenever possible. This includes assessments of pain intensity, fatigue, physical functioning, quality of life, and any other relevant clinical measures. These data will be included in the intention-to-treat analysis to preserve the integrity of the trial results.

2.10. Data management

Data will be entered into a secure, password-protected electronic database by trained personnel. To ensure data quality, double data entry, range checks, and consistency verifications will be performed. Participant confidentiality will be maintained through coded identification, and data will be stored on encrypted servers with regular backups. Further details can be provided upon request.

2.11. Statistical analysis

At the end of the data collection of all measures, statistical analysis will be performed by a researcher who was not involved in the recruitment, assessment or intervention of the participants. Data will be analyzed with the aid of IBM SPSS Statistics for Windows, version 25.0 (Armonk, NY: IBM Corp.). Normality and homoscedasticity will be determined using the Shapiro-Wilk test and Levene’s test, respectively. A mixed generalized model analysis for the outcomes of interest, evaluating the interaction between time (baseline and immediately after the 1st intervention, and follow-up) and groups. The Bonferroni test will be used as post hoc for significant interactions. The chi-square test will be used for categorical data. The significance level will be set at 5% (p ≤ 0.05) for all analyses.

Missing data will be handled using multiple imputation methods, assuming data are missing at random. An intention-to-treat (ITT) analysis will be performed, including all randomized participants in the groups to which they were assigned, regardless of adherence to the intervention protocol. Sensitivity analyses will be conducted to assess the robustness of the results. The number and reasons for missing data will be reported for each group to minimize potential bias.

2.12. Dissemination plans

The results of this trial will be disseminated through publication in peer-reviewed scientific journals and presentations at national and international conferences. A plain language summary of the findings will be provided to study participants upon completion of the trial. Additionally, the final outcomes will be updated on the Brazilian Registry of Clinical Trials (ReBEC, registration number RBR-3pxmycv). Efforts will also be made to communicate the results to healthcare professionals and policymakers through workshops and seminars, aiming to facilitate the translation of research findings into clinical practice.

3. Discussion

This protocol study describes a single-blind randomized clinical trial to investigate whether the combination of an aerobic exercise protocol and systemic PBM (transcutaneous ILIB) has beneficial effects in women with FM, with a reduction in pain and improvement in quality of life. The secondary results will be improvements in perceived fatigue, performance fatigue and physical function.

Individuals with FM experience intense pain and diminished quality of life, with an increase in fatigue and reduction in physical functioning, resulting in physical and psychosocial disabilities with important implications for family, work and dependence [1,2,5,9–12,14]. FM also exerts considerable socioeconomic impacts on the health care sector related to the treatment of symptoms in these patients [6]. Moreover, the chronic use of medications, such as analgesics, non-steroidal anti-inflammatory drugs and antidepressants, is related to a set of side effects, such as gastrointestinal problems, further compromising quality of life [103]. Thus, the development of non-pharmacological strategies that can contribute to reducing pain and fatigue as well as improving physical functioning and, consequently, quality of life is of extreme importance. Several studies stress the importance of physical exercise as a positive strategy for improving physical and functional capacity, with a consequent improvement in the symptoms of FM [16,20–29], highlighting aerobic exercise among the different physical exercise modalities. Aerobic exercise is capable of reducing pain and sensitivity at tender points and increasing physical capacity and has no side effects, thus favoring patient adherence to treatment [29]. Moreover, systemic PBM (transcutaneous ILIB) is a promising therapeutic option for the treatment of these patients, due mainly to its analgesic and systemic effects.

Despite evidence of the positive effects of ILIB as adjunct therapy in the treatment of symptoms of patients with chronic systemic diseases (modulation of inflammation, reduction in proinflammatory cytokines, reduction in pain and improvement in quality of life) [61,74], it is necessary to investigate the effects of this technique in individuals with FM. Among the different PBM administration methods, the most common of which is the spot technique in contact with the skin directly over the target tissue. However, transcutaneous ILIB offers the difference of exerting systemic effects and enables optimizing treatment through the widespread effect of the irradiation of blood on nearly all systems, thus exerting a generalized positive effect on pain conditions – which is a characteristic of FM. As no studies involving transcutaneous ILIB as a form of treatment for individuals with FM were found in the literature, the hypothesis was raised that an optimized effect could be achieved with combined intervention, improving pain, fatigue, physical functioning and quality of life in women with FM.

ILIB therapy has broad beneficial effects on inflammatory modulation and pain relief and is generally considered safe and well tolerated [80]. However, like any therapeutic intervention, ILIB may present risks and contraindications that must be carefully considered. Among the risks, local reactions at the application site, such as irritation or discomfort, may occur, although they are rarely severe. Absolute contraindications include the presence of active neoplasms due to the potential stimulation of cellular proliferation. In FM, despite the absence of widely described specific contraindications, individualized patient evaluation is essential, taking into account associated comorbidities and overall health status to minimize possible adverse effects. Therefore, rigorous monitoring during ILIB application and careful participant selection are essential to ensure the safety and efficacy of the treatment in this population.

Participant adherence to the physical exercise protocol may represent a potential limitation of this study, especially considering the exercise intolerance frequently reported by individuals with FM [30–33]. This clinical condition is characterized by heightened sensitivity to pain and fatigue, which can compromise engagement and continuity in rehabilitation programs based on physical activity. Although the proposed intervention combines strategies that are widely recognized as effective for managing FM, low exercise tolerance may negatively impact both adherence and clinical outcomes. To mitigate this risk, the protocol was carefully designed to include sessions supervised by trained professionals, personalized exercise intensity based on each participant’s functional capacity, and continuous motivational support. These measures aim to promote greater safety, comfort, and participant engagement, thereby contributing to the effectiveness and feasibility of the intervention

Active participation in treatment a crucial aspect, especially when working with interventions directed at chronic musculoskeletal disorders [104]. We expect the participants in our study to adhere to the treatments, as systemic PBM could assist in post-exercise tissue repair. We believe that our approach will be well-received. Based on these considerations, the conclusions of this study could contribute scientific knowledge on physical therapy as safe and effective in the treatment of women with FM.

4. Conclusion

The study will provide valuable insights into the combined of an aerobic exercise protocol and systemic PBM (transcutaneous ILIB) in women with FM. By exploring the potential benefits of this non-pharmacological approach, the study will contribute to advancing scientific knowledge in the field and open avenues for future research. Ultimately, it aims to enhance complementary therapies for managing FM, offering a promising alternative to traditional pharmacological treatments.

Funding Statement

This study was financed, in part, by the São Paulo Research Foundation (FAPESP), Brasil. Process Numbers [#2022/08624–2 and #2023/07420–7], and by the Coordination for the Improvement of Higher Education Personnel (CAPES), Brazil, Finance Code 001. The sponsor and funders had no role in the design, conduct, data analysis, or reporting of this trial.

Article highlights

• The study combines aerobic exercise and TILIB to treat pain, fatigue, and improve function in women with FM.

• The study is a randomized, placebo-controlled, blind trial, where participants will be blinded to the intervention applied.

• Follow-ups at 16, 26, and 52 weeks assess the treatment’s short- and medium-term effectiveness.

• This approach could offer a promising non-pharmacological alternative to traditional treatments for FM with fewer side effects.

Author contributions

Cristiano Carvalho: Conceptualization, Methodology, Writing – Original Draft, Writing – Review & Editing, Visualization, Project administration, Data Curation. Patricia Gabrielli Vassão: Conceptualization, Methodology, Writing – Review & Editing, Thatiane Izabele Ribeiro Santos: Methodology, Writing – Original Draft, Writing – Review & Editing, Data Curation. Alice Torres Pontes: Writing – Original Draft, Writing – Review & Editing, Data Curation. Julia Ghraziely Justino de Oliveira: Writing – Review & Editing, Data Curation. Catharina Marabiza Pinheiro: Writing – Review & Editing, Data Curation. Maria Eduarda de Sousa Kawabe: Writing – Review & Editing, Data Curation. Bruna Genari Sena: Writing – Review & Editing, Data Curation. Carlos Eduardo Pinfildi: Methodology, Writing – Review & Editing. Victor Zuniga Dourado: Methodology, Writing – Review & Editing. Ricardo Luís Fernandes Guerra: Methodology, Writing – Review & Editing. Mariana Arias Avila Vera: Methodology, Writing – Review & Editing. Ana Claudia Muniz Renno: Conceptualization, Methodology, Writing – Review & Editing, Supervision, Funding acquisition.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethical declaration

The authors declare that they obtained approval from the UNIFESP Research Ethics Committee, under protocol number CAAE 66,837,323.60000.5505. Volunteers interested in participating in the research will be invited to sign a written informed consent form before starting any participation in the study.

Data sharing

De-identified individual participant data, the data dictionary, and statistical code will be available from the corresponding author upon reasonable request, subject to approval by the study steering committee and data sharing agreements.