TYPE Original Research PUBLISHED 10 November 2022 DOI 10.3389/fphys.2022.1046613 Effectiveness, cost-utility and OPEN ACCESS physiological underpinnings of EDITED BY Antonio Roberto Zamunér, Catholic University of Maule, Chile the FIBROWALK REVIEWED BY Richard Gevirtz, multicomponent therapy in Alliant International University, United States Mateus Dias Antunes, online and outdoor format in University of São Paulo, Brazil *CORRESPONDENCE individuals with fibromyalgia: Albert Feliu-Soler, albert.feliu@uab.cat Study protocol of a randomized, † These authors have contributed equally to this work and share first authorship controlled trial (On&Out study) ‡ These authors share senior authorship SPECIALTY SECTION Mayte Serrat 1,2†, Sònia Ferrés 2,3†, William Auer 3†, This article was submitted to Exercise Physiology, Míriam Almirall 1, Enrique Lluch 4,5,6, Francesco D’Amico 7, a section of the journal Frontiers in Physiology Michael Maes 8, Sonia Lorente 9,10, Jaime Navarrete 3,11, RECEIVED 16 September 2022 Jesús Montero-Marín 11,12, Randy Neblett 13, Jo Nijs 6,14,15, ACCEPTED 20 October 2022 Xavier Borràs 3,11‡, Juan V. Luciano 11,17‡ and PUBLISHED 10 November 2022 Albert Feliu-Soler 11,17*‡ CITATION Serrat M, Ferrés S, Auer W, Almirall M, 1 Unitat d’Expertesa en Síndromes de Sensibilització Central, Servei de Reumatologia, Vall d’Hebron Lluch E, D’Amico F, Maes M, Lorente S, Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain, 2Escoles Navarrete J, Montero-Marín J, Universitàries Gimbernat, Autonomous University of Barcelona, Barcelona, Spain, 3Department of Neblett R, Nijs J, Borràs X, Luciano JV Basic, Developmental and Educational Psychology, Faculty of Psychology, Autonomous University of and Feliu-Soler A (2022), Effectiveness, Barcelona, Barcelona, Spain, 4Department of Physiotherapy, Faculty of Physiotherapy, University of cost-utility and physiological Valencia, Valencia, Spain, 5Physiotherapy in Motion, Multi-Specialty Research Group (PTinMOTION), underpinnings of the FIBROWALK Department of Physiotherapy, University of Valencia, Valencia, Spain, 6Pain in Motion International multicomponent therapy in online and Research Group, Brussels, Belgium, 7Care Policy and Evaluation Centre (CPEC), London School of outdoor format in individuals with Economics and Political Science (LSE), London, United Kingdom, 8Department of Psychiatry, Faculty of fibromyalgia: Study protocol of a Medicine, Chulalongkorn University, Bangkok, Thailand, 9Department of Psychobiology and randomized, controlled trial Methodology of Health Science, Autonomous University of Barcelona, Barcelona, Spain, 10Pediatric (On&Out study). Area, PNP, Hospital de Terrassa, Consorci Sanitari de Terrassa, Terrassa, Spain, 11Psychological Front. Physiol. 13:1046613. Research in Fibromyalgia and Chronic Pain (AGORA Research Group), Parc Sanitari Sant Joan de Déu, doi: 10.3389/fphys.2022.1046613 Barcelona, Spain, 12Warneford Hospital, Department of Psychiatry, University of Oxford, Oxford, United COPYRIGHT Kingdom, 13PRIDE Research Foundation, Dallas, TX, United States, 14Pain in Motion Research Group © 2022 Serrat, Ferrés, Auer, Almirall, (PAIN), Department of Physiotherapy, Human Physiology, and Anatomy, Faculty of Physical Education Lluch, D’Amico, Maes, Lorente, & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium, 15Department of Health and Navarrete, Montero-Marín, Neblett, Nijs, Rehabilitation, Unit of Physiotherapy, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Borràs, Luciano and Feliu-Soler. This is University of Gothenburg, Gothenburg, Sweden, 16Chronic Pain Rehabilitation, Department of Physical an open-access article distributed Medicine and Physiotherapy, University Hospital Brussels, Bierbeek, Belgium, 17Department of Clinical under the terms of the Creative and Health Psychology, Faculty of Psychology, Autonomous University of Barcelona, Barcelona, Spain Commons Attribution License (CC BY). The use, distribution or reproduction in Introduction: The On&Out study is aimed at assessing the effectiveness, cost- other forums is permitted, provided the original author(s) and the copyright utility and physiological underpinnings of the FIBROWALK multicomponent owner(s) are credited and that the intervention conducted in two different settings: online (FIBRO-On) or original publication in this journal is cited, in accordance with accepted outdoors (FIBRO-Out). Both interventions have proved to be efficacious in academic practice. No use, distribution the short-term but there is no study assessing their comparative effectiveness or reproduction is permitted which does nor their long-term effects. For the first time, this study will also evaluate the not comply with these terms. cost-utility (6-month time-horizon) and the effects on immune-inflammatory biomarkers and Brain-Derived Neurotrophic Factor (BDNF) levels of both Frontiers in Physiology 01 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 interventions. The objectives of this 6-month, randomized, controlled trial (RCT) are 1) to examine the effectiveness and cost-utility of adding FIBRO- On or FIBRO-Out to Treatment-As-Usual (TAU) for individuals with fibromyalgia (FM); 2) to identify pre–post differences in blood biomarker levels in the three study arms and 3) to analyze the role of process variables as mediators of 6- month follow-up clinical outcomes. Methods and analysis: Participants will be 225 individuals with FM recruited at Vall d’Hebron University Hospital (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs. TAU + FIBRO-On vs. TAU + FIBRO-Out. A comprehensive assessment to collect functional impairment, pain, fatigue, depressive and anxiety symptoms, perceived stress, central sensitization, physical function, sleep quality, perceived cognitive dysfunction, kinesiophobia, pain catastrophizing, psychological inflexibility in pain and pain knowledge will be conducted pre-intervention, at 6 weeks, post- intervention (12 weeks), and at 6-month follow-up. Changes in immune- inflammatory biomarkers [i.e., IL-6, CXCL8, IL-17A, IL-4, IL-10, and high- sensitivity C-reactive protein (hs-CRP)] and Brain-Derived Neurotrophic Factor will be evaluated in 40 participants in each treatment arm (total n = 120) at pre- and post-treatment. Quality of life and direct and indirect costs will be evaluated at baseline and at 6-month follow-up. Linear mixed-effects regression models using restricted maximum likelihood, mediational models and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed. Ethics and dissemination: This study has been approved by the Ethics Committee of the Vall d’Hebron Institute of Research. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities. Trial registration number NCT05377567 (clinicaltrials.gov). KEYWORDS fibromyalgia, online, outdoor, pain neuroscience education, effectiveness, cost-utility, cytokines, BDNF 1 Introduction condition presenting higher costs, with direct costs (i.e., medication, visits to healthcare professionals, medical Fibromyalgia (FM) is a highly prevalent syndrome (2.7% tests, emergency room visits and hospital admissions) being worldwide, 2.5% in Europe and 2.4% in Spain) (Queiroz, 2013) up to three times higher than the observed in other chronic which mainly affects women, around 40–50 years of age (Häuser pain conditions and similar sociodemographic characteristics et al., 2015). FM is characterized by the presence of chronic (Berger et al., 2007; Leadley et al., 2012; Wylezinski et al., 2019). widespread musculoskeletal pain, fatigue and sleep problems (Häuser et al., 2015) and, very often, it is also accompanied by anxiety (13%–63.8%) and depressive disorders (20%–80%) 1.1 Recommended treatments for FM and (Fietta et al., 2007). Remarkably, FM is the chronic pain the emergence of online and outdoors condition with the highest rate of unemployment, sick leave, therapeutic approaches disability claims and absenteeism (Leadley et al., 2012) and 23%– 66% of individuals with this syndrome are forced to leave work Up to date, the available treatments for FM are not curative due to its aftermaths (Assefi et al., 2003; Gerdle et al., 2008). and their clinical efficacy is generally rather low (Häuser et al., Furthermore, individuals with FM are usually considered “hyper- 2015). In relation to pharmacological treatments, the European frequent users’’ of health services with 6% of adult patients League Against Rheumatism (EULAR) recommends reserving attending primary care and 10%–20% attending rheumatology pharmacological treatment only for those cases with severe pain services having a diagnosis of FM (Gerdle et al., 2008; Häuser and for sleep disturbances (Häuser et al., 2015; Macfarlane et al., et al., 2015). Regarding this latter point, FM is the medical 2017). In line with this, non-pharmacological strategies appear to Frontiers in Physiology 02 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 promote broader clinical effects and show slightly larger effect kinesiophobia, physical function, fatigue, and anxiety and sizes compared to pharmacological treatments (Nüesch et al., depressive symptomatology (Serrat et al., 2020; Serrat et al., 2013, Perrot et al., 2014). Non-pharmacological strategies include 2021a; Serrat et al., 2021b; Serrat et al., 2022b). interventions such as pain education, cognitive behavioral The COVID-19 pandemic has enforced the emergence of therapy (CBT), mindfulness, therapeutic physical exercise, new therapeutic approaches alternative to face-to-face treatment among others, which aim primarily at alleviating symptoms since mobility restrictions and infection risk have generally and improving patients’ quality of life (Macfarlane et al., limited this classical format of therapy. In this regard, there is 2017). More specifically, Pain Neuroscience Education (PNE) a growing body of evidence on the efficacy of alternative forms of (Van Oosterwijck et al., 2013; Nijs et al., 2014; Amer-Cuenca therapy such as online (Schwamm et al., 2020; Weiling et al., et al., 2020) is aimed at changing patients’ pain beliefs, 2020; Serrat et al., 2021a; White et al., 2022) and outdoor emphasizing how overprotective behaviors can accentuate (Buckley et al., 2018; Stanhope et al., 2020) formats in chronic pain experience (Moseley and Butler, 2015). PNE has been pain populations including FM. found to be effective for reducing pain disability, Beyond pandemics, teletherapy approaches such as online catastrophizing, avoidance behaviors and physical inactivity in FIBROWALK (Serrat et al., 2021a) are highly promising when patients with FM (Malfliet et al., 2017). Concurrently, there is compared to traditional face-to-face when dealing with specific high agreement among clinical guidelines that CBT and logistic barriers such as time, travel or access difficulties in rural therapeutic physical exercise should constitute the main areas, or health barriers such as patients’ fatigue, among other therapeutic elements when treating FM (Jones et al., 2006; symptoms which may interfere with treatment adherence. Online Bernardy et al., 2010; Sosa-Reina et al., 2017; Bernardy et al., programs which are highly scalable and accessible per definition 2018); furthermore, combining both interventions has been may also help in decongest healthcare services (which are shown to be particularly effective (Witek-Janusek et al., 2008; particularly overstretched worldwide since the COVID-19 Black et al., 2013). There is also mounting evidence that pandemic), significantly reduce healthcare staff costs, and help mindfulness training can be an efficacious and cost-effective increase widespread access to evidence-based treatment for FM approach for improving quality of life, functional impairment, (Assefi et al., 2003; Friedman et al., 2012; Moman et al., 2019). In anxiety, depression, and other symptoms in patients with FM this regard, in a recent systematic review on the efficacy of online (Haugmark et al., 2019; Pérez-Aranda et al., 2019). psychological interventions for people with chronic health Mounting empirical evidence suggests that multicomponent conditions, online treatments were found to be efficacious for approaches integrating at least therapeutic physical exercise and improving depressive symptomatology and distress in people a psychological/educational intervention can be effective in with FM, supporting the usefulness of these low cost, easily individuals with FM (e.g., Van Wilgen et al., 2007; Castel accessible, and highly scalable therapeutic approaches for et al., 2013; Thieme et al., 2017) and some authors propose treating this syndrome (White et al., 2020). Furthermore, an that these multicomponent interventions should be the “gold important aspect when implementing treatments, especially for standard” in FM (Rivera et al., 2006; Häuser et al., 2008; De chronic conditions, is to promote self-management and online Miquel et al., 2010; Macfarlane et al., 2017; Thieme et al., 2017). interventions may facilitate this aspect (Leadley et al., 2012). In this regard, a metanalysis exploring the efficacy of different Simultaneously, nature-based therapeutic approaches such as the pharmacological and non-pharmacological therapies on outdoor FIBROWALK (Serrat et al., 2020) have shown to be fibromyalgia symptoms (Papadopoulou et al., 2016) suggested useful in improving mental health in different clinical conditions that multidisciplinary treatments would be the most beneficial (Trøstrup et al., 2019), including chronic pain and FM (López- ones among non-pharmacological interventions for treating FM, Pousa et al., 2015; Serrat et al., 2020; Stanhope et al., 2020). In this since statistically significant improvements were found in all FM sense, it is interesting that therapeutic programs conducted symptoms comprising OMERACT-10 response criteria outdoors have been shown to be effective in improving (i.e., pain, sleep, function, fatigue, anxiety, depression, mental health, pain and general health, and it is suggested cognition). Furthermore, four recent RCTs published after the that exposure to the natural environment (both in urban aforementioned metanalysis, provided additional evidence on green areas and in nature) may produce additive positive the short-term efficacy (i.e., post-intervention) of a 3-month effects at both affective (positive and negative emotions and multicomponent intervention for FM (i.e., the FIBROWALK stress) and cognitive (attention, memory, motivation, etc.) levels program) comprising CBT, mindfulness training, therapeutic thus enhancing the beneficial effects of the program (Buckley physical exercise and PNE (Serrat et al., 2020; Serrat et al., et al., 2018). In this regard, when compared to therapeutic 2021a; Serrat et al., 2021b; Serrat et al., 2022b). Interestingly, exercise conducted indoors, exercising in natural settings was the FIBROWALK program showed to be clinically efficacious associated with greater feelings of revitalization and positive when tested in hospital, outdoors and also in online settings engagement, reductions in tension, confusion, anger, and compared to Treatment-As-Usual (TAU) alone and provided depressive symptomatology, and increased energy (Thompson clinically relevant improvements in functionality, pain, Coon et al., 2011). Furthermore, there is evidence that exercising Frontiers in Physiology 03 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 outdoors (vs. indoors) may also promote directed attention and increase the activity of the hypothalamic-pituitary-adrenal axis, social interactions, which may positively influence future as well as prostaglandin and substance P synthesis, thereby intention of maintaining an exercise routine (Rogerson et al., reducing the pain threshold (Zhou et al., 2016). On the other 2016). Regarding the possible effects of the intervention format of hand, at a central level, pro-inflammatory cytokines along with the FIBROWALK intervention was found to be beneficial in other inflammatory-related by-products are known to alter the hospital, outdoors and virtual settings at short term with synthesis, reuptake and release of different neurotransmitters in apparently larger effect sizes in the outdoor format when the CNS (e.g., serotonin, noradrenaline, dopamine, glutamate. compared to indoor hospital or online settings (Serrat et al., These neurotransmitters are involved in both pain perception 2020; Serrat et al., 2021a; Serrat et al., 2021b; Serrat et al., 2022b). and the regulation of diverse affective, cognitive and motivational However, no clinical trial with a parallel design has yet been processes, contributing to the neuroplastic changes observed in conducted to evaluate potential differences in the short- and the FM, abnormal pain experience and to other FM symptoms, such long-term efficacy between these different formats or in as fatigue, sleep disturbances, cognitive impairment, and affective therapeutic adherence. The present study aims to address this problems (Miller et al., 2013; Rodriguez-Pintó et al., 2014; important knowledge gap. Andrés-Rodríguez et al., 2020). Although recommended, there is a striking lack of empirical Several studies have suggested that FM and other central evidence regarding the cost-effectiveness of multicomponent sensitivity syndromes present not only with chronic low-grade interventions for FM, including FIBROWALK. Bearing in inflammation but also with abnormalities in biomarkers related mind that costs are of crucial relevance for policy-makers, to neuronal plasticity, such as BDNF (Deitos et al., 2015). The who usually consider as first-choice treatment those BDNF is a multifunctional neurotrophin with numerous therapeutic approaches with the lowest associated cost per functions in the brain (Jensen et al., 2012; Cagnie et al., 2014), quality-adjusted life-year (QALY), economic evaluations of including a driving force behind (maladaptive) neuroplasticity multicomponent interventions in FM should be performed to and central sensitization (Nijs et al., 2015), and it is believed to be ensure (if cost-effective) their implementation in healthcare specifically associated with the occurrence and/or progression of systems. mnemonic symptoms associated with a variety of conditions characterized by cognitive impairment (Napadow et al., 2012). BDNF is known to play a key role in a variety of neuroplasticity 1.2 Immune-inflammatory status and processes, including pain modulation, pain transduction, BDNF levels in individuals with FM nociception, and hyperalgesia (Nugraha et al., 2012), all of which are known to be altered in FM. In this regard, plasma There are several potential physiological factors which have levels of BDNF have also been found to be augmented in been proposed underpinning the FM symptomatology. In this individuals with FM (Haas et al., 2010; Polli et al., 2020) and regard, the central nervous system (CNS) seems to have a leading DNA methylation in exon nine appears to be driving the higher role (Häuser et al., 2015), involving altered function in pain BDNF protein levels in patients with FM (Polli et al., 2020); neural pathways (Sluka and Clauw, 2016; Sawaddiruk et al., however, we have to bear in mind that associations between 2017). At the same time, there is evidence suggesting an BDNF levels and patients’ clinical complaints have not been imbalance between pro- and anti-inflammatory cytokine levels found always consistent (Zanette et al., 2014; Jha and Trivedi, at both the peripheral and central levels in individuals with FM 2018) and that some studies have found no differences between contributing to a chronic state of low-grade inflammation FM patients and healthy controls on BDNF levels (Ranzolin et al., (Rodriguez-Pintó et al., 2014; Bäckryd et al., 2017; Albrecht 2016). Furthermore, there are reciprocal associations between et al., 2019; Andrés-Rodríguez et al., 2019). This BDNF and immune-inflammatory pathways, which may explain proinflammatory state may be a key contributor to impaired the involvement of BDNF in the immune pathophysiology of pain processing as could lead to the sensitization of peripheral mood disorders (Perrot and Russell, 2014), with BDNF acting as nerves and to central sensitization (Rodriguez-Pintó et al., 2014; a conserved regulatory process that protects against the Littlejohn, 2015), possibly through activation of glial cells (Nijs detrimental effects of immune activation including et al., 2017). neurotoxicity (Mehterov et al., 2022). A recent meta-analysis concluded that patients with FM may Some of these biomarkers may also influence treatment present increased levels of blood IL-6, IL-4 and IL-17A compared response in individuals with chronic pain conditions including to healthy controls (Andrés-Rodríguez et al., 2020). Coherently, FM. Related to this, higher pretreatment levels of IL-6 and TNF-α increased levels in other markers indicative of an inflammatory have been found to be associated with lesser improvements in state [e.g., high-sensitivity C-reactive protein (hs-CRP)] were pain intensity and other patient-reported outcomes after also reported (Andrés-Rodríguez et al., 2020). Some of these cognitive behavioral interventions administered in individuals proinflammatory cytokines (e.g., IL-6) are known to facilitate with chronic pain (Lasselin et al., 2016). Furthermore, higher sensitization of peripheral nerves to nociceptive stimuli and to baseline levels of CXCL8 were also found to attenuate clinical Frontiers in Physiology 04 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 benefits (i.e., in pain, fatigue, stiffness and quality of sleep) after an 8-week standardized mindfulness program in patients with FM (Andrés-Rodríguez et al., 2019). 1.3 Effects of non-pharmacological interventions on immune-inflammatory markers and BDNF in individuals with FM In a systematic review of longitudinal studies in FM, multicomponent programs, physical exercise and dietary modification were found to have effects on inflammatory markers in FM patients (Sanada et al., 2015). In this regard, reductions in levels of the pro-inflammatory cytokines IL-6 and CXCL8 were observed in FM patients following these interventions, suggesting a potential anti-inflammatory effect. Similarly, in a recent study (Andrés-Rodríguez et al., 2019) evaluating the effects of mindfulness training on immune-inflammatory markers, it was also reported that levels of the anti-inflammatory cytokine IL-10 remained higher in patients assigned to mindfulness than those allocated to the TAU arm. In another study assessing the effects of an 8-week compassion-based intervention (i.e., Attachment-Based Compassion Therapy, ABCT) for FM, a global anti-inflammatory FIGURE 1 effect along with reductions in BDNF levels in individuals with FM Flowchart of the On&Out study based on the Consolidated when compared to an active control condition (i.e., relaxation Standards of Reporting Trials guidelines. Fibro-Out, FIBROWALK training) were also reported (Montero-Marin et al., 2019). These Outdoors; Fibro-On, FIBROWALK Online; ITT, intention-to-treat; TAU, Treatment-As-Usual. changes in BDNF levels were significantly related and followed by ameliorations in FM functional impairment, showing significant indirect effects, which means that reductions in BDNF might function as a crucial treatment mediator. In this study, baseline BDNF levels were similar to those obtained in a previous study with dysfunction (secondary outcomes); 2) to identify pre–post patients suffering from central sensitivity syndromes with persistent differences in levels of different physiological variables somatic or visceral nociception in which, after treatment, these levels (i.e., immune-inflammatory markers and BDNF levels) and normalized, approaching to those observed in pain-free individuals correlate these changes with those observed at self-report (Deitos et al., 2015). Regarding the effects of psychosocial measures and 3) evaluate the role of psychological process interventions (mainly psychotherapy and psychoeducation) on variables considered to be potential mediators of the immune function in adults with different health conditions, in an interventions from a theoretical point of view extensive systematic review and meta-analysis (Shields et al., 2020), (i.e., kinesiophobia, pain catastrophizing, psychological many different improvements in immune function (including levels inflexibility in pain and pain knowledge) and the evaluated of pro-inflammatory biomarkers) were robustly reported. physiological variables as mediators of long-term clinical Interestingly, these effects were more remarkable after the improvements. For the sake of personalized treatment in FM, application of CBT and multicomponent programs. Importantly, the design of the present study will allow us to explore whether there are no available studies assessing the effects of multicomponent certain patient profiles or baseline psychobiological interventions such as FIBROWALK in physiological markers in characteristics may help predict the short- and long-term fibromyalgia aimed at understanding physiological mechanisms clinical response to the specific evaluated treatments. underpinning its efficacy. The objectives of the On&Out study are 1) to examine the effectiveness and cost-utility of adding the FIBROWALK 2 Materials and methods intervention in online or in outdoors format to TAU in the management of patients with FM for improving functional 2.1 Trial design impairment (primary outcome) and pain, fatigue, depressive and anxiety symptoms, perceived stress, central sensitization, This RCT protocol was developed following the Standard physical function, sleep quality and perceived cognitive Protocol Items: Recommendations for Interventional Trials Frontiers in Physiology 05 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 (SPIRIT) (Chan et al., 2013) and was recorded in the ClinicalTrials. Diagnosis of FM according to the ACR 2010/2011 criteria. 3. gov trial register in May 2022 (NCT05377567). We designed a 6- Understanding written and spoken Spanish. The general month, parallel group, randomized (using a computer-generated exclusion criteria will be: 1. Psychological treatment received randomization list), single-blind, controlled trial (RCT) with three within the last year or current. 2. Comorbid presence of severe treatment arms. The effectiveness of the FIBROWALK program mental disorder (e.g., schizophrenia) or other terminal clinical (i.e., multicomponent program based on therapeutic exercise, PNE, conditions or scheduled treatments that may interrupt study CBT, and mindfulness training) in FIBRO-On (online) and in follow-up. 3. Inability to complete the weekly sessions/modules FIBRO-Out (outdoors) formats adjuvant to TAU, compared to of the program on a regular basis. TAU alone in patients with FM recruited from the Central For the biomarkers substudy, usual contraindications for Sensitivity Syndromes Specialized Unit from the HUVH, will be measuring blood immune-inflammatory markers will be taken evaluated. The Consolidated Standards of Reporting Trials 2010 into account to establish the following additional inclusion/ (CONSORT) (Schulz et al., 2010) and the Consolidated Health exclusion criteria for the biomarkers substudy: only Economic Evaluation Reporting Standards (CHEERS) (Husereau participants of female sex, with no autoimmune-type disease, et al., 2013) will be followed. The expected flowchart of participants in no recent physical trauma, not being vaccinated during the last the study is displayed in Figure 1. week, no symptoms suggestive of cold/infection on the day of blood collection, no needle phobia, not pregnant or breastfeeding, not using oral or local corticosteroids or any 2.2 Recruitment strategy anti-cytokine biologic drugs or oral contraceptives will be included in the biomarkers substudy. Potential participants are individuals with FM diagnosis (ACR 2010/2011 criteria) made by a rheumatologist and seeking health services currently or in the last year at the 2.5 Procedure and randomization Central Sensitivity Syndromes Specialized Unit at HUVH. The recruitment of participants will be carried out in two ways: 1) consecutive recruitment from consultation by the 2.3 Sample size calculation rheumatologists of the HUVH Central Sensitivity Syndromes Specialized Unit and 2) by screening a list of patients (with Two-hundred and twenty-five individuals who meet the contact telephone number) corresponding to patients who selection criteria for the study will be recruited. The estimated contacted the Unit during the last 6 months. The clinicians sample size needed is n = 63 participants per condition involved in the project (i.e., MA and MS) will proceed to considering a moderate effect size (Cohen’s d = 0.5) for the carry out the telephone screening and those who meet the difference between the active arms at post-intervention selection criteria of the study will be invited to participate. compared to the control group for the primary variable After obtaining written informed consent, the instrument (i.e., FIQR score) with an alpha = 0.05 and 1-b power = 0.80. battery -including clinical and economic measures-described With an expected dropout rate of 20%–25%, the final sample size below will be administered (online assessment). Two research is estimated at 75 individuals per arm. The effect size used for the assistants will coordinate the study assessments to ensure an sample size calculation corresponds to the average effect size for adequate understanding of all administered self-reported multicomponent interventions in FM vs. control group (Nüesch measures. Random assignment of participants to study arms et al., 2013). Previous RCTs evaluating the FIBROWALK will be executed after baseline assessments as recommended by intervention indicated effect sizes between d = 0.4 (Serrat the CONSORT guidelines (Schulz et al., 2010). Once written et al., 2021a) and d = 1.83 (Serrat et al., 2020). Using as a consent and baseline assessment have been completed, study reference previous studies of the group evaluating the effect of participants will be given a unique personal code and different non-pharmacological treatments in FM patients on randomized using randomization software (1:1:1 ratio). The blood values of immuno-inflammatory markers (Andrés- computer-generated randomization will apply a permuted Rodríguez et al., 2019; Montero-Marin et al., 2020), it is block design to ensure that the groups are balanced taking estimated that a sample size of 40 subjects per arm will be biomarkers substudy eligibility criteria (No=Not meeting sufficient to be able to detect changes in the evaluated variables. criteria for biomarkers substudy; Yes = Meeting criteria) into account. The randomization list will be stored in an encrypted file on a password-protected computer in the clinical trials 2.4 Eligibility criteria supervisor’s office to assure concealment of allocation. Participants will be informed of their group allocation by All participants will meet the following general inclusion the administrative personnel, who will send a notification via criteria: 1. Individuals between 18 and 65 years of age. 2. email. Frontiers in Physiology 06 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 Patients who meet the selection criteria for the biomarkers problems of access to the videos by patients with little substudy will be rescheduled 3–5 days after the first assessment to technological experience, a highly-accessible and user-friendly obtain blood samples (up to the required N of 40 subjects per platform will be used (e.g. Youtube). To verify that participants arm). Fasting blood extractions will be performed in a pre-set adhered to FIBRO-On program, participants will be asked to time window (8a.m.–10a.m.) to reduce circadian variability in the complete a brief weekly questionnaire (5–10 items) asking for levels of the biomarkers evaluated. In order to limit the effects of very basic concepts explained in the videos (e.g., “Please, provide medication on the study variables, patients will be asked to a short example of a catastrophic thought”). Participants who do refrain from taking any occasional anti-inflammatory drugs in not answer the weekly questionnaire or those informing of any the 72 h prior to blood sampling. issue interfering with the adherence to treatment protocol (e.g., The research assistants, who will be blinded to not being able to do the homework, watching the videos, randomization, will coordinate the three subsequent clinical answering the questionnaire, etc.) will be contacted (via SMS assessments: at 6 weeks, at post-intervention and at 6 months and/or telephone calls) by the therapist in charge (MS) and some after the baseline assessment (follow-up). The same procedure as guidance will be facilitated. If necessary, individuals who were in baseline will be followed for the collection of biological unable to view or answer the questionnaire in a specific week samples at post-intervention, respecting the pre-set time interval. could request an extension of the date. There was no therapeutic The study will be organized in two consecutive periods with interaction with the participants, but participants were invited to six study groups (i.e., 2 TAU, 2 FIBRO-Out, 2 FIBRO-On) contact the therapist by email if they experienced any problems. conducted in parallel in each period. All the groups will The FIBRO-On program was created during the COVID-19 include 18–20 participants (i.e., FIBRO-On, FIBRO-Out, lockdown and since then, it has been successfully applied at TAU), so the N = 75 is expected to be reached at the end of the Central Sensitivity Syndromes Specialized Unit from the the study. HUVH (Serrat et al., 2021a; Serrat et al., 2022b). See Tables 1, 2 for more details. 2.6 Interventions 2.6.3 FIBRO-Out The FIBRO-Out program includes the implementation of the 2.6.1 TAU 12-session FIBROWALK multicomponent program (Serrat et al., Although there is no gold standard treatment for FM, in the 2020) in an outdoor environment as an add-on to TAU. It will be Spanish healthcare context, the TAU for FM is mainly conducted weekly and in group format (18–20 participants/ pharmacological and is adjusted to the symptomatologic group) and it will be carried out in a green area in an urban profile of each patient. It is usually also accompanied by environment (i.e., “Parc del Cargol”) located in the neighborhood guidelines for aerobic physical exercise adapted to the of the HUVH (Barcelona). FIBROWALK includes components individual’s limitations. Participants assigned to this treatment of PNE, CBT, mindfulness training and therapeutic exercise. arm will be offered to participate in the FIBRO-On or FIBRO- PNE aims to reconceptualize pain and is included in all sessions Out program (whichever is their choice) at the end of the study. of the program. This is an educational program that teaches pain patients the difference between harm and pain, how the pain 2.6.2 FIBRO-On program is activated when actual or potential harm is appraised This program is also based in the FIBROWALK program by the brain that seeks to generate an active protective response (Serrat et al., 2020) and is virtually identical to the FIBRO-Out and how this assessment can be erroneous depending on program described below. The FIBRO-On program will also be different contextual factors. It is based on the “Explaining administered as an adjuvant intervention to TAU. All contents of Pain” program by Butler and Moseley (2010). Examples, the FIBROWALK (explanations and guidelines for the practice of images and metaphors are used to facilitate the understanding the components of PNE, physical exercise, CBT and of the educational content of the program (Nijs et al., 2011). mindfulness) will be explained by means of videos together Multi-component physical exercises such as stretching, balance with slide presentations. The contents in the videos will be training, posture correction, limb extension and low-impact taught by the first author (MS) who is both a physiotherapist walking (i.e., Nordic walking) are performed with a moderate with more than 17 years of experience and a health psychologist training load. Exercises are individualized, establishing a baseline with more than 8 years of experience. Furthermore, MS was the of minimum performance and guiding progression throughout creator of the FIBROWALK program. Although the virtual the 12-week program. Following the recommendations of the sessions are 60 min long, a general recommendation is to American College of Sports Medicine (Pescatello et al., 2014), each expend 120 min to perform all the exercises indicated in each therapeutic physical exercise session is structured in three parts: specific video. Every week, links to the videos of the warm-up, main exercise and cool-down. At the beginning of each corresponding module will be sent by email so that patients session, an interval of approximately 15 min is set aside to discuss can access them whenever possible during the week. To limit the most important aspects of the task between sessions, as well as Frontiers in Physiology 07 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 TABLE 1 Outline of the FIBROWALK program (with FIBRO-Out and FIBRO-On specifications). Educational and psychological contents in the FIBROWALK program • Pain Neuroscience Education (PNE) • Cognitive Behavioral Therapy (CBT) • Mindfulness training (MT) Physical therapeutic exercises in the FIBROWALK program • Warm-up: activation and mobility exercises • Therapeutic exercises: moderate aerobic-cardiovascular and muscle strengthening exercises combined with some balance and coordination exercises performed in a playful manner with cognitive and emotional targets (multitask works) where the level of difficulty and dedication time gradually increases • Cooling-down: flexibility and relaxation exercises Homework • Moderate intensity walking is recommended from the first session in a progressive pattern: 1st month - once per week, 2 nd month - twice per week, 3rd month - three times per week • Exercises based on PNE, CBT and MT contents are also proposed every week (e.g., identifying danger signals, modifying sleep habits, challenging negative automatic thoughts, doing a 10-min body scan meditation) • Double tasks: combining TE with CBT by fostering different cognitive/affective regulation skills throughout exercise (e.g., identifying external and internal stimuli which may promote positive affect during the exercise, discovering automatic thoughts during the exercise and uncovering patterns between thoughts with negative emotions, pain experience and fatigue; diminishing catastrophic thinking; recognizing the achievements, improving self-efficacy) Contents in each session# Session 1: PNE (1.2) + CBT (1) + MT (1) Session 2: PNE (3.4) + CBT (2) + MT (2) Session 3: PNE (5.6) + CBT (3) + MT (3) Session 4: PNE (7.8) + CBT (4) + MT (4) Session 5: PNE (9.10) + CBT (5) + MT (5) Session 6: PNE (11) + CBT (6) + MT (6) Session 7: PNE (12) + CBT (7.8) + MT (7.8) Session 8: PNE (13) + CBT (9) + MT (9) Session 9: PNE (14) + CBT (10) + MT (10) Session 10: Family Session (PNE 1–16) Session 11: PNE (15) + CBT (11) + MT (11) Session 12: PNE (16) + CBT (12) + MT (12) Overall structure of the sessions for the FIBRO-Out and FIBRO-On versions of the FIBROWALK program FIBRO-Out program (face-to-face sessions) • Review Phase (15′): Brief review of contents of the previous session • Educational and psychological contents and Physical therapeutic exercises (1h 40′) • Homework explanation (5′) FIBRO-On program (online videos) • Review Phase (2′): Brief review of contents of the previous session • Educational and psychological contents and Physical therapeutic exercises (55′) • Homework explanation (3′) Handouts and specific practices are facilitated in each video session and, although the FIBRO-On videos’ duration is of 60 min each, the recommendation is to expend 120 min to do all the exercises proposed Note: Both versions of the FIBROWALK (i.e., FIBRO-Out and FIBRO-On) are equivalent regarding contents and distribution of them across sessions. #The numbers between brackets correspond to specific contents of the program explained on Table 2. PNE , pain neuroscience education; CBT , cognitive behavioral therapy; TE , therapeutic exercise; MT , mindfulness training. Frontiers in Physiology 08 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 TABLE 2 Contents of the FIBROWALK program (i.e., Pain Neuroscience Education, Therapeutic Exercise, Cognitive Behavioral Therapy, and Mindfulness Training). Pain neuroscience education (PNE) 1. Disassembling beliefs 2. Danger signals: modulation and modification 3. Concept of pain, fatigue, and pain system 4. Concept of central nervous system and central sensitization. The role of the brain 5. Acute vs. chronic pain: The purpose of acute pain and how it originates in the nervous central system 6. Pain vs. damage 7. Pain neuromatrix theory and representation of the virtual body 8. Nociception, nociceptors, action potential, peripheral sensitization, and synapses 9. Ascending and descending inhibitory pathways, spinal cord 10. Relationship with attention, perception, pain cognitions, and pain behaviors 11. Allodynia and hyperalgesia, hypersensitivity of the nervous central system 12. Pain memory, pain perception, and autoimmune evaluation error 13. Relationship with stress. Etiology 14. Neuroplasticity and how the pain becomes chronic 15. Relationship with emotions 16. Re-education, gradual activity, and therapeutic exercise Therapeutic Exercise (TE) 1. Essential and necessary movement 2. Set a basal minimum of activity 3. Individualized gradual program 4. Small increases, patterns 5. Activities contingent on the task, not over time 6. Involvement in the tasks of daily life 7. Lifestyle change: cognitive coping strategies 8. Double tasks: focused on the following cognitive/affective targets: positive affect, negative affect, self-efficacy, catastrophic thinking, pain and fatigue Cognitive Behavioral Therapy (CBT) 1. Relaxation and breathing 2. Modulating factors of pain 3. Catastrophizing and fear of movement (fear avoidance model) 4. Painful experiences: confrontation (fear avoidance model) 5. Vital values and setting goals 6. Organization of time 7. Sleep patterns 8. Sexual issues 9. Handling of attention 10. Cognitive restructuring 11. Emotional regulation tasks focused on identifying and promoting a more adaptive use of the following cognitive/affective regulation skills: self-blame, acceptance, rumination, focus on the positive, focus on plans, positive reassessment, put in perspective, catastrophizing, blaming others 12. Troubleshooting Mindfulness Training (MT) 1. An Introduction to Body Scanning 2. Elementary Awareness (Continued on following page) Frontiers in Physiology 09 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 TABLE 2 (Continued) Contents of the FIBROWALK program (i.e., Pain Neuroscience Education, Therapeutic Exercise, Cognitive Behavioral Therapy, and Mindfulness Training). Pain neuroscience education (PNE) 3. Sitting Practice and introduction to Yoga 4. Mindfulness and the brain 5. Mindfulness and communication: guilt, empathy, and conflict management 6. Responding vs. reacting 7. Dig deeper into personal practice 8. Mindfulness and Compassion: Strength vs. Cooperation 9. Stress Management 10. Thoughts Management 11. Management of difficult emotions or feelings 12. Dig deeper into personal practice Note: More details on the interventions and program-associated materials and clinical guidelines (Serrat et al., 2022b) can be accessed through a reasonable request to the corresponding author. to review the concepts already explained in the previous proposed following the trans-theoretical model of stages of treatment sessions. The psychological approach in the change (Prochaska, 2008). For a summary of the contents of FIBROWALK program is based on CBT and aims to promote the FIBROWALK program, see Tables 1, 2. cognitive changes (e.g., reduce catastrophizing about pain), In RCTs of non-pharmacological treatments, it is improve emotional regulation, increase sleep quality, enhance recommended that more than one therapist deliver each problem-solving strategies and facilitate the establishment of life treatment to create a more realistic and generalizable values and goals (Moix and Kovacs, 2009). Mindfulness exercises impression of effectiveness (Ost, 2014). FIBRO-Out are also performed with the aim of training attention to present intervention will be conducted by six different therapists experience and fostering a non-evaluative attitude towards that (i.e., three health psychologists and three physiotherapists) experience (Kabat-Zinn, 2013). Mindfulness exercises are based with experience in the field of chronic pain and FM. on the Mindfulness-Based Stress Reduction (MBSR) program Psychotherapists and physiotherapists will work in pairs in (Kabat-Zinn, 2013), for which evidence of efficacy and cost- each study group, leading psychotherapeutic or effectiveness in FM patients has been demonstrated (Pérez- physiotherapeutic FIBROWALK components. The Aranda et al., 2019). CBT and mindfulness training help physiotherapist in charge of the group will conduct the first patients to become aware of their own thoughts, emotions block of each session of the program (PNE + therapeutic and behaviors so that, once identified, they can be regulated exercise; 1 h duration) and the psychologist will conduct the or managed facilitating the same situation (e.g., pain) to be second block (CBT + mindfulness; 1 h duration). Four experienced in a more flexible and fulfilling way, with less different pairs of therapists will be generated to lead the associated suffering. Consistent with PNE, directing attention four FIBRO-Out groups (18–20 participants per group) that to the present (rather than to future concerns or past losses or will be carried out for this study. The outdoor FIBROWALK threats) may provide the appropriate safety setting to reduce the program has already been the subject of a previous perception of alarm or danger associated with pain and allow for investigation by the group (Serrat et al., 2020) and very successful re-education of the pain program (Moseley G. L., 2003; high levels of adherence were observed, with 90% of Moseley L., 2003; Moseley et al., 2015). The framework of patients attending 10 or more sessions out of 12. motivational interviewing (Nijs et al., 2020) and the cognitive- behavioral model of fear avoidance (Vlaeyen et al., 1995) are part of the theoretical background of CBT in the FIBROWALK 2.7 Treatment fidelity evaluation of the program. The intervention is carried out by encouraging FIBRO-Out arm social interactions, supported by role-playing techniques to promote understanding of content and enhance adherence to All therapists involved in this treatment arm will have prior treatment. In order to promote an adequate motivational state for experience in CBT or physiotherapy applied to individuals with FM the performance of all the exercises and practices in the or chronic pain and will receive an 8-h face-to-face training prior to FIBROWALK program, individualized modifications will be starting the RCT with the aim of standardization. The six therapists Frontiers in Physiology 10 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 TABLE 3 Summary of the assessments in the RCT. Baseline 6 weeks Post-intervention Follow-up (12 weeks) (6 months) Sociodemographic and clinical characteristics of the sample Sociodemographic data X Clinical data X Primary outcome measure FIQR X X X X Secondary outcome measures VAS Pain X X X X VAS Fatigue X X X X HADS X X X X PSS X X X X PF-SF-36 X X X X B-PSQI X X X X MISCI X X X X CSI X X X X PGIC/PSIC X Process measures PCS X X X X TSK-11 X X X X PIPS X X X X R–NPQ X X X X Cost-utility measures CSRI X X EQ-5D X X Other self-reported measures CEQ X X Perceived adverse effects of the interventions X X Fidelity evaluation (adherence of the therapists to the FIBROWALK X guidelines) physiological markers Immune-inflammatory markers X X BDNF X X Note: BDNF, Brain-Derived Neutrophic Factor; B-PSQI, brief version of the pittsburgh sleep quality index; CEQ, Credibility/Expectancy Questionnaire; CSI, central sensitization inventory, short form; CSRI, client service receipt inventory; HADS, hamilton anxiety depression scale; MISCI, multidimensional inventory of subjective cognitive impairment; PCS, Pain Catastrophizing Scale; PF-SF-36, Physical Function from the Short Form-36 Health Survey; PGIC/PSIC, Patient Global Impression of Change/Pain Specific Impression of Change; PIPS , psychological inflexibility in pain scale; PSS, perceived stress scale; R-NPQ, revised neurophysiology of pain questionnaire; TSK, tampa scale for kinesiophobia; VAS, Visual-analogue scale. in the FIBRO-Out program will be trained by fulfilling the FIBRO- evaluated for treatment fidelity for independent experts at the end of On program (which includes all the same components as the outdoor their intervention. This program manual will be used for training, format) and participating as co-therapists in a brief FIBRO-Out supervision of the therapists and also for monitoring the program’s program (i.e., 4 sessions, 2 h each) for people with FM with the close quality and performance. To monitor treatment fidelity within the face-to-face supervision of the clinical manager of the study (MS). All FIBRO-Out arm, research assistants will audio-tape all treatment program-related doubts raised in each training session will be shared sessions and two independent experts in the program will rate within the therapist group and solved by MS. Furthermore, every adherence to each component of the FIBRO-Out. A random week during the intervention, meetings will be held between the sample of tapes, stratified by therapist and therapy session will be therapists and MS to allow them to discuss any difficulties rated using the instruments described below. Treatment fidelity will experienced and find ways to overcome them. To allow quality be assessed with a measure of fidelity criteria based on the guidelines control of the provided treatment, the training of the therapists will be for the FIBROWALK intervention, which will be generated by MS based on the FIBROWALK manual and guidelines (Serrat et al., before the start of the interventions. The results of the evaluation of 2021a; Serrat et al., 2021b; Serrat, 2022a) and the therapists will be the therapist’s adherence to the program will not only allow Frontiers in Physiology 11 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 monitoring of the program’s quality but also allow providing detailed and depression) of 7 items each responding on a Likert scale of feedback to the therapists about their performance. 4 points. Total scores of each scale (HADS-A and HADS-D) All study participants will be asked to continue taking the range from 0 to 21, where higher scores indicate greater symptom same medication regimen for the duration of the study period severity. The Spanish version of the HADS has demonstrated (6 months). satisfactory internal consistency for anxiety (α = 0.83) and depression (α = 0.87) subscales inpatients with FM (Luciano et al., 2014b). 2.8 Study measures - The Perceived Stress Scale, short form (PSS; Herrero and Meneses, 2006) is a 4-item scale used to evaluate the degree to Assessment of outcome and process measures will be carried out which respondents appraise situations as stressful in the last at baseline, 6 weeks after starting treatment, at post-intervention month with responses scored on a Likert scale between 0 = (12 weeks) and at 6-month follow-up after starting the trial (follow- “never” and 4 = “very often,” and with total scores ranging from up. Cost-utility assessment will be conducted at baseline and at the 0 to 16 for the short 4-item version of the scale. Higher scores follow-up and biomarkers evaluation at baseline and post- indicate greater perceived stress. The Spanish version of the 4- intervention. The research assistants in charge of the evaluations item version of the PSS shows acceptable internal consistency will be extensively trained by researchers (MS, AF-S), who have (Cronbach’s α = 0.77). broad experience in applying the study measures. - The physical function subscale of the Short Form-36 Health The following domains will be assessed (see Table 3 for a Survey (PF-SF-36; Alonso et al., 1995) is used to measure physical summary of assessments): function. This dimension comprises a total of 10 items, which are answered on a Likert scale of 3 points. Total scores on each scale - Socio-demographic questionnaire: gender, date of birth, marital are transformed and can range from 0 to 100, with higher scores status, cohabitation, educational level and employment status. indicating better physical function. The Spanish version of the - Clinical data: date of FM diagnosis, years with a FM PF-SF-36 shows adequate internal consistency (α = 0.94). diagnosis, comorbidity with other diagnosed medical/ - Brief version of the Pittsburgh Sleep Quality Index psychiatric conditions, type and dosage of current (B-PSQI; Sancho-Domingo et al., 2021). The PSQI is the medication, weight and height. most widely used questionnaire in research and clinical practice to assess sleep quality. The B-PSQI is a brief 2.8.1 Primary clinical outcome version of this measure including six questions about sleep The Revised Fibromyalgia Impact Questionnaire (FIQR; Luciano quality. The Spanish version of the B-PSQI shows adequate et al., 2013) is a 21-item questionnaire (0–10 scale) which assesses the internal consistency (α = 0.79). dimensions of physical dysfunction, overall impact of FM and - The Multidimensional Inventory of Subjective Cognitive severity of the symptoms (i.e., pain, energy, stiffness, sleep quality, Impairment (MISCI; Feliu-Soler et al., 2018) is a 10-item scale depression, memory issues, anxiety, pain to the touch, balance with a 5-point Likert scale (from 1 “Not at all/Never” to 5 “Very problems, and increased sensitivity to noises, lights, smells, or much/Always”) for assessing perceived cognitive dysfunction in temperatures), and is used to measure the impact of FM over the FM during last week. It includes the cognitive domains: mental past week. This questionnaire is currently considered the “gold clarity, memory, attention/concentration, executive functioning, standard” for assessing functional impairment in patients with and language. The MISCI was developed through classical test FM. A total score for FIQR ranging from 0–100 can be obtained theory and item response theory from cognitive functioning item by adding the 3 subscales, with higher scores indicating greater FM banks that were developed as part of the Patient Reported severity. The Spanish version of the FIQR has an excellent internal Outcomes Measurement Information System (PROMIS). The consistency (α = 0.91–0.95) (Luciano et al., 2013). Spanish version of the MISCI shows excellent internal reliability (α = 0.91). 2.8.2 Secondary clinical measures - The Central Sensitization Inventory, short form (CSI; - Visual-analogue scale of perceived pain (VAS-Pain; Serrano- Nishigami et al., 2018) is the brief form of the CSI (Cuesta- Atero et al., 2002) in which patients indicate their pain during the Vargas et al., 2016), and consists of two parts: part A includes last week on a 10 cm line (0 = No pain, 10 = Unbearable pain). nine items scored from 0 to 4, with higher total scores - Visual-analogue scale of perceived energy/fatigue (VAS- reflecting increased central sensitization symptoms; part B Fatigue; Serrano-Atero et al., 2002) in which patients indicate (which is not scored) determines whether one or more their fatigue during the last week on a 10 cm line (0 = Lots of specific disorders of central sensitization related to energy, 10 = No energy). pathophysiology (i.e., restless legs syndrome, chronic - Hospital Anxiety and Depression Scale (HADS; Luciano fatigue syndrome, FM, temporomandibular joint disorder, et al., 2014a). HADS is used to quantify the severity of anxiety migraine or tension headaches, irritable bowel syndrome, and depression symptoms. It consists of two dimensions (anxiety multiple chemical sensitivities, neck injury, anxiety or Frontiers in Physiology 12 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 panic attacks, and depression) have been diagnosed before. 2.9 Other self-reported measures Adequate internal consistency for the CSI-9 has been also reported (Cronbach’s alpha = 0.80). - The Patient Global Impression of Change (PGIC) and the Pain Specific Impression of Change (PSIC) (Scott and McCracken, 2.8.3 Cost-utility measures 2015) are measures to assess, respectively, self-perceived - Client Service Receipt Inventory (CSRI; Vázquez-Barquero meaningful clinical change (on a 7-point Likert scale, from et al., 1997). The CSRI is a questionnaire for economic 1 = “Much better” to 7 = “Much worse”) in general or in the evaluation. The version used in this study is designed to following specific domains: physical and social functioning, retrospectively collect data on the use of health and social work-related activities, mood, and pain. services during the previous 6 months. - Adapted version of Credibility/Expectancy Questionnaire - EuroQoL-5D-5L (EQ-5D-5L; Badia et al., 1999). The EQ- (CEQ; Devilly and Borkovec, 2000). It is a 6-item questionnaire 5D-5L is an instrument for assessing health-related quality of life. widely used to assess treatment expectancy as well as the It consists of two parts: the first part assesses the individual’s credibility of the FIBRO-On and FIBRO-Out interventions. difficulties in relation to mobility, self-care, pain/discomfort and The first part of the CEQ comprises three items focused on anxiety/depression; and the second part assesses the patient’s therapy credibility (i.e., the extent to which the treatment appears current perceived health status on an analogue-visual scale from a)logical and b) useful, and c) the confidence with which the 0 (“the worst health you can imagine”) to 100 (“the best health treatment’s patient would recommend this one to a friend with you can imagine”). the same health condition); and three more items evaluating expectations (i.e., the extent to which the patient thinks an 2.8.4. Process measures improvement will happen as a consequence of the treatment; - Pain Catastrophizing Scale (PCS; García-Campayo et al., the extent to which the patient really feels that the intervention 2008). The PCS is used to evaluate catastrophic thoughts will reduce him/her symptoms, and the extent to which the associated with pain. It consists of three dimensions (e.g., patient really feels a symptom improvement will occur). After rumination, magnification, and helplessness) with 13 items in finishing the treatment, the patient’s opinion regarding the total, which are answered on a Likert scale of 5 points. Total treatment received will be also gathered by using the second scores on each scale range from 0 to 52, with higher scores part of the CEQ which includes the same questions as in the first indicating more catastrophic thoughts. The Spanish version of part of the CEQ but in past tense. The CEQ showed overall the PCS shows adequate internal consistency (α = 0.79). adequate internal consistency (α = 0.84–0.85) in a previous study - Psychological Inflexibility in Pain Scale (PIPS; Wicksell et al., in a similar clinical sample (Pérez-Aranda et al., 2019). 2008). The PIPS is a 12-item scale that assesses psychological - An ad hoc item (i.e., Have you experienced, during the course inflexibility in pain patients, and includes two factors: avoidance of the treatment, any unwanted symptom that you think might be and cognitive fusion with pain. The items consist of different directly or indirectly associated with the intervention?) to check statements that are considered to be related to chronic pain, for the presence of adverse effects (e.g., headaches, dizziness, psychological inflexibility, suffering and disability (coherent with sleep problems, etc.) associated with the evaluated interventions. the ACT theory). All the items are rated on a 7-point Likert scale This measure has been used in a previous study (Pérez-Aranda that ranges from “1 = never true” to “7 = always true”, with higher et al., 2019) and will be administered both at 6-week and post- scores indicating more psychological inflexibility. The Spanish intervention assessments. version of the PIPS (Rodero et al., 2013) shows adequate internal - Patients’ adherence evaluation to the FIBRO-On and consistency (α = 0.90). FIBRO-Out programs. An ad hoc instrument (i.e., personal - Tampa Scale for Kinesiophobia (TSK; Gómez-Pérez et al., practice log) for the weekly recording of home practice will be 2011). The TSK is a measure aimed at assessing fear of movement developed to determine level of adherence to psychotherapeutic and comprises 11 items in a 4-point Likert scale with a total score and therapeutic exercise recommended homework. ranging from 11 to 44, with higher scores indicating greater pain and fear of movement. The Spanish version of the TSK has an adequate internal consistency (α = 0.79). 2.10 Physiological markers - The Revised Neurophysiology of Pain Questionnaire (R-NPQ; Torres-Lacomba et al., 2021). The R-NPQ consists Blood samples will be collected in vials which will be of 13 statements (True/False/I do not know) about pain centrifuged and the resulting serum will be stored frozen at neurophysiology and has been extensively used to assess pain -80°C until analysis. All samples (pre and post) will be analyzed in biology knowledge. The R-NPQ score ranges from 0 to 13 (sum a single analytical batch in order to reduce inter-assay variability of all correct items), and can be also expressed as a rate of (approximately 15%). Serum levels of the cytokines IL-6, CXCL8, correctly answered items. Excellent internal consistency for the IL-4, IL-10, IL-17A and hs-CRP will be assessed. For the R-NPQ has been reported in Spanish samples (α = 0.87–0.92). quantification of cytokines, Milliplex® reagents from Frontiers in Physiology 13 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 MerckMillipore analyzed on a Luminex® platform will be used. be calculated for each pairwise comparison, using the pooled The highly sensitive Human High Sensitivity T Cell multiplex kit baseline SD to weight the differences in the pre–post mean values will be used (catalogue number: HSTCMAG28SPMX11). The hs- and to correct for the population estimate (Morris, 2008). The CRP will be quantified by turbidimetry on a Siemens Atellica rule of thumb for effect size interpretation will be the classical autoanalyzer. BDNF levels will be evaluated using an ELISA kit cutoffs for Cohen’s d of 0.20 = small, 0.50 = medium, and 0.80 = (reference SEA011Hu-96T). Sample analysis will be performed large. All secondary clinical endpoints will be analyzed using the by the Echevarne Laboratory. Detection concentration ranges: same statistical procedure. Benjamini–Hochberg correction for IL-6 (0.64–10,000 pg/ml), CXCL8 (0.64–10,000 pg/ml), IL-4 multiple comparisons will be applied to control for false rate (0.64–10,000 pg/ml), IL-10 (2.6–40,000 pg/ml), IL-17A discovery (Glickman et al., 2014). All the analyses will be (1.3–20,000 pg/ml), hs-CRP (0.1–50 mg/L), and BDNF replicated using a “completers” approach including all (31.2–2,000 pg/ml). Biomarkers will be assessed only at participants who finished the study, and a per-protocol baseline and post-intervention because of the following approach, taking into account only those patients who reasons: a) evidence of changes in immune-inflammatory attended at least 75% of the sessions (9 out of 12). markers and BDNF levels after non-pharmacological In addition, to assess clinical significance of the improvement interventions with a similar duration (Sanada et al., 2015; on the primary outcome (FIQR), all the participants will be Montero-Marín et al., 2019; Pérez-Aranda et al., 2019); b) allocated into the categories of “responder” and “non-responder” lower risk of sample loss (vs. assessing at 6 months); c) by using the criteria of presenting at least a 20% reduction in the possibility to use pre-post change as a mediator of clinical pre–post FIQR total score or not, respectively (Bennett et al., changes at 6 months follow-up; and d) budget constraints. 2009). This classification will be used to compute the number needed to treat (NNT) for each treatment when compared to the others. The NNT refers to the estimated number of patients who 2.11 Statistical analyses need to be treated with a new proposed treatment (i.e., rather than the control comparison treatment) for one additional SPSS v26.0, STATA v16.0 and Mplus v7.4 will be used for the patient to benefit. A 95% CI for each NNT will be calculated. statistical analyses. Descriptive statistics will be calculated for all This index allows findings from RCTs to be more meaningful to variables and presented as means and standard deviations if clinicians. Furthermore, in order to explore potential predictors continuous, or as absolute numbers and percentages (%) if of treatment response in each intervention arm, t-tests and χ2- categorical. The Levene test will be used to assess the equality tests will also be performed to assess potential baseline of variances of continuous variables and Kolmogorov–Smirnov differences in sociodemographic, clinical and physiological to test sample normality and distribution. One-way ANOVAs variables between responders vs. non-responders within the (with post hoc Tukey’s HSD or Games-Howell tests) for FIBRO-Out and FIBRO-On arms. Finally, baseline differences continuous values and χ2 tests with continuity corrections for between participants who completed all study assessments and categorical values will be computed on all baseline measures and those who did not will also be evaluated (with t and χ2-tests) to socio-demographic variables to examine between-group detect any potential attrition bias. differences at baseline. The differences between FIBRO-On and FIBRO-Out on perceived clinical improvement (assessed with PGIC and 2.11.1 Analysis of clinical effectiveness PSIC) and on treatment expectation/opinion (i.e., with the The primary effectiveness analysis will be conducted on an CEQ) will be computed using χ2 tests and Student’s t tests, intention-to-treat (ITT) basis with the FIQR total score as a respectively. primary clinical endpoint (McCoy, 2017) and by linear mixed- effects regressions with restricted maximum likelihood (REML). 2.11.2 Mediation analyses REML accounts for the correlation between repeated measures We will compute pre–post change scores for all process for each individual and produces less biased estimates of variance measures in the study and pre–follow-up change scores for parameters when using small sample sizes or unbalanced data primary and secondary outcomes. Bivariate Pearson (Egbewale et al., 2014). No imputation of missing data will be correlations will be calculated between the pre–post change conducted, since it has been reported that multiple imputation is scores for the process variables and the pre–follow-up change not necessary for all types of missing data (missing completely at scores for the clinical endpoints to detect statistically random, missing at random, and missing not at random) before significant relationships. The direct and indirect computing longitudinal mixed model analysis (Twisk et al., associations between the treatment condition (i.e., FIBRO- 2013). Unstandardized regression coefficients (B) and 95% On vs. TAU, FIBRO-Out vs. TAU, or FIBRO-On vs. FIBRO- confidence intervals (95% CIs) will be computed for the Out, as independent variable), process variables (mediators), ‘group x time’ interaction between groups at 6-week, post- and primary and secondary outcomes (dependent variables) treatment and 6-month follow-up assessments. Cohen’s d will will be computed by using path analyses. With this statistical Frontiers in Physiology 14 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 approach, we are considering temporality into account, multiplying the minimum daily wage in Spain in 2022 by the which increases the prospect of establishing conclusions number of days on sick leave reported by each participant. Unit about causality. Simple and multiple mediation costs will be reported in Euros (€). (simultaneously testing multiple variables as mediators) The utilities represent the rating of the patients’ quality of life models will be computed. on a scale from 0 (“as bad as death”) to 1 (“perfect health”). For Similarly, for obtaining more detail about psychological the cost-utility analysis, the ratio between the cost of each mechanisms fostered during intervention and its role in the intervention and its consequences in terms of QALYs will be observed effect at post-intervention, mediation analyses will calculated. QALYs will be computed using Spanish EQ-5D also be conducted by using change scores of process measures tariffs. Following the International Society for between baseline and 6-week assessment and change scores Pharmacoeconomics and Outcomes Research (ISPOR) core for clinical measures between baseline and post-intervention recommendations for cost-effectiveness analyses alongside assessments. The direct paths between treatment condition RCTs (Ramsey et al., 2015), we will calculate the incremental and clinical outcomes and the indirect effect path through the cost-utility ratios (ICUR) for each pairwise comparison (TAU vs. mediation variables will be tested in all the models. FIBRO-On, TAU vs. FIBRO-Out, FIBRO-On vs. FIBRO-Out), Regression coefficients (B) of bias-corrected bootstrapped defined as the difference in mean costs divided by the difference indirect effects will be calculated as well as their SEs and in mean QALYs. Given that the duration of the study is 95% CIs (Lockhart et al., 2011). Parameters of indirect effects 6 months, neither costs nor outcomes are subject to are considered statistically significant when the 95% CI did discounting. QALYs at 6 months after the start of the not include 0. Participants with missing data will be excluded interventions will be approximated by calculating the area for this analysis. under the curve. Cost-effectiveness analyses will be performed using the 2.11.3 Cost-utility analysis Zellner’s seemingly unrelated regression (SUR) model The economic evaluation will be reported according to the (Greene, 2003) with the STATA’s sureg command. Using Consolidated Health Economic Evaluation Reporting Standards the SUR method for cost-effectiveness purposes implies the statement (Husereau et al., 2013) and the Good Research use of a bivariate system of regressions that includes both costs Practices for Cost-Effectiveness Analysis Alongside Clinical and outcomes (with the latter being either QALYs or EurQol- Trials (Ramsey et al., 2015). The approach we will follow is 5D-5L VAS, depending on the model considered) as the estimating costs from the healthcare and the government dependent variables of the two separate equations, which perspectives, taking the previous 6 months as the time frame. will be estimated jointly. The regressions of costs and Catalonia has full governance of health and social care and, as in outcomes are therefore part of two regressions on treatment every other Spanish region, healthcare is universal and publicly allocation (i.e., whether they are assigned to TAU, FIBRO-Out, financed. The government perspective includes both direct or FIBRO-On) plus an additional set of control variables healthcare costs assumed by the Catalan government (measured at baseline) if necessary: age, gender, marital (excluding out-of-pocket costs and costs associated with status, education level, employment status, baseline private insurance) and indirect costs related to productivity costs, or baseline outcome, depending on the equation losses assumed by the Spanish government. The healthcare considered. perspective includes only direct healthcare costs. Costs will be Estimates of incremental cost and of incremental effect estimated for the 6 months before starting the intervention (at values using the SUR method described above will be baseline assessment) and for the 6 months before the follow-up derived with 1,000 bootstrap replications in order to address assessment. a possible skewness in the distribution of the dependent Direct costs will be calculated as the sum of medication costs variables (Briggs et al., 1997). We also will construct and health service use (primary, specialized and emergency care acceptability curves to represent the probability of the consultations, hospital admissions) and cost of staff to run the intervention being cost-effective, given a varying threshold interventions. The cost of medication will be calculated by for the willingness to pay for each QALY gained in each determining the price per milligram during the study intervention compared to the others. The robustness of the according to the Vademecum International (Red Book), and cost-utility results will also be tested in different case scenarios; including VAT. Total medication costs will be computed by more precisely, we will use ITT approach as the primary multiplying the price per milligram by the daily dose in analysis, imputing missing values for those variables missing milligrams and the number of days receiving the specified at 6-month follow-up by using multiple imputation methods treatment. The unit costs of medical tests and health services with the chained equations approach (Royston and White, will be obtained from the SOIKOS health database (http://www. 2015). Additional scenarios (sensitivity analysis) will be also oblikue.com/bddcostes/). Indirect costs (lost productivity) will be conducted repeating the same statistical analyses in a complete computed according to the human capital approach, by case analysis, including only those participants with complete Frontiers in Physiology 15 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 assessments at baseline and at 6-month follow-up, and in a per- legislation. All data will be computer processed and stored. protocol analysis including only those participants who Blood samples will be stored encrypted, and will not be attended at least 75% of the sessions (9 out of 12). directly traceable back to individuals. Blood samples will STATA 16.0 statistical software will be used for cost-utility be used only in ways to which the participants consented analyses. and may only be made available to a new research project after Ethical Research Committee approval and participants 2.11.4 Analysis of changes in biomarkers provide a new agreement. Furthermore, the participants have The effect of interventions on immune-inflammatory the right to request, without explanation, that their samples markers and BDNF levels will be evaluated also with REML. be destroyed or made completely anonymous. In those cases where cytokine concentrations are under detection level of the test, the detection limit value will be assigned. Cytokines, hs-CRP and BDNF values will be subjected to a 2.13 Blinding natural logarithmic transformation to normalize the significantly skewed data distributions. In order to Randomization and group allocation will be completely masked comprehensively integrate pro-inflammatory with anti- for the study assessors and study participants will be asked not to inflammatory markers, indexes indicative of inflammatory communicate with the assessor about the treatment received. The balance will be calculated (e.g., IL-6/IL-10, CXCL8/IL-10 and study participants will be provided with a summary of evidence of the hs-CRP/IL-10) in a similar way to previous studies (Andrés- FIBROWALK program which constitute the basis for FIBRO-On Rodríguez et al., 2019). Since some pharmacological treatments and FIBRO-Out programs. As it is usual in non-pharmacological such as antidepressants are reported to potentially affect some trials, neither participants nor the therapists can be blinded to cytokine levels (Hannestad et al., 2011), differences in such levels treatment allocation. The therapists in the FIBRO-On and between patients taking vs. not taking these drugs will be also FIBRO-Out arms will not be involved in any assessment task of evaluated. In case of any statistically significant effect, the study. antidepressant status (“taking” = 1, “not taking” = 0) will also be included as a co-variable in the REML analyses for each specific biomarker. 2.14 Forecast execution dates Initial recruitment of patients: September 2022. 2.12 Ethical issues of the project Finalization of patient recruitment: January 2023. Finalization of patient monitoring period: July 2023. Written informed consent will be obtained from all Publication of results: December 2023. participants prior to randomization. Participants will be provided with a general overview of the aims and characteristics of the study and the interventions before 3 Discussion signing the informed consent. They will also be assured that they will be participating voluntarily and can The On&Out study will evaluate the effectiveness, cost-utility withdraw at any time from the study with the guarantee and the physiological effects of adding the FIBROWALK that they will continue to receive the most appropriate program in Online (i.e., FIBRO-On) or in Outdoor format medical treatment prescribed by their general practitioner. (i.e., FIBRO-Out) to TAU. In order to determine the The study will be conducted in compliance with the mechanisms of action of these interventions, we will also Declaration of Helsinki (version in force; currently evaluate potential process measures of these interventions, as Fortaleza, Brazil, October 2013). The study will be well as physiological markers with evidence of alteration in FM conducted in accordance with the protocol and with the and that are likely modifiable by non-pharmacological relevant legal requirements: Law 14/2007 of July 3, on interventions. Three previous studies evidenced the short-term Biomedical Research. The VHIR Research Committee efficacy (i.e., post-intervention) compared to TAU of both the Board evaluated and approved the study protocol in May FIBRO-On (Serrat et al., 2021a; Serrat et al., 2022b) and FIBRO- 2022 [PR (AG)99/2022]. All patient data will be treated as Out programs (Serrat et al., 2020); however, the present RCT will confidential and only the research team will be allowed to evaluate for the first time if these clinical effects are maintained at access it after recodification of name and personal identity 6-month follow-up along with the aforementioned analyses on number (so no individual can be directly identified). Only the cost-utility, mediation and physiological markers. principal investigator (AF-S) and the clinician coordinator of The fact that FIBROWALK’s tested interventions are in the study (MS) will have access to the code key which will be online format (FIBRO-On) or in group format (FIBRO-Out) stored separately in a safe place in accordance with Spanish can make them more cost-effective, and therefore of interest for Frontiers in Physiology 16 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 health managers. Additionally, both formats can be considered multicomponent intervention for FM. In this sense, it is “safe” in epidemiological terms (compared to face-to-face indoor necessary to introduce new practices in the provision of classical interventions) as they do not imply in closed spaces healthcare services to improve efficiency in the use of shared with other people where exists a higher risk for contagion resources. In this regard, boosting treatments aimed at (e.g., Bazant and Bush, 2021). Furthermore, particularly for the changing lifestyles and patterns of cognition and behavior (as FIBRO-On intervention, these therapies can also be followed it is aimed in FIBROWALK) constitutes a strategy of financial under strict social distancing measures and even in lockdown sustainability as, in the long-term, it will allow an extension of the circumstances. If the results of this RCT are strong enough in culture of health understood holistically and, therefore, a terms of efficacy and cost-utility, FIBRO-Out and/or FIBRO-On decrease in the burden of disease on society as a whole. Our could be considered for their inclusion in the public healthcare study will also explore immune-inflammatory and Spanish system to treat individuals suffering from FM. neuroprotective pathways behind the efficacy of the evaluated Additionally, this RCT may also pave the way for further treatments, and will combine clinical and process measures RCTs testing the efficacy of these interventions in other which may lead to a better characterization of the syndrome, chronic diseases cursing with central sensitization (e.g., to new therapeutic interventions, and to a better prediction of irritable bowel syndrome, chronic headache, treatment response in order to better determine what works for temporomandibular disorder, pelvic pain syndromes), along whom in the field of personalized medicine. Finally, it is also with other emerging conditions such as persistent post- worth mentioning that the present RCT will involve six therapists COVID syndrome which may display overlapped symptoms (three psychologists and three physiotherapists) in delivering the with FM (Haider et al., 2022). FIBRO-Out intervention; doing so (instead of only one therapist The On&Out study will also evaluate the effect of the delivering the therapy) can provide more realistic and FIBROWALK multicomponent programs on immuno- generalizable results (Ost, 2014) which can be useful for the inflammatory markers and BDNF levels that seem to be future implementation of these interventions in healthcare altered in FM and/or play a role in the effectiveness of non- systems. pharmacological treatments (Rodriguez-Pintó et al., 2014; There are also some potential limitations that should also be Andrés-Rodríguez et al., 2019; Montero-Marin et al., 2019). It recognized in this RCT. One of the main risks of this project may should also be noted that, to date, the effect of any be dropouts and non-adherence, which are expected to be higher multicomponent program on such biomarkers in FM has not than in previous studies that only evaluated the short-term efficacy been evaluated by means of a RCT design. Furthermore, the of the interventions (Serrat et al., 2020; Serrat et al., 2021a; Serrat evaluation of changes in these biomarkers and their association et al., 2021b; Serrat et al., 2022b). In this regard, since previous with clinical change will further deepen the understanding of the studies showed very high adherence to the programs (over 90%; role of the immune system and neuroprotective agents in FM and Serrat et al., 2020; Serrat et al., 2022b), a dramatically high dropout related disorders cursing with central sensitization. Associated in the present study is not expected; however, to limit the effect of with this substudy of the project, it should be noted that the these dropouts and lack of adherence in our results, we will inclusion of biomarkers may also make it possible to determine conduct several sensitivity analyses (ITT, completers, per different patient profiles (based on their psychobiological protocol analysis). We also have to note the lack of blinding of characteristics) which could be predictive of a greater or lesser participants and therapists, which is a typical bias in any RCT response to the treatments under study. This aspect is fully including non-pharmacological treatments. Although a weekly connected with the emerging field of personalized treatments questionnaire will be administered to check the adherence to and can contribute to optimizing the use of healthcare services FIBRO-On program (i.e., watching the videos), there is a risk while also enhancing the efficacy and cost-effectiveness of the that some participants in the FIBRO-On group do not watch the interventions evaluated (Thase, 2014; Lopresti, 2017; Carvalho videos and inform differently. It is also relevant to highlight that et al., 2019). this RCT will be carried out in a specialized unit of tertiary referral This study has some strengths that should be highlighted. hospital in the context of clinical practice. Related to this, stricter The inclusion of a relatively large sample and of a comprehensive inclusion/exclusion criteria could not be established due to set of measures will allow us to compare the short term (pre-post) pressures in daily clinical practice (i.e., most patients will be and long-term (6 months) effectiveness of two different formats admitted). At the same time, this latter point may have a of the FIBROWALK multicomponent program on core FM positive aspect by increasing the external validity of the study outcomes and psychological process measures. Furthermore, and so the generalization of the results into the “real” clinical the identification of cost-effective interventions is a priority practice. for the national health system, especially for highly prevalent Up to date, there is no study assessing the cost-effectiveness of conditions such as FM. This study will evaluate for the first time multicomponent approaches for FM neither evaluating the long- the cost-effectiveness of two formats (which can be particularly term effectiveness of such type of interventions in online or outdoor useful in the pandemic and post-pandemic era) of a formats. If one or both treatments evaluated in this present RCT Frontiers in Physiology 17 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 (i.e., FIBRO-On and/or FIBRO-Out) shows to be effective and cost- draft preparation, MS, SF, WA, MA, and AF-S; Writing—review effective they should be included as part of the standard of care for and editing, MS, SF, WA, MA, XB, FD, SL, EL, MM, JN, JM-M, treating FM. Furthermore, since both interventions are, per RN, JL, and AF-S; Visualization, MS, SF, WA, MA, JL, and AF-S; definition, conducted out of the hospital settings, they could also Supervision, MS, MA, JL, and AF-S; Project administration, MS, be safely administered in the context of future pandemics, and (in the MA, and AF-S; Funding administration, MS, MA, AF-S. All particular case of the FIBRO-On program) in circumstances of low authors have read and agreed to the published version of the accessibility to effective treatments for FM (e.g., in remote areas), manuscript. highly congested healthcare services and/or low availability of clinical resources. The On&Out project is also aimed at determining psychophysiological patient profiles which can be useful for Funding identifying potential treatment beneficiaries (i.e., treatment responders) beforehand which may in turn improve healthcare The project has been funded in part by the Spanish Ministry resources allocation. Last but not least, the present study may also for Science and Innovation (MCIN) State R + D + I Program help us in deepening our knowledge on which psychological and Oriented to the Challenges of Society (ref. PID 2020-117667RA- physiological mechanisms underpin the clinical effects of non- I00) and co-financed with European Union ERDF funds. The last pharmacological interventions in FM, further contributing to the author (AF-S) acknowledges the funding from the Serra Húnter potential detection of novel therapeutic targets. program (Generalitat de Catalunya; reference number UAB-LE- 8015). JM-M has a “Miguel Servet” contract from the ISCIII (CP21/00080). JN has a research contract awarded by the ISCIII Data availability statement (ICI20/00080). The original contributions presented in the study are included in the article/supplementary material, further Conflict of interest inquiries can be directed to the corresponding author. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could Ethics statement be construed as a potential conflict of interest. The studies involving human participants were reviewed and approved by Ethics Committee of the Vall d’Hebron Institute of Publisher’s note Reseach. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated Author contributions organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or Conceptualization, MS, AF-S; Methodology, MS, SF, MA, JL, claim that may be made by its manufacturer, is not guaranteed or XB, and AF-S; Resources, MS, MA, and AF-S; Writing—original endorsed by the publisher. References Albrecht, D. S., Forsberg, A., Sandström, A., Bergan, C., Kadetoff, D., Protsenko, E., Assefi, N. P., Coy, T. V., Uslan, D., Smith, W. R., and Buchwald, D. (2003). et al. (2019). Brain glial activation in fibromyalgia - a multi-site positron emission Financial, occupational, and personal consequences of disability in patients with tomography investigation. Brain Behav. Immun. 75, 72–83. doi:10.1016/j.bbi.2018.09.018 chronic fatigue syndrome and fibromyalgia compared to other fatiguing conditions. J. Rheumatol. 30, 804–808. Alonso, J., Prieto, L., and Antó, J. M. (1995). The Spanish version of the SF-36 health survey (the SF-36 health questionnaire): An instrument for measuring Bäckryd, E., Tanum, L., Lind, A. L., Larsson, A., and Gordh, T. (2017). clinical results. Med. Clin. 104, 771–776. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to Amer-Cuenca, J. J., Pecos-Martín, D., Martínez-Merinero, P., Lluch Girbés, E., the cerebrospinal fluid and to plasma. J. Pain Res. 10, 515–525. doi:10.2147/ Nijs, J., Meeus, M., et al. (2020). How much is needed? Comparison of the JPR.S128508 effectiveness of different pain education dosages in patients with fibromyalgia. Pain Med. 21, 782–793. doi:10.1093/pm/pnz069 Badia, X., Roset, M., Montserrat, S., Herdman, M., and Segura, A. (1999). The Spanish version of EuroQol: A description and its applications. European quality of Andrés-Rodríguez, L., Borràs, X., Feliu-Soler, A., Pérez-Aranda, A., Rozadilla- life scale. Med. Clin. 112 (1), 79–85. Sacanell, A., Montero-Marin, J., et al. (2019). Immune-inflammatory pathways and clinical changes in fibromyalgia patients treated with mindfulness-based stress Bazant, M. Z., and Bush, J. W. (2021). A guideline to limit indoor airborne reduction (MBSR): A randomized, controlled clinical trial. Brain Behav. Immun. 80, transmission of COVID-19. Proc. Natl. Acad. Sci. U. S. A. 118 (17), e2018995118. 109–119. doi:10.1016/j.bbi.2019.02.030 doi:10.1073/pnas.2018995118 Frontiers in Physiology 18 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 Bazzichi, L., Da Valle, Y., Rossi, A., Giacomelli, C., Sernissi, F., Giannaccini, G., cognitive impairment in patients with fibromyalgia. J. Appl. Biobehav. Res. 23, et al. (2013). A multidisciplinary approach to study the effects of balneotherapy and e12134. doi:10.1111/jabr.12134 mud-bath therapy treatments on fibromyalgia. Clin. Exp. Rheumatol. 31 (6), Fietta, P., Fietta, P., and Manganelli, P. (2007). Fibromyalgia and psychiatric S111–S120. disorders. Acta Biomed. 78, 88–95. Bennett, R. M., Friend, R., Jones, K. D., Ward, R., Han, B. K., and Ross, R. L. Friedberg, F., Williams, D. A., and Collinge, W. (2012). Lifestyle-oriented non- (2009). The revised fibromyalgia impact questionnaire (FIQR): Validation and pharmacological treatments for fibromyalgia: A clinical overview and applications psychometric properties. Arthritis Res. Ther. 11, R120. doi:10.1186/ar2783 with home-based technologies. J. Pain Res. 5, 425–435. doi:10.2147/JPR.S35199 Berger, A., Dukes, E., Martin, S., Edelsberg, J., and Oster, G. (2007). García Campayo, J., Rodero, B., Alda, M., Sobradiel, N., Montero, J., and Moreno, Characteristics and healthcare costs of patients with fibromyalgia syndrome. Int. S. (2008). Validation of the Spanish version of the pain catastrophizing scale in J. Clin. Pract. 61, 1498–1508. doi:10.1111/j.1742-1241.2007.01480.x fibromyalgia. Med. Clin. 131, 487–492. doi:10.1157/13127277 Bernardy, K., Fuber, N., Kollner, V., and Häuser, W. (2010). Efficacy of cognitive- Gerdle, B., Björk, J., Cöster, L., Henriksson, K., Henriksson, C., and Bengtsson, A. behavioral therapies in fibromyalgia syndrome. A systematic review and (2008). Prevalence of widespread pain and associations with work status: A metaanalysis of randomized controlled trials. J. Rheumatol. 37, 1991–2005. population study. BMC Musculoskelet. Disord. 9, 102. doi:10.1186/1471-2474-9-102 doi:10.3899/jrheum.100104 Glickman, M. E., Rao, S. R., and Schultz, M. R. (2014). False discovery rate control Bernardy, K., Klose, P., Welsch, P., and Häuser, W. (2018). Efficacy, acceptability is a recommended alternative to Bonferroni-type adjustments in health studies. and safety of cognitive behavioural therapies in fibromyalgia syndrome - a J. Clin. Epidemiol. 67, 850–857. doi:10.1016/j.jclinepi.2014.03.012 systematic review and meta-analysis of randomized controlled trials. Eur. J. Pain 22, 242–260. doi:10.1002/ejp.1121 Gómez-Pérez, L., López-Martínez, A. E., and Ruiz-Párraga, G. T. (2011). Psychometric properties of the Spanish version of the Tampa scale for Black, D. S., Cole, S. W., Irwin, M. R., Breen, E., St Cyr, N. M., Nazarian, N., et al. kinesiophobia (TSK). J. Pain 12, 425–435. doi:10.1016/j.jpain.2010.08.004 (2013). Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Greene, W. (2003). Econometric analysis. Englewood Cliffs, NJ, USA: Prentice- Psychoneuroendocrinology 38, 348–355. doi:10.1016/j.psyneuen.2012.06.011 Hall. Briggs, A. H., Wonderling, D. E., and Mooney, C. Z. (1997). Pulling cost-effectiveness Gu, J., Strauss, C., Bond, R., and Cavanagh, K. (2015). How do mindfulness-based analysis up by its bootstraps: A non-parametric approach to confidence interval cognitive therapy and mindfulness-based stress reduction improve mental health estimation. Health Econ. 6, 327–340. doi:10.1002/(sici)1099-1050(199707)6:4<327::aid- and wellbeing? A systematic review and meta-analysis of mediation studies. Clin. hec282>3.0.co;2-w(199707)6:4<327::aid-hec282>3.0.co;2-w Psychol. Rev. 37, 1–12. doi:10.1016/j.cpr.2015.01.006 Buckley, R. C., Brough, P., and Westaway, D. (2018). Bringing outdoor therapies Gueorguieva, R., and Krystal, J. H. (2004). Move over ANOVA: Progress in into mainstream mental health. Front. Public Health 6, 119. doi:10.3389/fpubh. analyzing repeated-measures data and its reflection in papers published in the 2018.00119 archives of general psychiatry. Arch. Gen. Psychiatry 61, 310–317. doi:10.1001/ archpsyc.61.3.310 Butler, D. S., and Moseley, G. L. (2010). Explaining pain. Adelaide, South Australia: Noigroup Publications. Haas, L., Portela, L. V., Böhmer, A. E., Oses, J. P., and Lara, D. R. (2010). Increased plasma levels of brain derived neurotrophic factor (BDNF) in patients with Cagnie, B., Coppieters, I., Denecker, S., Six, J., Danneels, L., and Meeus, M. (2014). fibromyalgia. Neurochem. Res. 35, 830–834. doi:10.1007/s11064-010-0129-z Central sensitization in fibromyalgia? A systematic review on structural and functional brain mri. Semin. Arthritis Rheum. 44, 68–75. doi:10.1016/j.semarthrit.2014.01.001 Haider, S., Janowski, A. J., Lesnak, J. B., Hayashi, K., Dailey, D. L., Chimenti, R., et al. (2022). A comparison of pain, fatigue, and function between post-COVID- Carrillo-de-la-Peña, M. T., Triñanes, Y., González-Villar, A., Romero-Yuste, S., 19 condition, fibromyalgia, and chronic fatigue syndrome: A survey study. Pain, Gómez-Perretta, C., Arias, M., et al. (2015). Convergence between the 1990 and 10–1097. doi:10.1097/j.pain.0000000000002711 2010 ACR diagnostic criteria and validation of the Spanish version of the Fibromyalgia Survey Questionnaire (FSQ). Rheumatol. Int. 35, 141–151. doi:10. Hannestad, J., DellaGioia, N., and Bloch, M. (2011). The effect of antidepressant 1007/s00296-014-3074-3 medication treatment on serum levels of inflammatory cytokines: A meta-analysis. Neuropsychopharmacology 36, 2452–2459. doi:10.1038/npp.2011.132 Carvalho, A. F., Fernandes, B. S., and Brunoni, A. R. (2019). Mindfulness-based stress reduction for fibromyalgia: A step closer to precision psychiatry? Brain Behav. Haugmark, T., Hagen, K. B., Smedslund, G., and Zangi, H. A. (2019). Immun. 81, 8–9. doi:10.1016/j.bbi.2019.06.020 Mindfulness- and acceptance-based interventions for patients with fibromyalgia - a systematic review and meta-analyses. PLoS One 14, e0221897. doi:10.1371/ Castel, A., Fontova, R., Montull, S., Periñán, R., Poveda, M. J., Miralles, I., et al. journal.pone.0221897 (2013). Efficacy of a multidisciplinary fibromyalgia treatment adapted for women with low educational levels: A randomized controlled trial Arthritis Care Res. 65 (3), Häuser, W., Ablin, J., Fitzcharles, M. A., Littlejohn, G., Luciano, J. V., Usui, C., 421–431. et al. (2015). Fibromyalgia. Nat. Rev. Dis. Prim. 1, 15022. doi:10.1038/nrdp.2015.22 Chan, A. W., Tetzlaff, J. M., Altman, D. G., Laupacis, A., Gøtzsche, P. C., Krleža- Häuser, W., Arnold, B., Eich, W., Felde, E., Flügge, C., Henningsen, P., et al. Jerić, K., et al. (2013). SPIRIT 2013 statement: Defining standard protocol items for (2008). Management of fibromyalgia syndrome–an interdisciplinary evidence- clinical trials. Ann. Intern. Med. 158, 200–207. doi:10.7326/0003-4819-158-3- based guideline. Ger. Med. Sci. 6, Doc14. 201302050-00583 Herrero, J., and Meneses, J. (2006). Short web-based versions of the perceived Cuesta-Vargas, A. I., Roldan-Jimenez, C., Neblett, R., and Gatchel, R. J. (2016). stress (PSS) and center for epidemiological studies-depression (cesd) scales: A Cross-cultural adaptation and validity of the Spanish central sensitization comparison to pencil and paper responses among internet users. Comput. Hum. inventory. Springerplus 5, 1837. doi:10.1186/s40064-016-3515-4 Behav. 22, 830–846. doi:10.1016/j.chb.2004.03.007 De Miquel, C. A., Campayo, J., Flórez, M. T., Arguelles, J. M., Tarrio, E. B., Husereau, D., Drummond, M., Petrou, S., Carswell, C., Moher, D., Greenberg, Montoya, M. G., et al. (2010). Interdisciplinary consensus document for the D., et al. (2013). Consolidated health economic evaluation reporting treatment of fibromyalgia. Actas Esp. Psiquiatr. 38, 108–120. standards (CHEERS) statement. BMC Med. 11, 80. doi:10.1186/1741-7015- 11-80 Deitos, A., Dussán-Sarria, J. A., Souza, A. d., Medeiros, L., Tarragô, M., Sehn, F., et al. (2015). Clinical value of serum neuroplasticity mediators in identifying the Jensen, K. B., Loitoile, R., Kosek, E., Petzke, F., Carville, S., Fransson, P., et al. central sensitivity syndrome in patients with chronic pain with and without (2012). Patients with fibromyalgia display less functional connectivity in the brain’s structural pathology. Clin. J. Pain 31, 959–967. doi:10.1097/AJP.0000000000000194 pain inhibitory network. Mol. Pain 8, 32. doi:10.1186/1744-8069-8-32 Devilly, G. J., and Borkovec, T. D. (2000). Psychometric properties of the Jha, M. K., and Trivedi, M. H. (2018). Personalized antidepressant selection and credibility/expectancy questionnaire. J. Behav. Ther. Exp. Psychiatry 31, 73–86. pathway to novel treatments: Clinical utility of targeting inflammation. Int. J. Mol. doi:10.1016/s0005-7916(00)00012-4 Sci. 19, 233. doi:10.3390/ijms19010233 Dworkin, R. H., Turk, D. C., Farrar, J. T., Haythornthwaite, J. A., Jensen, M. P., Jones, K. D., Adams, D., Winters-Stone, K., and Burckhardt, C. S. (2006). A Katz, N. P., et al. (2005). Core outcome measures for chronic pain clinical trials: comprehensive review of 46 exercise treatment studies in fibromyalgia (1988–2005). IMMPACT recommendations. Pain 113, 9–19. doi:10.1016/j.pain.2004.09.012 Health Qual. Life Outcomes 4 (1), 67. doi:10.1186/1477-7525-4-67 Egbewale, B. E., Lewis, M., and Sim, J. (2014). Bias, precision and statistical power of Kabat-Zinn, J. (2013). Full catastrophe living. revised edition. Hachette UK. analysis of covariance in the analysis of randomized trials with baseline imbalance: A Karos, K., McParland, J. L., Bunzli, S., Devan, H., Hirsh, A., Kapos, F. P., et al. simulation study. BMC Med. Res. Methodol. 14, 49. doi:10.1186/1471-2288-14-49 (2020). The social threats of COVID-19 for people with chronic pain. Pain 161, Feliu-Soler, A., Pérez-Aranda, A., Andrés-Rodríguez, L., Butjosa, A., Díaz, N. S., 2229–2235. doi:10.1097/j.pain.0000000000002004 Trujols, J., et al. (2018). Digging into the construct of fibrofog: Psychometric Lasselin, J., Kemani, M. K., Kanstrup, M., Olsson, G. L., Axelsson, J., Andreasson, properties of the Spanish version of the multidimensional inventory of subjective A., et al. (2016). Low-grade inflammation may moderate the effect of behavioral Frontiers in Physiology 19 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 treatment for chronic pain in adults. J. Behav. Med. 39, 916–924. doi:10.1007/ Moseley, G. L. (2003). A pain neuromatrix approach to patients with chronic s10865-016-9769-z pain. Man. Ther. 8, 130–140. doi:10.1016/s1356-689x(03)00051-1 Laupacis, A., Sackett, D. L., and Roberts, R. S. (1988). An assessment of clinically Moseley, G. L., and Butler, D. S. (2015). Fifteen years of explaining pain: The past, useful measures of the consequences of treatment. N. Engl. J. Med. 318, 1728–1733. present, and future. J. Pain 16, 807–813. doi:10.1016/j.jpain.2015.05.005 doi:10.1056/NEJM198806303182605 Moseley, L. (2003). Unraveling the barriers to reconceptualization of the problem in Leadley, R. M., Armstrong, N., Lee, Y. C., Allen, A., and Kleijnen, J. (2012). chronic pain: The actual and perceived ability of patients and health professionals to Chronic diseases in the European union: The prevalence and health cost understand the neurophysiology. J. Pain 4, 184–189. doi:10.1016/s1526-5900(03)00488-7 implications of chronic pain. J. Pain Palliat. Care Pharmacother. 26, 310–325. Napadow, V., Kim, J., Clauw, D. J., and Harris, R. E. (2012). Decreased intrinsic doi:10.3109/15360288.2012.736933 brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Littlejohn, G. (2015). Neurogenic neuroinflammation in fibromyalgia and Rheum. 64, 2398–2403. doi:10.1002/art.34412 complex regional pain syndrome. Nat. Rev. Rheumatol. 11, 639–648. doi:10. Nieto, R., Pardo, R., Sora, B., Feliu-Soler, A., and Luciano, J. V. (2020). Impact of 1038/nrrheum.2015.100 COVID-19 lockdown measures on Spanish people with chronic pain: An online Lockhart, G., MacKinnon, D. P., and Ohlrich, V. (2011). Mediation analysis in study survey. J. Clin. Med. 9, 3558. doi:10.3390/jcm9113558 psychosomatic medicine research. Psychosom. Med. 73, 29–43. doi:10.1097/PSY. Nijs, J., Loggia, M. L., Polli, A., Moens, M., Huysmans, E., Goudman, L., et al. 0b013e318200a54b (2017). Sleep disturbances and severe stress as glial activators: Key targets for López-Pousa, S., Bassets Pagès, G., Monserrat-Vila, S., de Gracia Blanco, M., treating central sensitization in chronic pain patients? Expert Opin. Ther. Targets 21 Hidalgo Colomé, J., and Garre-Olmo, J. (2015). Sense of well-being in patients (8), 817–826. doi:10.1080/14728222.2017.1353603 with fibromyalgia: Aerobic exercise program in a mature forest-A pilot study. Nijs, J., Malfliet, A., Ickmans, K., Baert, I., and Meeus, M. (2014). Treatment of Evid. Based. Complement. Altern. Med. 2015, 614783. doi:10.1155/2015/ central sensitization in patients with ’unexplained’ chronic pain: An update. Expert 614783 Opin. Pharmacother. 15, 1671–1683. doi:10.1517/14656566.2014.925446 Lopresti, A. L. (2017). Cognitive behaviour therapy and inflammation: A systematic Nijs, J., Meeus, M., Versijpt, J., Moens, M., Bos, I., Knaepen, K., et al. (2015). review of its relationship and the potential implications for the treatment of depression. Brain-derived neurotrophic factor as a driving force behind neuroplasticity in Aust. N. Z. J. Psychiatry 51, 565–582. doi:10.1177/0004867417701996 neuropathic and central sensitization pain: A new therapeutic target? Expert Opin. Luciano, J. V., Aguado, J., Serrano-Blanco, A., Calandre, E. P., and Rodriguez- Ther. Targets 19 (4), 565–576. doi:10.1517/14728222.2014.994506 Lopez, C. M. (2013). Dimensionality, reliability, and validity of the revised Nijs, J., Paul van Wilgen, C., Van Oosterwijck, J., van Ittersum, M., and Meeus, M. fibromyalgia impact questionnaire in two Spanish samples. Arthritis Care Res. (2011). How to explain central sensitization to patients with ’unexplained’ chronic Hob. 65, 1682–1689. doi:10.1002/acr.22034 musculoskeletal pain: Practice guidelines. Man. Ther. 16, 413–418. doi:10.1016/j. Luciano, J. V., Barrada, J. R., Aguado, J., Osma, J., and García-Campayo, J. math.2011.04.005 (2014a). Bifactor analysis and construct validity of the HADS: A cross-sectional and Nijs, J., Wijma, A. J., Willaert, W., Huysmans, E., Mintken, P., Smeets, R., et al. longitudinal study in fibromyalgia patients. Psychol. Assess. 26, 395–406. doi:10. (2020). Integrating motivational interviewing in pain neuroscience education for 1037/a0035284 people with chronic pain: A practical guide for clinicians. Phys. Ther. 100, 846–859. Luciano, J. V., D’Amico, F., Cerdà-Lafont, M., Peñarrubia-María, M. T., Knapp, doi:10.1093/ptj/pzaa021 M., Cuesta-Vargas, A. I., et al. (2014b). Cost-utility of cognitive behavioral therapy Nishigami, T., Tanaka, K., Mibu, A., Manfuku, M., Yono, S., and Tanabe, A. versus U.S. Food and drug administration recommended drugs and usual care in (2018). Development and psychometric properties of short form of central the treatment of patients with fibromyalgia: An economic evaluation alongside a 6- sensitization inventory in participants with musculoskeletal pain: A cross- month randomized controlled trial. Arthritis Res. Ther. 16, 451. doi:10.1186/ sectional study. PloS one 13, e0200152. doi:10.1371/journal.pone.0200152 s13075-014-0451-y Nüesch, E., Häuser, W., Bernardy, K., Barth, J., and Jüni, P. (2013). Comparative Luciano, J. V., Guallar, J. A., Aguado, J., López-Del-Hoyo, Y., Olivan, B., efficacy of pharmacological and non-pharmacological interventions in fibromyalgia Magallón, R., et al. (2014c). Effectiveness of group acceptance and commitment syndrome: Network meta-analysis. Ann. Rheum. Dis. 72, 955–962. doi:10.1136/ therapy for fibromyalgia: A 6-month randomized controlled trial (EFFIGACT annrheumdis-2011-201249 study). Pain 155, 693–702. doi:10.1016/j.pain.2013.12.029 Nugraha, B., Karst, M., Engeli, S., and Gutenbrunner, C. (2012). Brain-derived Macfarlane, G. J., Kronisch, C., Dean, L. E., Atzeni, F., Häuser, W., Fluß, E., et al. neurotrophic factor and exercise in fibromyalgia syndrome patients: A mini review. (2017). EULAR revised recommendations for the management of fibromyalgia. Rheumatol. Int. 32, 2593–2599. doi:10.1007/s00296-011-2348-2 Ann. Rheum. Dis. 76, 318–328. doi:10.1136/annrheumdis-2016-209724 Ost, L. G. (2014). The efficacy of acceptance and commitment therapy: An Malfliet, A., Van Oosterwijck, J., Meeus, M., Cagnie, B., Danneels, L., Dolphens, updated systematic review and meta-analysis. Behav. Res. Ther. 61, 105–121. doi:10. M., et al. (2017). Kinesiophobia and maladaptive coping strategies prevent 1016/j.brat.2014.07.018 improvements in pain catastrophizing following pain neuroscience education in fibromyalgia/chronic fatigue syndrome: An explorative study. Physiother. Theory Papadopoulou, D., Fassoulaki, A., Tsoulas, C., Siafaka, I., and Vadalouca, A. Pract. 33, 653–660. doi:10.1080/09593985.2017.1331481 (2016). A meta-analysis to determine the effect of pharmacological and non- pharmacological treatments on fibromyalgia symptoms comprising OMERACT- McCoy, C. E. (2017). Understanding the intention-to-treat principle in 10 response criteria. Clin. Rheumatol. 35 (3), 573–586. doi:10.1007/s10067-015- randomized controlled trials. West. J. Emerg. Med. 18, 1075–1078. doi:10.5811/ 3144-2 westjem.2017.8.35985 Pérez-Aranda, A., Feliu-Soler, A., Montero-Marín, J., García-Campayo, J., Mease, P., Arnold, L. M., Choy, E. H., Clauw, D. J., Crofford, L. J., Glass, J. M., Andrés-Rodríguez, L., Borràs, X., et al. (2019). A randomized controlled efficacy et al. (2009). Fibromyalgia syndrome module at OMERACT 9: Domain construct. trial of mindfulness-based stress reduction compared with an active control group J. Rheumatol. 36, 2318–2329. doi:10.3899/jrheum.090367 and usual care for fibromyalgia: The EUDAIMON study. Pain 160, 2508–2523. Miller, A. H., Haroon, E., Raison, C. L., and Felger, J. C. (2013). Cytokine targets doi:10.1097/j.pain.0000000000001655 in the brain: Impact on neurotransmitters and neurocircuits. Depress. Anxiety 30, Perrot, S., and Russell, I. J. (2014). More ubiquitous effects from non- 297–306. doi:10.1002/da.22084 pharmacologic than from pharmacologic treatments for fibromyalgia syndrome: J. Moix and F. M. Kovacs (Editors) (2009). Manual del dolor. Tratamiento A meta-analysis examining six core symptoms. Eur. J. Pain 18, 1067–1080. doi:10. cognitivo-conductual del dolor crónico (Barcelona: Paidós). 1002/ejp.564 Moman, R. N., Dvorkin, J., Pollard, E. M., Wanderman, R., Murad, M. H., Pescatello, L. S., Arena, R., Riebe, D., and Thompsonet, P. D. (2014). ACSM’s Warner, D. O., et al. (2019). A systematic review and meta-analysis of unguided guidelines for exercise testing and prescription. Philadelphia, Pennsylvania: Wolters electronic and mobile health technologies for chronic pain-is it time to start Kluwer/Lippincott Williams & Wilkins. prescribing electronic health applications? Pain Med. 20, 2238–2255. doi:10. Pinto-Meza, A., Serrano-Blanco, A., Peñarrubia, M. T., Blanco, E., and Haro, J. M. 1093/pm/pnz164 (2005). Assessing depression in primary care with the PHQ-9: Can it be carried out Montero-Marin, J., Andrés-Rodríguez, L., Tops, M., Luciano, J. V., Navarro-Gil, over the telephone? J. Gen. Intern. Med. 20, 738–742. doi:10.1111/j.1525-1497.2005. M., Feliu-Soler, A., et al. (2019). Effects of attachment-based compassion therapy 0144.x (ABCT) on brain-derived neurotrophic factor and low-grade inflammation among Polli, A., Ghosh, M., Bakusic, J., Ickmans, K., Monteyne, D., Velkeniers, B., et al. fibromyalgia patients: A randomized controlled trial. Sci. Rep. 9, 15639. doi:10.1038/ (2020). DNA methylation and brain-derived neurotrophic factor expression s41598-019-52260-z account for symptoms and widespread hyperalgesia in patients with chronic Morris, S. B. (2008). Estimating effect sizes from pretest-posttest-control group fatigue syndrome and comorbid fibromyalgia. Arthritis Rheumatol. 72 (11), designs. Organ. Res. Methods 11, 364–386. doi:10.1177/1094428106291059 1936–1944. doi:10.1002/art.41405 Frontiers in Physiology 20 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 Prochaska, J. O. (2008). Decision making in the transtheoretical model of concept RCT performed alongside the state of alarm in Spain. Int. J. Environ. Res. behavior change. Med. Decis. Mak. 28, 845–849. doi:10.1177/0272989X08327068 Public Health 18, 10300. doi:10.3390/ijerph181910300 Queiroz, L. P. (2013). Worldwide epidemiology of fibromyalgia. Curr. Pain Serrat, M. (2022a). Integrating pain neuroscience education in multicomponent Headache Rep. 17, 356. doi:10.1007/s11916-013-0356-5 approaches for people with fibromyalgia: A practical guide for clinicians. Unpublished. Ramsey, S. D., Willke, R. J., Glick, H., Reed, S. D., Augustovski, F., Jonsson, B., et al. (2015). Cost-effectiveness analysis alongside clinical trials II-an ISPOR Good Serrat, M., Sanabria-Mazo, J. P., Almirall, M., Musté, M., Feliu-Soler, A., Méndez- research practices task force report. Value Health 18, 161–172. doi:10.1016/j.jval. Ulrich, J. L., et al. (2021b). Effectiveness of a multicomponent treatment based on pain 2015.02.001 neuroscience education, therapeutic exercise, cognitive behavioral therapy, and mindfulness in patients with fibromyalgia (FIBROWALK study): A randomized Ranzolin, A., Duarte, A. L., Bredemeier, M., da Costa Neto, C. A., Ascoli, B. controlled trial. Phys. Ther. 101, pzab200. pzab 200. doi:10.1093/ptj/pzab200 M., Wollenhaupt-Aguiar, B., et al. (2016). Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with Sharpe, L., Jones, E., Ashton-James, C. E., Nicholas, M. K., and Refshauge, K. fibromyalgia - a controlled cross-sectional study. Cytokine 84, 25–28. (2020). Necessary components of psychological treatment in pain management doi:10.1016/j.cyto.2016.05.011 programs: A delphi study. Eur. J. Pain 24, 1160–1168. doi:10.1002/ejp.1561 Remor, E. (2006). Psychometric properties of a European Spanish version of the Shields, G. S., Spahr, C. M., and Slavich, G. M. (2020). Psychosocial interventions perceived stress scale (PSS). Span. J. Psychol. 9, 86–93. doi:10.1017/ and immune system function: A systematic review and meta-analysis of s1138741600006004 randomized clinical trials. JAMA Psychiatry 77, 1031–1043. doi:10.1001/ jamapsychiatry.2020.0431 Rivera, J., Alegre, C., Ballina, F. J., Carbonell, J., Carmona, L., Castel, B., et al. (2006). Documento de consenso de la Sociedad Española de Sluka, K. A., and Clauw, D. J. (2016). Neurobiology of fibromyalgia and Reumatología sobre la fibromialgia. Reumatol. Clin. 2 (1), S55–S66. doi:10. chronic widespread pain. Neuroscience 338, 114–129. doi:10.1016/j. 1016/S1699-258X(06)73084-4 neuroscience.2016.06.006 Rodero, B., Pereira, J. P., Pérez-Yus, M. C., Casanueva, B., Serrano-Blanco, A., Sosa-Reina, M. D., Nunez-Nagy, S., Gallego-Izquierdo, T., Pecos-Martín, D., Rodrigues da Cunha Ribeiro, M. J., et al. (2013). Validation of a Spanish version of Monserrat, J., and Álvarez-Mon, M. (2017). Effectiveness of therapeutic exercise the psychological inflexibility in pain scale (PIPS) and an evaluation of its relation in fibromyalgia syndrome: A systematic review and meta-analysis of with acceptance of pain and mindfulness in sample of persons with fibromyalgia. randomized clinical trials. Biomed. Res. Int. 2017, 2356346. doi:10.1155/ Health Qual. Life Outcomes 11, 62. doi:10.1186/1477-7525-11-62 2017/2356346 Rodriguez-Pintó, I., Agmon-Levin, N., Howard, A., and Shoenfeld, Y. (2014). Spitzer, R. L., Kroenke, K., and Williams, J. B. (1999). Validation and utility of a Fibromyalgia and cytokines. Immunol. Lett. 161, 200–203. doi:10.1016/j.imlet.2014. self-report version of PRIME-MD: The PHQ primary care study. Primary care 01.009 evaluation of mental disorders. Patient health questionnaire. JAMA 282, 1737–1744. doi:10.1001/jama.282.18.1737 Rogerson, M., Gladwell, V. F., Gallagher, D. J., and Barton, J. L. (2016). Influences of green outdoors versus indoors environmental settings on psychological and Stanhope, J., Breed, M. F., and Weinstein, P. (2020). Exposure to greenspaces social outcomes of controlled exercise. Int. J. Environ. Res. Public Health 13, 363. could reduce the high global burden of pain. Environ. Res. 187, 109641. doi:10.1016/ doi:10.3390/ijerph13040363 j.envres.2020.109641 Royston, P., and White, I. R. (2011). Multiple imputation by chained equations Thase, M. E. (2014). Using biomarkers to predict treatment response in major (MICE): Implementation in stata. J. Stat. Softw. 45, 1–20. doi:10.18637/jss.v045.i04 depressive disorder: Evidence from past and present studies. Dialogues Clin. Neurosci. 16, 539–544. doi:10.31887/DCNS.2014.16.4/mthase Sanada, K., Díez, M. A., Valero, M. S., Pérez-Yus, M. C., Demarzo, M. M., García- Toro, M., et al. (2015). Effects of non-pharmacological interventions on Thieme, K., Mathys, M., and Turk, D. C. (2017). Evidenced-based guidelines on inflammatory biomarker expression in patients with fibromyalgia: A systematic the treatment of fibromyalgia patients: Are they consistent and if not, why not? review. Arthritis Res. Ther. 17, 272. doi:10.1186/s13075-015-0789-9 Have effective psychological treatments been overlooked? J. Pain 18, 747–756. doi:10.1016/j.jpain.2016.12.006 Sancho-Domingo, C., Carballo, J. L., Coloma-Carmona, A., and Buysse, D. J. (2021). Brief version of the Pittsburgh Sleep Quality Index (B-PSQI) and Thompson Coon, J., Boddy, K., Stein, K., Whear, R., Barton, J., and Depledge, M. measurement invariance across gender and age in a population-based sample. H. (2011). Does participating in physical activity in outdoor natural environments Psychol. Assess. 33, 111–121. doi:10.1037/pas0000959 have a greater effect on physical and mental wellbeing than physical activity indoors? A systematic review. Environ. Sci. Technol. 45, 1761–1772. doi:10.1021/ Sawaddiruk, P., Paiboonworachat, S., Chattipakorn, N., and Chattipakorn, S. C. es102947t (2017). Alterations of brain activity in fibromyalgia patients. J. Clin. Neurosci. 38, 13–22. doi:10.1016/j.jocn.2016.12.014 Torres-Lacomba, M., Navarro-Brazález, B., Bailón-Cerezo, J., Vergara-Pérez, F., de la Rosa-Díaz, I., and Prieto-Gómez, V. (2021). Assessment tools of patient Schulz, K. F., Altman, D. G., and Moher, D.CONSORT Group (2010). CONSORT competences: The Spanish version of the R-NPQ and three practical cases in women 2010 statement: Updated guidelines for reporting parallel group randomised trials. with breast cancer and persistent pain. Int. J. Environ. Res. Public Health 18, 4463. BMJ 340, c332. doi:10.1136/bmj.c332 doi:10.3390/ijerph18094463 Schwamm, L. H., Erskine, A., and Licurse, A. (2020). A digital embrace to blunt Trøstrup, C. H., Christiansen, A. B., Stølen, K. S., Nielsen, P. K., and Stelter, R. the curve of COVID19 pandemic. NPJ Digit. Med. 3, 64. doi:10.1038/s41746-020- (2019). The effect of nature exposure on the mental health of patients: A systematic 0279-6 review. Qual. Life Res. 28, 1695–1703. doi:10.1007/s11136-019-02125-9 Schwarz, M. J., Offenbaecher, M., Neumeister, A., Ewert, T., Willeit, M., Praschak- Twisk, J., de Boer, M., de Vente, W., and Heymans, M. (2013). Multiple Rieder, N., et al. (2002). Evidence for an altered tryptophan metabolism in fibromyalgia. imputation of missing values was not necessary before performing a Neurobiol. Dis. 11, 434–442. doi:10.1006/nbdi.2002.0563 longitudinal mixed-model analysis. J. Clin. Epidemiol. 66, 1022–1028. doi:10. Scott, W., and McCracken, L. M. (2015). Patients’ impression of change following 1016/j.jclinepi.2013.03.017 treatment for chronic pain: Global, specific, a single dimension, or many? J. Pain 16, Van Oosterwijck, J., Meeus, M., Paul, L., De Schryver, M., Pascal, A., Lambrecht, 518–526. doi:10.1016/j.jpain.2015.02.007 L., et al. (2013). Pain physiology education improves health status and endogenous Serrano-Atero, M. S., Caballero, J., Cañas, A., García-Saura, P. L., Serrano- pain inhibition in fibromyalgia: A double-blind randomized controlled trial. Clin. Álvarez, C., and Prieto, J. (2002). Pain assessment (I). Rev. Soc. Esp. Dolor 9, 94–108. J. Pain 29, 873–882. doi:10.1097/AJP.0b013e31827c7a7d Serrat, M., Albajes, K., Navarrete, J., Almirall, M., Lluch Girbé, E., Neblett, R., et al. van Wilgen, C. P., Bloten, H., and Oeseburg, B. (2007). Results of a (2022b). Effectiveness of two video-based multicomponent treatments for multidisciplinary program for patients with fibromyalgia implemented in the fibromyalgia: The added value of cognitive restructuring and mindfulness in a primary care. Disabil. Rehabil. 29 (15), 1207–1213. doi:10.1080/ three-arm randomised controlled trial. Behav. Res. Ther. 158, 104188. doi:10.1016/j. 09638280600949860 brat.2022.104188 Vázquez-Barquero, J. L., Gaite, L., Cuesta, M. J., Garcia Usieto, E., Knapp, M., and Serrat, M., Almirall, M., Musté, M., Sanabria-Mazo, J. P., Feliu-Soler, A., Méndez- Beecham, J. (1997). Spanish version of the CSRI: An interview for cost assessment in Ulrich, J. L., et al. (2020). Effectiveness of a multicomponent treatment for mental health. Arch. Neurobiol. 60, 171–184. fibromyalgia based on pain neuroscience education, exercise therapy, Velly, A. M., and Mohit, S. (2018). Epidemiology of pain and relation to psychological support, and nature exposure (NAT-FM): A pragmatic psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 87, 159–167. randomized controlled trial. J. Clin. Med. 9, 3348. doi:10.3390/jcm9103348 doi:10.1016/j.pnpbp.2017.05.012 Serrat, M., Coll-Omaña, M., Albajes, K., Solé, S., Almirall, M., Luciano, J. V., et al. Vlaeyen, J., Kole-Snijders, A., Boeren, R., and van Eek, H. (1995). Fear of (2021a). Efficacy of the FIBROWALK multicomponent program moved to a virtual movement/(re)injury in chronic low back pain and its relation to behavioral setting for patients with fibromyalgia during the COVID-19 pandemic: A proof-of- performance. Pain 62, 363–372. doi:10.1016/0304-3959(94)00279-N Frontiers in Physiology 21 frontiersin.org Serrat et al. 10.3389/fphys.2022.1046613 Weiling, L., Chew, A., and Gunasekeran, D. V. (2020). Digital health for patients Witek-Janusek, L., Albuquerque, K., Chroniak, K. R., Chroniak, C., Durazo-Arvizu, with chronic pain during the COVID-19 pandemic. Br. J. Anaesth. 125, 657–660. R., and Mathews, H. L. (2008). Effect of mindfulness based stress reduction on doi:10.1016/j.bja.2020.08.003 immune function, quality of life and coping in women newly diagnosed with early stage breast cancer. Brain Behav. Immun. 22, 969–981. doi:10.1016/j.bbi.2008.01.012 White, V., Linardon, J., Stone, J. E., Holmes-Truscott, E., Olive, L., Mikocka-Walus, A., et al. (2022). Online psychological interventions to reduce symptoms of depression, Wylezinski, L. S., Gray, J. D., Polk, J. B., Harmata, A. J., and Spurlock, C. F., anxiety, and general distress in those with chronic health conditions: A systematic review 3rd (2019). Illuminating an invisible epidemic: A systemic review of the and meta-analysis of randomized controlled trials. Psychol. Med. 52, 548–573. doi:10. clinical and economic benefits of early diagnosis and treatment in 1017/S0033291720002251 inflammatory disease and related syndromes. J. Clin. Med. 8, 493. doi:10. 3390/jcm8040493 Wicksell, R. K., Renöfält, J., Olsson, G. L., Bond, F. W., and Melin, L. (2008). Avoidance and cognitive fusion-central components in pain related Zanette, S. A., Dussan-Sarria, J. A., Souza, A., Deitos, A., Torres, I. L., and Caumo, disability? Development and preliminary validation of the psychological W. (2014). Higher serum S100B and BDNF levels are correlated with a lower inflexibility in pain scale (PIPS). Eur. J. Pain 12, 491–500. doi:10.1016/j. pressure-pain threshold in fibromyalgia. Mol. Pain 10, 46. doi:10.1186/1744-8069- ejpain.2007.08.003 10-46 Frontiers in Physiology 22 frontiersin.org