PTJ: Physical Therapy & Rehabilitation Journal | Physical Therapy, 2021;101:1–12

https://doi.org/10.1093/ptj/pzab200
Advance access publication date September 2, 2021
Original Research

Effectiveness of a Multicomponent Treatment Based on

Pain Neuroscience Education, Therapeutic Exercise,
Cognitive Behavioral Therapy, and Mindfulness in
Patients With Fibromyalgia (FIBROWALK Study):
A Randomized Controlled Trial

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Mayte Serrat , PT, MSc1 ,2 ,† , Juan P. Sanabria-Mazo , MSc3 ,4 ,† , Míriam Almirall , MSc1 ,
Marta Musté , BD1 , Albert Feliu-Soler , PhD5 , Jorge L. Méndez-Ulrich , PhD6 ,‡ ,
Antoni Sanz , PhD4* , Juan V. Luciano , PhD3 ,5 ,‡
1 Unitatd’Expertesa en Síndromes de Sensibilització Central, Hospital de la Vall d’Hebron, Barcelona, Spain
2 Escoles Universitàries Gimbernat, Universitat Autònoma de Barcelona, Sant Cugat del Vallès, Spain
3 Teaching, Research, and Innovation Unit - Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain
4 Department of Basic, Developmental and Educational Psychology. Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
5 Departament of Clinical & Health Psychology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
6 Department of Methods of Research and Diagnosis in Education, Universitat de Barcelona, Barcelona, Spain

*Address all correspondence to Dr Sanz at: [email protected]

† Mayte Serrat and Juan P. Sanabria-Mazo contributed equally to this article and should be considered co-first authors.
‡ Jorge L. Méndez-Ulrich and Juan V. Luciano contributed equally to this article and should be considered co-senior authors.

Abstract
Objective. The purpose of this study was to evaluate the effectiveness of a 12-week multicomponent treatment based on
pain neuroscience education, therapeutic exercise, cognitive behavioral therapy, and mindfulness—in addition to treatment
as usual—compared with treatment as usual only in patients with fibromyalgia.
Methods. This randomized controlled trial involved a total of 272 patients who were randomly assigned to either multicom-
ponent treatment (n = 135) or treatment as usual (n = 137). The multicomponent treatment (2-hour weekly sessions) was
delivered in groups of 20 participants. Treatment as usual was mainly based on pharmacological treatment according to the
predominant symptoms. Data on functional impairment using the Revised Fibromyalgia Impact Questionnaire as the primary
outcome were collected as were data for pain, fatigue, kinesiophobia, physical function, anxiety, and depressive symptoms
(secondary outcomes) at baseline, 12 weeks, and, for the multicomponent group only, 6 and 9 months. An intention-to-
treat approach was used to analyze between-group differences. Baseline differences between responders (>20% Revised
Fibromyalgia Impact Questionnaire reduction) and nonresponders also were analyzed, and the number needed to treat was
computed.
Results. At posttreatment, significant between-group differences with a large effect size (Cohen d > 0.80) in favor of
the multicomponent treatment were found in functional impairment, pain, kinesiophobia, and physical function, whereas
differences with a moderate size effect (Cohen d > 0.50 and <0.80) were found in fatigue, anxiety, and depressive symptoms.
Nonresponders scored higher on depressive symptoms than responders at baseline. The number needed to treat was 2 (95%
CI = 1.7–2.3).
Conclusion. Compared with usual care, there was evidence of short-term (up to 3 months) positive effects of the
multicomponent treatment for fibromyalgia. Some methodological shortcomings (eg, absence of follow-up in the control
group and monitoring of treatment adherence, potential research allegiance) preclude robust conclusions regarding the
proposed multicomponent program.
Impact. Despite some methodological shortcomings in the design of this study, the multicomponent therapy FIBROWALK
can be considered a novel and effective treatment for patients with fibromyalgia. Physical therapists should detect patients
with clinically relevant depression levels prior to treatment because depression can buffer treatment effects.
Lay Summary. Fibromyalgia is prevalent and can be expensive to treat. This multicomponent treatment could significantly
improve the core symptoms of fibromyalgia compared with usual treatment.
Keywords: Fibromyalgia, Multicomponent Treatment, Pain Neuroscience Education, Therapeutic Exercise, Cognitive Behavioral Therapy, Mindfulness

Received: May 8, 2020. Revised: April 27, 2021. Accepted: May 28, 2021
© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved.
For permissions, please email: [email protected]
2 Multicomponent Treatment for Fibromyalgia

Introduction life.37 Therefore, personalized therapeutic exercise should be

Fibromyalgia is a syndrome characterized by chronic integrated into the multicomponent packages used for treating
widespread musculoskeletal pain, fatigue, stiffness, sleep fibromyalgia.15
disturbances, and distress.1,2 The estimated prevalence of Psychological treatments that have shown promise in the
fibromyalgia is approximately 2% in the general population management of fibromyalgia include CBT and mindfulness.
worldwide and 2.45% in Spain.3 Regarding etiology, it CBT-based treatments strengthen self-efficacy and promote
is posited that fibromyalgia involves hypersensitization of adaptive coping strategies in patients experiencing chronic
the central nervous system characteristic of the central pain.38,39 A meta-analysis of 29 RCTs testing the effectiveness
sensitization syndromes, of which fibromyalgia is the of CBT-based interventions for fibromyalgia observed signif-
flagship.4,5 Central sensitization syndromes are characterized icant and small to medium mean effect sizes in pain relief,
by a malfunction in the balance between descending inhibitory improvement of quality of life, reduction of negative mood,
and facilitatory pathways, which cause hyperalgesia and disability, and fatigue.38 Mindfulness-based interventions are
allodynia. a form of structured training aimed at helping people to relate

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The altered function of the descending nociceptive inhibitory to their physical and psychological conditions in more accept-
pathway5,6 is a biological mechanism moderated by cognitive ing and non-judgmental ways.40 It has significant effects on
biases, such as negative and maladaptive thoughts, as well as pain intensity, anxiety, depression, and quality of life.12 Recent
emotional and behavioral factors that lead to dysfunctional high-quality trials have demonstrated the efficacy and cost
beliefs, which, in turn, can distort perception and facilitate utility of including mindfulness as an adjuvant therapy for the
the experience of pain.7,8 Due to the involvement of all the management of fibromyalgia.12,41
above factors and the complexity of fibromyalgia therapeutic Therefore, the main objective of this RCT was twofold:
management, there is a need to develop interdisciplinary and (1) to analyze the effectiveness of a 12-week multicomponent
multicomponent approaches.9–12 In this regard, multicom- treatment (FIBROWALK protocol), based on PNE, therapeu-
ponent treatments including various empirically validated tic exercise, CBT, and mindfulness training, as an add-on
therapeutic ingredients are currently considered the gold to treatment as usual (TAU) to improve functional impact
standard.11,13–15 (primary outcome) as well as pain, fatigue, kinesiophobia,
Since the seminal meta-analysis performed by Häuser physical function, anxiety, and depressive symptoms (sec-
and collaborators,13 multicomponent treatments involving ondary outcomes) compared with TAU; and (2) to explore the
physical exercise and cognitive behavioral therapy (CBT) are differences between responders and nonresponders in terms
increasingly being recommended to manage the wide range of sociodemographic and clinical characteristics.
fibromyalgia symptoms and tackle the multifactorial causes
of the syndrome. However, although the literature suggests
that multicomponent treatments are the gold standard for Methods
fibromyalgia management, there is still no consensus about Design
which combination of therapeutic ingredients should be used. An RCT was conducted in the context of real-life clinical prac-
García and colleagues16 performed a systematic review of tice with data collected at baseline (pre), at the end of the 12-
interventions for fibromyalgia and concluded that multimodal week intervention (post), and, for the multicomponent treat-
and multidisciplinary approaches should be implemented ment only, at 6 and 9 months (follow-up). This RCT received
in daily practice. Specifically, the following ingredients approval from the Ethics Committee of Clinical Investigation
were recommended: aerobic exercise, muscle strength, CBT- (PR(AG)120/2018) of the University Hospital Vall d’Hebron
based interventions, and some forms of relaxation after in Barcelona (UHVH) and was registered at ClinicalTrials.gov
exercise. As far as we know, there is no evidence about these (NCT04284566). This study is reported according to the
techniques together or in combination with pain neuroscience guidelines issued by the Consolidated Standards of Reporting
education (PNE) or mindfulness, whose recent empiri- Trials.42 Those patients in the TAU group were given the
cal support for fibromyalgia is promising as commented opportunity to receive the multicomponent treatment once the
above. study had finished.
PNE is based on the reconceptualization of an individual’s
understanding of pain, emphasizing that any credible evidence
of danger or safety in body tissues can increase or decrease Participants
pain perception, respectively.17–19 This therapeutic approach A total of 272 patients who met the eligibility criteria were
has been extensively investigated in various chronic pain con- recruited from November 2018 to August 2019 by a physical
ditions.20–32 A recent systematic review33 has supported the therapist (M.S.) of the Central Sensitivity Syndromes Spe-
efficacy of PNE in the improvement of pain-related disability, cialized Unit at the UHVH.43 The inclusion criteria were
pain catastrophizing, avoidance behavior, and inactivity. It is (1) fulfil the 2010/2011 American College of Rheumatology
important to point out that PNE seems even more effective fibromyalgia diagnostic criteria. The diagnosis was verified by
when it is combined with therapeutic exercise, gradual expo- a rheumatologist (M.A.) of the Central Sensitivity Syndromes
sure techniques, or CBT.34–36 Specialized Unit; (2) adults ≥18 years old; and (3) provide
Concerning therapeutic exercise, recent meta-analyses written informed consent. The exclusion criteria were having
have supported its effectiveness for improving a wide range terminal illnesses or programmed interventions that might
of fibromyalgia symptoms. For instance, Sosa-Reina and interrupt the study. No stringent eligibility criteria were estab-
colleagues conducted a meta-analysis of 14 randomized lished due to the naturalistic nature of the RCT. Excluding
controlled trials (RCTs) and found that therapeutic exercise patients with lower education or comorbidities might have
reduces pain and depressive symptoms and increases global turned away many patients from our RCT who would other-
well-being and both components of health-related quality of wise be eligible; that is, we put emphasis on external validity.
Serrat et al 3

The participants were recruited consecutively in different Taking the American College of Sports Medicine guide-
waves. The first wave was conducted from November to lines46 as framework, all participants randomized to the “mul-
February (2 groups of 20 patients), the second wave from ticomponent treatment” group received the same exercise pro-
March to June (4 groups of 20 patients), and the third wave tocol. To increase the level of difficulty and commitment, each
from August to October (1 group of 20 patients). All recruited session had a 3-part structure—warm-up, main exercise, and
patients were considered capable of following the multicom- cool-down—and as homework, individualized walking guide-
ponent therapy if they were allocated to it. Lack of adherence lines were given and progression was monitored throughout
to drugs or home activities was not an exclusion criterion the 12-week multicomponent treatment.
given the nature of our trial, and we analyzed data from all The program included multicomponent exercises such as
participants who underwent random allocation. Treatment stretching, balance training, posture correction, and low-
allocation was performed by the clinical trials unit in accor- impact walking at a training load of 60% to 80% of
dance with computer-generated randomization sequences. maximum heart rate determined by 220 − age (see an outline
of the exercise program in Fig. 1 and the Suppl. Appendix). It

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is well known that exercise intensity is a crucial element of an
Procedure exercise program. If minimal threshold values are not met, it
can result in lack of exercise effect, whereas excessive intensity
The main researcher (M.S.), through an initial interview after
causes overtraining and low exercise adherence. In that sense,
verifying the inclusion and exclusion criteria, provided an
to increase the adherence to treatment, the intervention was
overview of the study to all the participants. All participants
carried out in a playful way with the support of role-playing
gave written informed consent before random assignment.
techniques, by fostering social interactions, goal setting, self-
They were also informed of their right to withdraw from the
monitoring, and reinforcement.
study at any time with the guarantee that they could continue
The guidelines of the motivational interview47,48 and the
to receive their usual treatment.
cognitive-behavioral fear-avoidance model49 were part of the
Each participant who voluntarily agreed to take part in
theoretical framework used for the present study. The inter-
the study was assigned to an alphanumeric code list and was
vention was carried out by fostering social interactions, with
randomly assigned using the SPSS v26.0 to either the mul-
the support of role-playing techniques to better understand
ticomponent treatment or TAU. This process was carried out
the information and to emphasize adherence to treatment. All
using numbered envelopes containing sheets with information
sessions had the same predefined structure, which is detailed
regarding participant allocation. The envelopes were coded by
in Figures 1 and 2. Patients who did not attend a session or
the clinical trials unit to ensure concealment of randomization.
did not practice the exercises were called or emailed to foster
Due to the characteristics of the study, participants and the
adherence.
therapist (M.S.) were not blind to the group allocations. Only
TAU was mainly based on pharmacological treatment
the interviewer (M.M.) was blind to participants’ random
(duloxetine, amitriptyline, pregabalin, or tramadol) according
assignment in the RCT.
to the predominant symptoms in monotherapy or combina-
tion therapy of 2 or more drugs. The rheumatologist from the
UHVH (M.A.) monitored the pharmacological treatment.
Multicomponent Treatment The patients were instructed to continue their prescribed
The multicomponent treatment was carried out in groups of treatment with no change throughout the 3-month period.
20 patients per session, with a frequency of one 2-hour weekly In Spain, some counseling about aerobic exercise adjusted to
session for 12 weeks. The first author (M.S.), the professional patients’ physical limitations and education is usually pro-
who delivered the treatments, is both a physical therapist vided by first-line clinicians and specialists, but pharmacolog-
(>15 years of experience) and a health psychologist (>6 years ical treatment is still the dominant treatment option. For eth-
of experience). In addition, she has also been trained in CBT ical reasons, control patients were offered the same treatment
and mindfulness. as the intervention group once the trial was concluded. Data
The multicomponent treatment included PNE, therapeutic of those control patients receiving the intervention once the
exercise, CBT, and mindfulness training. PNE was not only a trial had ended were not part of this study.
part of multicomponent therapy but was also the fundamental
component that guided the approach taken by all the strate- Study Measures
gies involved. In short, PNE involves a profound change in All patients were evaluated before (“pre”) and after (“post”)
the way in which pain is conceptualized, of everything that we treatment using an online battery of measures. Only patients
transmit to the patient, and how we explain it to them. All the receiving the multicomponent treatment were evaluated at 6-
aspects of PNE were reinforced point by point in each session and 9-month follow-up. (Fig. 3).
with the Spanish version of the book entitled Explain Pain.44
Most patients had primary or secondary studies, and they had
Socio-Demographic and Clinical Characteristics
no specific learning, behavioral, or intellectual difficulty. The-
oretical concepts included in both CBT and PNE components A socio-demographic and clinical ad-hoc questionnaire was
of the treatment were adapted to an informal language to used to obtain the following general and clinical patient data:
ensure they were understood by patients without great effort. age, educational level, socioeconomic status, marital status,
To communicate the information to the patients in the most and comorbid medical conditions.
comprehensive way, a presentation was used with images,
examples, and metaphors.22 Individualized gradual programs Primary Outcome
were implemented following the transtheoretical model of The Revised Fibromyalgia Impact Questionnaire (FIQR)50
stages of change developed by Prochaska and Diclemente.44 was used to measure the functional impairment during the
4 Multicomponent Treatment for Fibromyalgia

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Figure 1. Outline of active group sessions in the multicomponent treatment (adapted with permission from Serrat et al43 ). The numbers in parentheses
(from 1 to 12) of the Conceptual Phase of PNE, CBT, and MT and the numbers (from 1 to 8) on physical phase are explained on Figure 2. a The physical
phase was designed following the recommendations of the American College of Sports Medicine (ACSM).45

last week. It is divided into 3 dimensions: physical dysfunction are answered on a 4-point Likert scale (from 0–11). Total
(scores from 0–30), overall impact (scores from 0–20), and scores of the Tampa Scale for Kinesiophobia can range from
intensity of symptoms (scores from 0–50). It consists of 21 11 to 44, where higher scores indicate a greater fear of pain
items answered on a 0–10 numerical scale where higher scores and movement. The Spanish version shows adequate internal
indicate greater functional impairment. The Spanish version consistency (α = .79)55 and in our sample was α = .87.
shows adequate internal consistency (Cronbach α = .93),51–53 Hospital Anxiety and Depression Scale (HADS)56 was used
which in our study was α = .94. to measure depressive and anxiety symptoms. It consists of 2
dimensions (anxiety and depression) of 7 items each, with a
Secondary Outcomes 4-point Likert scale response format. A total score measuring
Visual Analog Scale of the FIQR50 was used to measure general distress can also be computed. Total scores of each
fatigue and pain, with scores ranging from 0 to 10. Higher scale (HADS-A and HADS-D) range from 0 to 21, where
scores indicate greater perceived fatigue and pain, respec- higher scores indicate higher symptom severity. The Spanish
tively. version shows adequate internal consistency for HADS-A
Tampa Scale for Kinesiophobia54 was used to measure (α = .83) and for HADS-D (α = .87)57 and in our sample was
kinesiophobia. This scale is composed of 11 items, which α = .83 and .85, respectively.
Serrat et al 5

Th Physical Functioning component of the 36-Item Short Results

Form Survey (SF-36)58 was used to measure physical func- From August to November 2019, 420 patients met the selec-
tioning. This subscale comprises a total of 10 items with a tion criteria and were asked to participate in the study. Of
3-point Likert scale response format. Total scores are trans- these, 272 accepted and were randomly allocated to the mul-
formed to range from 0 to 100, with higher scores indicating ticomponent treatment (n = 135) or TAU (n = 137). All partic-
better physical functioning. The Spanish version shows ade- ipants were included in the ITT analysis. The distribution of
quate internal consistency (α = .94)59 and in our sample was included patients is described in Figure 3.
α = .85.
Baseline Differences Between Multicomponent
Statistical Analyses Treatment Versus TAU
Data analyses were computed with SPSS v26.0. Descrip- As shown in Table 1, there were significant between-group
tive statistics were calculated for all measures of the study differences in terms of gender distribution, body mass index,
and were presented as means and SDs for the continuous and physical function. The mean age of all patients was

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variables and as frequencies and percentages (%) for the 54 years (SD = 8.96), body mass index was 27 (SD = 5.55),
categorical variables. Continuous variables were analyzed and the mean number of years diagnosed with fibromyalgia
using the Levene test for testing equal variances and the was 17 (SD = 16.66). Of the sample, 22.4% were actively
Kolmogorov–Smirnov test to evaluate normality. For the con- employed, 45.6% reported having a secondary education
tinuous variables, Student’s t test was used to examine the level, and for 84.5%, their condition was comorbid with
between-group differences in sociodemographic and clini- chronic fatigue.
cal characteristics. For the categorical variables, the χ 2 test
was used. Between-Group Differences in the Primary and
The between-group differences were analyzed following an Secondary Outcome Measures
intention-to-treat (ITT) approach. Specifically, we conducted In the multicomponent treatment, there were 23% dropouts,
a 2 × 2 mixed ANCOVA with group (TAU + multicompo- whereas in the control group there were none. When compar-
nent treatment vs TAU) as between-subjects factor and study ing baseline differences between dropouts and non-dropouts
period as the within-subjects factor (pre vs post), introducing in terms of sociodemographic and clinical variables, we found
baseline scores in the SF-36 (physical function) as a covariate. that dropouts were older (58.35 ± 8.52 vs 52.62 ± 8.27,
The partial eta-square (ηp2 ) was estimated for the 2 complete P = .001, d = 0.68) and had higher physical function scores
models (main effects of group and phase, and group × phase (28.44 ± 20.49 vs 20.34 ± 12.03, P = .04, d = 0.48).
interaction). We also conducted an intragroup analysis for An ITT and a completers approach were used to compare
the multicomponent treatment group (pre, post, follow-up the posttreatment effects of the different conditions on the
+6, follow-up +9), with the baseline values as reference primary and secondary outcomes. Means and SD of the
for comparison. The effect size (Cohen d) for each pairwise differences between the pre-test and post-test values in both
comparison was reported, using the grouped reference SD to approaches are shown in Table 2 (ITT) and Supplementary
weigh the differences in the previous and subsequent means Table 1 (completers). The effect size was somewhat smaller
and to correct the population estimate.60,61 Separate models with the ITT approach, but significant large and moderate dif-
were estimated for each of the secondary outcomes using the ferences were found in both approaches. Significant improve-
same analytical strategy. All outcomes were analyzed using the ments (P = .001) with a large effect size (Cohen d > 0.80)
last observation carried forward method for imputing missing between groups were found for functional impairment, pain,
values. kinesiophobia, and physical function and with a moderate
To assess the clinical relevance of the improvement in the effect size (Cohen d > 0.50 and <0.80) for fatigue, anxiety,
primary outcome (FIQR), patients who, within 12 weeks and depressive symptoms.
of the multicomponent treatment, presented a reduction in
the FIQR score ≥20% in the total score with respect to the Number Needed to Treat
baseline (pre-post) were considered as responders. Reduc-
A total of 70 patients (51.85%) receiving the multicomponent
tions of 20% or greater in the FIQR total score are con-
treatment reached the criterion of ≥20% FIQR reduction, and
sidered to be clinically relevant.62 Differences in baseline
a total of 7 patients (5.2%) showed a reduction >70% on
variables between responders and nonresponders to the mul-
their FIQR score. Only 1 patient in the TAU group was consid-
ticomponent treatment were compared using the Student’s
ered as a responder using the FIQR improvement criterion of
t test for quantitative variables and χ 2 test for categorical
≥20%. We analyzed the baseline differences between respon-
variables. This classification (responders vs nonresponders)
ders and nonresponders for all variables (Tab. 3). The non-
was used to calculate the number needed to treat (NNT) in
responder group scored significantly higher than responders
the multicomponent treatment group compared with TAU.
on depressive symptoms at baseline (P = .01; d = 0.45). There
NNT refers to the estimated number of participants who
were no significant differences between groups in terms of any
need to be treated in the TAU + multicomponent treatment
other socio-demographic or clinical variables.
(ie, rather than the TAU alone) for 1 additional patient to
The absolute risk reduction in the multicomponent
benefit.
treatment group compared with TAU was 51.85% (95%
CI = 42.57%–59.67%) with NNT 2 (95% CI = 1.7–2.3),
Role of the Funding Source meaning that 2 patients would need to be treated in the
The funders played no role in the design, conduct, or reporting multicomponent treatment group instead with TAU alone
of this study. for 1 of them to become a responder.
6 Multicomponent Treatment for Fibromyalgia

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Figure 2. Steps of the multicomponent treatment. Pain neuroscience education (PNE), therapeutic exercise, cognitive behavioral therapy (CBT), and
mindfulness (adapted with permission from Serrat et al43 ). CNS = central nervous system.

Within-Group Differences in the Intervention Discussion

Group at Follow-Up Our results indicated that the multicomponent treatment
Data for all the studied variables showed a similar trend was an effective adjuvant for patients with fibromyalgia
throughout the 6- and 9-month follow-up (Suppl. Tab. 2). compared with TAU alone. Specifically, significant differences
Despite showing a slight worsening of symptoms at 6 months, with medium to large effect sizes were found in functional
which increased at 9 months, the improvements at the 6- and impairment, pain, kinesiophobia, and physical function.
9-month follow-up remained statistically significant (P = .01 Despite showing a slight worsening of symptoms at 6 months,
for all variables studied, with a large effect size; Cohen which increased at 9 months in the multicomponent treatment
d > 0.80). group, improvements at 6- and 9-month follow-up remained
Serrat et al 7

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Figure 3. Flowchart of participants in the study following the CONSORT statement.

statistically significant for all study outcomes. Our results are recommend using bona-fide active treatments as comparison
in line with previous literature on multicomponent treatments in future research on our multicomponent treatment program.
for fibromyalgia 11,13–15 showing that an approach based In addition, due to the nature of the study, we do not know
on the aforementioned ingredients seems to be effective for which exact ingredients of the therapy made it effective, so
improving a wide range of fibromyalgia symptoms. further research is needed in this regard.
However, the use of TAU as a comparison condition is a To our knowledge, different multicomponent programs
clear limitation of this study because TAU-treated patients have been tested (eg, physical activity plus CBT) as an
obviously received “less treatment hours” than those in the add-on of usual care for the management of fibromyalgia.
multicomponent treatment condition. This issue poses threats 12,13,21,32,33,41 Overall, they have demonstrated to be

to the internal validity of our RCT and, therefore, we strongly effective therapeutic options leading to improvements in
8 Multicomponent Treatment for Fibromyalgia

Table 1. Baseline Differences Between Participants Allocated to TAU + Multicomponent Treatment and TAUa

TAU + Multicomponent Treatment (n = 135) TAU (n = 137) t/x2 Pb

General measures
Women, n (%) 131 (97) 137 (100) 4.12 .05
Age, y, mean (SD) 53.98 (8.65) 53.24 (9.26) .68 .50
BMI (kg/m2 ), mean (SD) 27.95 (5.92) 26.08 (4.99) 2.82 .01
Years of illness, mean (SD) 17.47 (11.79) 15.84 (9.37) 1.26 .21
Married or in couple, n (%) 92 (68.1) 82 (59.9) 5.94 .11
Cohabitating, n (%) 119 (88.1) 119 (86.9) .10 .75
Secondary studies, n (%) 59 (43.7) 65 (47.4) 9.53 .09
Labor assets, n (%) 21 (15.6) 40 (29.2) 13.69 .09
Disability in process, n (%) 39 (28.9) 42 (30.7) .10 .75
Comorbidity
Chronic fatigue, n (%) 113 (83.7) 118 (86.1) .31 .58

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Multiple chemical sensitivity, n (%) 47 (34.8) 37 (27.0) 1.94 .16
Irritable bowel syndrome, n (%) 63 (46.7) 76 (48.2) .06 .80
Migraines, n (%) 77 (57.0) 80 (58.4) .05 .82
Medication
>2 medications, n (%) 23 (32.9) 31 (47.7) 4.81 .31
Primary outcome, mean (SD)
FIQR_Functional impairment (0–100) 75.43 (12.37) 73.9 (9.76) 1.13 .26
Secondary outcomes, mean (SD)
VAS Pain (0–10) 8.03 (1.04) 7.79 (1.12) 1.84 .07
VAS Fatigue (0–10) 7.90 (1.44) 7.80 (1.41) .58 .56
TSK-11 Kinesiophobia (11–44) 31.43 (7.07) 30.42 (6.85) 1.20 .23
HADS Anxiety (0–21) 14.14 (4.37) 13.35 (3.93) 1.57 .12
HADS Depression (0–21) 12.64 (4.58) 11.94 (4.11) 1.33 .18
SF-36 Physical function (0–100) 22.26 (14.81) 26.61 (14.02) 2.49 .01
a Thevalues represent means and SD or frequency (f) and percentages (%) in their respective order of presentation. BMI = body mass index; FIQR = Revised
Fibromyalgia Impact Questionnaire; HADS = Hospital Anxiety and Depression Scale; SF-36 = SF-36 Health Survey; TAU = treatment as usual; TSK-11 =
Tampa Scale for Kinesiophobia; VAS = Visual Analogue Scale. b Bold type indicates statistically significant group differences.

Table 2. Between-Group Differences From an ITT Approacha

TAU + Multicomponent TAU

Phase × Group Interaction
Treatment (n = 135) (n = 137)

Pre Post Pre Post f Pb ηp 2 dc

Primary outcome, mean (SD)
FIQR Functional impairment (0–100) 75.43 (12.37) 58.58 (19.91) 73.9 (9.76) 79.77 (9.72) 190.93 .01 .42 1.36
Secondary outcomes, mean (SD)
VAS Pain (0–10) 8.03 (1.04) 6.33 (1.98) 7.79 (1.12) 8.09 (.98) 128.73 .01 .32 1.13
VAS Fatigue (0–10) 7.90 (1.44) 6.75 (1.86) 7.80 (1.41) 7.69 (1.68) 20.79 .01 .07 .56
TSK-11 Kinesiophobia (11–44) 31.43 (7.07) 20.08 (9.43) 30.42 (6.85) 31.76 (6.25) 172.01 .01 .39 1.47
HADS Anxiety (0–21) 14.14 (4.37) 11.09 (4.72) 13.35 (3.93) 14.23 (3.83) 77.19 .01 .22 .73
HADS Depression (0–21) 12.64 (4.58) 9.70 (4.96) 11.94 (4.11) 13.01 (3.62) 85.14 .01 .24 .77
SF-36 Physical function (0–100) 22.26 (14.81) 41.19 (20.54) 26.61 (14.02) 19.56 (13.69) 190.35 .01 .42 1.25

a FIQR = Revised Fibromyalgia Impact Questionnaire; HADS = Hospital Anxiety and Depression Scale; SF-36 = SF-36 Health Survey; TAU = treatment as
usual; TSK-11 = Tampa Scale for Kinesiophobia; VAS = Visual Analogue Scale. Effect considering covariate SF-36 baseline scores. ηp 2 = partial ηp 2 as effect
size. d = Cohen d. b Bold type indicates statistically significant group differences. c Bold type indicates large size effect (Cohen d > .80).

mental health, well-being, and physical function.11,13,19–27 and under what circumstances. Frequently, only one-fourth
However, in most cases, the reported effect sizes ranged to one-third of patients receiving group therapy show
from small to moderate magnitudes.18 There are many recent clinically relevant improvement.9 There are some interesting
examples of trials sustaining the efficacy of these treatments initiatives highlighting the need for a paradigm shift that
for improving a wide range of outcomes in fibromyalgia. For propose tailoring treatments to individual characteristics and
instance, a recent uncontrolled pilot study62 examining the measurement-based care and focus on specific therapeutic
efficacy of a multicomponent therapy (exercise therapy plus processes to improve overall effectiveness.9,11,16,64,65
CBT) for fibromyalgia that was similar in duration (12 weeks) We want to highlight that this is the first study, to our
delivered a multidisciplinary team (an occupational therapist, knowledge, to demonstrate the effectiveness of a multicom-
a physical therapist, and a psychologist) yielded significant ponent treatment that specifically integrates PNE in patients
improvements mainly at the 12-week follow-up in functional with fibromyalgia. PNE has been extensively investigated in
status, depressive symptoms, perceived pain, grip strength, different chronic pain conditions,20–33 but its effectiveness
and 6-minute walking test. Notwithstanding, a next step has not been shown before in combination with other non-
in this field is to know what treatment works for whom pharmacological therapies in fibromyalgia patients.
Serrat et al 9

Table 3. Baseline Differences Between Responders and Nonrespondersa

Responders (n = 70) Nonresponders (n = 65) t/χ 2 Pb

General measures
Women, n (%) 69 (98.6) 62 (95.4) 1.19 .27
Age, mean (SD) 53.19 (8.86) 54.82 (8.40) 1.10 .27
BMI (kg/m2 ), mean (SD) 27.15 (5.46) 28.81 (6.32) 1.63 .11
Years of illness, mean (SD) 17.97 (12.64) 16.94 (10.89) −.51 .61
Married or in couple, n (%) 52 (74.3) 40 (61.5) 6.11 .11
Live accompanied, n (%) 64 (91.4) 55 (84.6) 1.50 .22
Secondary studies, n (%) 31 (44.3) 28 (43.1) 3.53 .47
Labor assets, n (%) 15 (21.4) 15 (23.1) 5.51 .70
Disability in process, n (%) 17 (24.3) 22 (33.8) 1.50 .22
Comorbidity
Chronic fatigue, n (%) 60 (85.7) 53 (81.5) .43 .51

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Multiple chemical sensitivity, n (%) 24 (34.3) 23 (35.4) .02 .89
Irritable bowel syndrome, n (%) 32 (45.7) 31 (47.7) .05 .82
Migraines, n (%) 38 (54.3) 39 (60.0) .45 .50
Medication, n (%)
>2 medications, n (%) 23 (32.9) 31 (47.7) 4.81 .31
Primary outcome, mean (SD)
FIQR_Functional impairment (0–100) 75.43 (12.37) 73.9 (9.76) 1.13 .26
Secondary outcome, mean (SD)
VAS Pain (0–10) 7.87 (.98) 8.20 (1.09) 1.85 .07
VAS Fatigue (0–10) 7.69 (1.53) 8.14 (1.31) 1.84 .07
TSK-11 Kinesiophobia (11–44) 30.57 (7.26) 32.35 (6.80) 1.47 .14
HADS Anxiety (0–21) 13.79 (4.11) 14.52 (4.64) .98 .33
HADS Depression (0–21) 11.67 (4.08) 13.69 (4.88) 2.61 .01
SF-36 Physical function (0–100) 20.00 (10.60) 24.69 (18.07) 1.82 .07
a The values represent means and SD or frequency (f) and percentages (%) in their respective order of presentation. The ranges of measurements corresponding
to each instrument are presented in parentheses. BMI = body mass index; FIQR = Revised Fibromyalgia Impact Questionnaire; HADS = Hospital Anxiety and
Depression Scale; SF-36 = SF-36 Health Survey; TSK-11 = Tampa Scale for Kinesiophobia; VAS = Visual Analogue Scale. b Bold type indicates statistically
significant group differences.

Another major finding of our study was the significantly also once it is over. In our opinion, the inclusion of booster
higher baseline score in the depression scale in the group of sessions seems a recommendable option.
nonresponders. A recent study on multicomponent therapy in
fibromyalgia showed dropouts were associated with moderate
to severe depression.62 Although our findings require further Limitations and Strengths
replication, they warn of the importance of assessing depres- First, therapy sessions were not audio- or videotaped in this
sion levels in fibromyalgia patients, because mood alterations study. At least 20% of the sessions should be videotaped
might buffer treatment effects. Patients with high depression in future studies to assess treatment fidelity and therapist
levels may require more individualized treatment by mental competence. Second, practicing skills outside of the group
health professionals before implementing group multicompo- is considered of crucial importance for improving outcomes
nent therapy. in these types of therapies; however, treatment adherence to
At present, there are no highly effective treatments for home practice was not specifically analyzed in this study. In
fibromyalgia. However, using the approach presented in this our opinion, it may be worthwhile in the future to monitor
paper, 5.4% of the participants showed ≥70% improvement daily home practice and adherence to drugs through a paper-
in their FIQR score, and 51.85% reached the criterion of and-pencil or digital log. Third, as recently highlighted by
≥20% FIQR reduction. These data open up the possibility Ollevier and colleagues,63 there is a need for empirical evi-
of achieving better symptom outcomes in this syndrome with dence for the long-term efficacy of multicomponent therapies.
a paradigm shift in treatment. Future research on this type In our case, it was not possible to follow-up the control group
of multicomponent approach should also focus on long-term beyond a period of 3 months due to ethical reasons. An assess-
clinical outcomes (1- and 2-year follow-ups) compared with ment of the long-term effectiveness of our multicomponent
an active control group as well as the underlying mechanisms treatment is necessary in the context of real-world clinical
involved in the improved outcomes. practice. Fourth, using treatment as usual as control condition
There are some potential reasons for the slight loss of has a number of methodological drawbacks that were very
effectiveness of the multicomponent treatment at follow-up, well explained by Öst.66 Future RCTs should assess the effec-
such as the fact that patients were no longer attending weekly tiveness of the proposed multicomponent program compared
group sessions or may have reduced home practice. It is an with other active non-pharmacological conditions equivalent
important point to explore if this treatment could be effective to the multicomponent intervention in therapy time, thera-
for a long term or some type of periodic treatment is needed pist allegiance, or expectations. Fifth, the multicomponent
to maintain its beneficial effects. Thus, future studies should treatment tested here consisted of the combination of many
focus on how to increase the frequency and quality of home therapeutic ingredients delivered by the same professional.
practice, not only along the 12 weeks of group treatment but Also recommended by Öst,66 at least 3 trained therapists
10 Multicomponent Treatment for Fibromyalgia

should be implicated in RCTs of non-pharmacological ther- Writing: M. Serrat, J.P. Sanabria-Mazo, M. Almirall, M. Musté,
apies, and patients have to be randomized to therapists to A. Feliu-Soler, J.L. Méndez-Ulrich, A. Sanz, J.V. Luciano
examine a potential therapist’s effect on the outcomes. Sixth, Data collection: M. Serrat, J.P. Sanabria-Mazo, M. Musté
in this study, we did not evaluate the acquisition of knowledge Data analysis: M. Serrat, J.P. Sanabria-Mazo, M. Almirall, M. Musté,
and skills in the PNE. It would be necessary that future J.L. Méndez-Ulrich, A. Sanz, J.V. Luciano
Project management: M. Serrat, M. Almirall, M. Musté,
RCTs include an evaluation of the patient’s competencies and
J.L. Méndez-Ulrich
knowledge. Regarding this issue, the revised Neurophysiol- Fund procurement: M. Serrat, M. Musté
ogy of Pain Questionnaire67 might be a good option for Providing participants: M. Serrat, M. Almirall, M. Musté
assessing neurophysiology of pain knowledge. The revised Providing facilities/equipment: M. Serrat, M. Almirall, M. Musté
Neurophysiology of Pain Questionnaire is a psychometrically Providing institutional liaisons: M. Almirall, M. Musté
sound measure that evaluates how patients conceptualize Consultation (including review of manuscript before submitting):
biological mechanisms underpinning their pain. Finally, future M. Serrat, J.P. Sanabria-Mazo, M. Almirall, A. Feliu-Soler, A. Sanz,
“dismantling” studies should identify which of the therapeutic J.V. Luciano

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elements (or combination of them) make the most signifi-
cant contribution to the effects of our treatment before solid
conclusions can be drawn. Recently, methodologists have rec- Funding
ommended “factorial designs” to test the active components This study was supported by Vall d’Hebron Institute of Research
of complex therapies.68 These factorial designs permit to Funding, Autonomous University of Barcelona (Ideas Generation Pro-
explore main effects of components and interactions among gram, Price 2018), and Parc Sanitari Sant Joan de Déu. J.V.L. has a
components. In short, using our multicomponent treatment Miguel Servet contract awarded by the Institute of Health Carlos III
(ISCIII; CPII19/00003). J.P.S.-M. has a PFIS contract from the ISCIII
as an example, patients would be randomized in the RCT
(FI20/00034). A.F.-S. acknowledges the funding from the Serra Húnter
with a factorial design across 4 factors [presence or absence of
program (Generalitat de Catalunya; reference number UAB-LE-8015).
PNE (PNE+ vs PNE−), presence or absence of CBT (CBT+
vs CBT−), presence or absence of PT (PT+ vs PT−), and
presence or absence of MT (MT+ vs MT−)]. This means Ethics Approval
that patients would be randomized to all of the possible
This research was conducted in accordance with the ethical standards
combinations: all 4 components (PNE+; CBT+; PT+; MT+),
set forth in the 1964 Declaration of Helsinki and was approved by the
3 of the 4 components, 2 of the 4 components, 1 of the 4
hospital’s Ethics Committee of Clinical Investigation of the University
components; or none of these components (PNE−; CBT−; Hospital Vall d’Hebron in Barcelona [PR(AG)120/2018]. All partici-
PT−; MT−). This design would allow us to test not only the pants gave written informed consent before randomization.
main effect of each component but also their interactions.
Despite the limitations mentioned above, this is the first
study, to our knowledge, to demonstrate the potential effec- Clinical Trial Registration
tiveness of a multicomponent treatment that specifically inte-
This study was registered at ClinicalTrials.gov (NCT04284566).
grates PNE in patients with fibromyalgia. There are many
studies that support the individual effectiveness of each of the
treatment components that constitute this multicomponent Disclosures
therapy.11,13–15,19–28,69–74 The greatest strengths of this RCT
The authors completed the ICMJE Form for Disclosure of Potential
include the fact that it is based on an empirically validated
Conflicts of Interest and reported no conflicts of interest. An unre-
framework involving a large sample size. We also observed a viewed version of this article was posted on PsyArXiv Preprints.
relatively low dropout rate, possibly as a result the adequate
use of adherence strategies (phone and email contacts) estab-
lished with some participants to avoid treatment attrition as References
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