Study Protocol (Artículo de Ejemplo)

Feliu-Soler et al.
BMC Complementary and Alternative Medicine (2016) 16:81

DOI 10.1186/s12906-016-1068-2
STUDY PROTOCOL Open Access
Cost-utility and biological underpinnings of

Mindfulness-Based Stress Reduction (MBSR)
versus a psychoeducational programme
(FibroQoL) for fibromyalgia: a 12-month
randomised controlled trial (EUDAIMON
study)
Albert Feliu-Soler1,2, Xavier Borràs3, María T. Peñarrubia-María4,5, Antoni Rozadilla-Sacanell6, Francesco D’Amico7,
Rona Moss-Morris8, Matthew A. Howard9, Nicolás Fayed10, Carles Soriano-Mas2,11,12, Marta Puebla-Guedea5,13,
Antoni Serrano-Blanco1,5, Adrián Pérez-Aranda1, Raffaele Tuccillo14 and Juan V. Luciano1,5*
Abstract
Background: The EUDAIMON study focuses on fibromyalgia syndrome (FMS), a prevalent chronic condition
characterized by pain, fatigue, cognitive problems and distress. According to recent reviews and meta-analyses,
Mindfulness-Based Stress Reduction (MBSR) is a promising therapeutic approach for patients with FMS. The
measurement of biomarkers as part of the analysis of MBSR effects would help to identify the neurobiological
underpinnings of MBSR and increase our knowledge of FMS pathophysiology. The main objectives of this 12-month
RCT are: firstly, to examine the effectiveness and cost-utility for FMS patients of MBSR as an add-on to treatment
as usual (TAU) versus TAU + the psychoeducational programme FibroQoL, and versus TAU only; secondly, to
examine pre-post differences in brain structure and function, as well as levels of specific inflammatory markers in
the three study arms and; thirdly, to analyse the role of some psychological variables as mediators of 12-month
clinical outcomes.
Methods: Effectiveness, cost-utility, and neurobiological analyses performed alongside a 12-month RCT. The
participants will be 180 adult patients with FMS recruited at the Sant Joan de Déu hospital (St. Boi de Llobregat, Spain),
randomly allocated to one of the three study arms: TAU + MBSR vs. TAU + FibroQol vs. TAU. A comprehensive
assessment to collect functional, quality of life, distress, costs, and psychological variables will be conducted
pre-, post-intervention, and at 12-month post-intervention. Fifty per cent of study participants will be evaluated at
pre- and post-treatment using Voxel-Based Morphometry, Diffusion Tensor Imaging, pseudo-continuous Arterial Spin
Labeling, and resting state fMRI. A cytokine multiplex kit of high-sensitivity will be applied (cytokines IL-6, IL-8, IL-10 +
high-sensitivity CRP test).
(Continued on next page)
* Correspondence: jvluciano@pssjd.org
1
Teaching, Research & Innovation Unit, Parc Sanitari Sant Joan de Déu, C/Dr.
Antoni Pujadas 42, 08830, Sant Boi de Llobregat, Barcelona, Spain
5
Primary Care Prevention and Health Promotion Research Network (RedIAPP),
Madrid, Spain
Full list of author information is available at the end of the article
© 2016 Feliu-Soler et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Feliu-Soler et al. BMC Complementary and Alternative Medicine (2016) 16:81 Page 2 of 16
(Continued from previous page)

Discussion: The findings obtained from this RCT will indicate whether MBSR is potentially cost-effective for FMS and
contribute to knowledge of any brain and inflammatory changes associated with MBSR in FMS patients. Specifically, we
will determine whether there are morphometric and functional changes associated with participation in MBSR in brain
regions related to meta-awareness, body awareness, memory consolidation-reconsolidation, emotion regulation and in
networks postulated to underpin the sensory-discriminative, cognitive-evaluative and affective-motivational aspects of
the pain experience.
Trial registration: NCT02561416. Registered 23 September 2015.
Keywords: Fibromyalgia, Mindfulness-Based Stress Reduction, Psychoeducation, Neuroimaging, Cytokines, Cost-utility
Background connectivity were associated with pain reduction in FMS

Fibromyalgia (FMS) is a debilitating syndrome usually di- [12], suggesting a key role in the etiology of the disease.
agnosed in women between the ages of 20 and 50 years Reduced resting connectivity within the somatosensory
[1]. It is characterised by multifocal pain, fatigue, disturbed system and increased connectivity between the DMN and
sleep, cognitive problems, and high levels of distress [2]. A somatosensory processing regions such as S2 have been re-
survey performed in five European countries indicated cently reported [13], which may suggest that a general
that the estimated overall prevalence of FMS is 2.9 % in weakening of sensory integration may be also underlie
the general population [3]. Patients with FMS typically clinical pain in patients with FMS.
present comorbidities with psychiatric disorders such as In addition to the aforementioned abnormalities in the
anxiety (13–63.8 %) and depressive disorders (20–80 %) CNS, imbalances in inflammatory markers have also
[4]. In addition, FMS is associated with high direct (med- been also observed in FMS. Specifically, higher levels of
ical visits, multiple prescriptions of medications, etc.) and pro-inflammatory cytokines (IL1, IL6, and IL8) and
indirect (absenteeism, work loss, etc.) costs in industria- lower levels of anti-inflammatory cytokines (IL4 and
lised countries [5]. Among chronic pain conditions, FMS IL10) have been reported [14–16]. This cytokine imbal-
causes the highest rates of unemployment, the highest rate ance may produce a chronic inflammatory state in the
of incapacity benefits claim rate, and the greatest number CNS and the peripheral nervous system, facilitating the
of days absent from work [6]. FMS represents a great sensitisation of peripheral nerves to nociceptive stimuli,
challenge for health professionals because of the lack of increasing hypothalamic-pituitary-adrenal axis activity and
optimal treatment options. The effectiveness of pharmaco- the synthesis of prostaglandin and substance P, which
logical interventions is generally limited and more ubiqui- lower the pain threshold [14]. Furthermore, cytokines
tous effects have been found for non-pharmacological have further effects on the CNS by altering synthesis, re-
treatments [7]. uptake, and release of neurotransmitters involved in the
The Central Nervous System (CNS) seems to play a perception, and affective, cognitive and motivational regu-
crucial role in the pathogenesis of FMS [1, 8]. In this lation of pain, contributing to structural and functional
regard, structural and functional brain abnormalities in brain changes and to the perpetuation of pain [17]. Add-
several areas related to pain and stress response regula- itionally, pro-inflammatory cytokines augment tryptophan
tion (e.g., anterior cingulate cortex, insula, parahippo- metabolism, which may boost affective symptoms in FMS
campal gyrus, prefrontal cortex, somatosensorial cortex) [18–20] and activate glial cells that release a combination
have been observed in patients with FMS. Specifically, of substances into the cerebral spinal fluid that are associ-
significant grey matter reductions in the prefrontal cor- ated with pain amplification (P substance, glutamate,
tex, anterior cingulate cortex and insular cortex have nerve growth factor, and brain-derived neurotrophic
been reported [9]. Such alterations may contribute to factor) [21].
the impaired control of pain and abnormal processing of Contemplatives have pointed out that the practice of
painful stimuli [8]. Alterations in functional connectivity meditation reduces the experience of pain by controlling
within the brain’s pain inhibitory network; the default- expectations, the nature and orientation of attention to-
mode network (DMN) and the executive attention network wards the experience, and its related emotional response.
(EAN), as well as greater intrinsic connectivity between the Mindfulness-based interventions (MBIs) were conceived
insula and the DMN and EAN were also reported [10, 11]. in the late 1970s from the effort to integrate Buddhist
Furthermore, higher spontaneous pain at the time of the meditation into western psychological practice. In the
scan was found to be correlated with greater intrinsic last decade, there has been growing interest in the effect-
connectivity between the insula and both the DMN and iveness of MBIs for a range of physical and mental con-
the EAN [11]. Moreover, reductions in insula-DMN ditions [22], including chronic pain. Veehof et al. [23], in
a meta-analysis in chronic pain patients, showed that both during resting and when practicing mindfulness.
MBIs have significant effects on pain intensity, depression, Similarly, Jang et al. [31] reported greater functional
anxiety, physical wellbeing, and quality of life. Given that connectivity (at rest) in some areas of the DMN (i.e., the
there are no curative treatments available for patients with medial prefrontal cortex) in individuals with meditative
FMS [1], the putative use of MBIs as coadjuvants of usual experience, suggesting that meditation practice would be
care is highly promising. associated with functional changes in DMN areas even
Bawa and colleagues [24] recently found limited evi- when not practicing meditation. Furthermore, functional
dence for the effectiveness of MBIs in chronic pain. brain changes (e.g., increases in left frontal activation,
Their meta-analysis revealed that MBIs have a positive higher activity in insula, secondary somatosensorial cortex,
impact on perceived pain control although there was no anterior cingulate cortex, lower activity in right amygdala
evidence of a benefit in clinical outcomes. Separate sub- and in several DMN regions) have been observed after
group analysis found evidence of improved physical standard MBSR [32]. All the brain changes following mind-
functioning and quality of life for MBIs versus inactive fulness training are associated with increased learning and
control conditions. When compared to active control memory processes, emotion regulation, self-referential pro-
conditions, the effect of MBIs was equivalent to the ac- cessing, and perspective taking, an augmented experiential,
tive comparator. However, results were inconclusive present-focused mode of self-reference, higher interocep-
given that the included studies generally involved small tive awareness, more accurate processing of exteroceptive
samples. In line with these findings, a systematic review sensory events, higher attentional control and reduced
of 10 studies [25] indicated that although MBIs provide conceptual processing [29, 32, 33]. Interestingly, mindful-
some significant physical and psychological benefit for ness training seems to impact on pain experience as signifi-
patients with FMS, the divergence in the outcomes mea- cantly lower pain unpleasantness and intensity ratings
sured, sample sizes, and data presented failed to estab- (compared to resting state) were found after a brief mind-
lish definitive conclusions about the effectiveness of fulness training session when meditating in the presence of
MBIs. The specific effectiveness of Mindfulness-Based painful stimulation [34]. In this study, reductions in pain
Stress Reduction (MBSR) for FMS patients was evalu- intensity ratings were found to be associated with increased
ated by Lauche and colleagues [26], who found that activity in areas involved in the cognitive and affective
MBSR improves quality of life and reduces pain in the regulation of nociceptive processing (anterior cingulate
short term. Nevertheless, further high-quality RCTs are cortex and insula) and reductions in pain unpleasantness
still necessary because of the considerable methodo- ratings were associated with increased activity in brain
logical limitations of the meta-analysed studies (e.g., areas (orbitofrontal cortex) involved in reframing the con-
absence of randomization, high attrition rates, or small textual evaluation of sensory events and diminished thal-
sample sizes). amic activity, which may reflect a change in the interaction
There is a great amount of evidence of structural between afferent input and executive-order brain areas.
changes in experienced meditators compared to individuals Improvements in immune function after mindfulness
without meditative experience [27, 28]. These changes training have also been reported. In this regard, reduced
would be indicative of increases in meta-awareness (fronto- psychophysiological stress and inflammatory responses
polar cortex), exteroceptive and interoceptive body aware- (levels of the pro-inflammatory cytokine IL-6, C reactive
ness (sensory cortices and insula), memory consolidation protein, or in the expression of pro-inflammatory genes
and reconsolidation (hippocampus), self and emotion regu- related to NF-κB factor) have been reported after mindful-
lation (anterior, mid cingulate and orbitofrontal cortices), ness training [35–37]. For instance, there is some evidence
and intra- and interhemispheric communication (superior of beneficial effects of mindfulness training on cell-
longitudinal fasciculus, corpus callosum) associated with mediated immunity in patients with cancer [38], and HIV
meditation. Structural changes in specific brain areas (e.g., [35, 39]. Studies with larger samples and more adequate
hippocampus, posterior cingulate cortex, the temporo- methodologies (e.g., using more rigorous control groups,
parietal junction, and cerebellum) have been reported after longer follow-ups) are needed to better ascertain the
a MBSR intervention [29]. effects of MBSR on inflammatory processes. A recent
Significant differences in brain function have been ob- meta-analysis [40] examined the impact of mind-body
served between meditators and non-meditators. In this treatments (including meditation, Tai Chi, Qi Gong, and
regard, Brewer et al. [30] found reduced activation of Yoga) on inflammatory markers, finding that when all re-
two main DMN nodes (posterior cingulate cortex and sults from healthy and heterogeneous clinical samples
medial prefrontal cortex) and activations of the medial were pooled, there was some evidence supporting an anti-
prefrontal cortex, insula, and temporal lobes during inflammatory effect of mind-body treatments.
meditation in individuals with meditative experience, There is currently a total absence of empirical evi-
showing a differential pattern of functional connectivity dence regarding the cost-effectiveness of MBIs for FMS
syndrome. Worldwide, mindfulness research is rapidly will undergo neurobiological evaluations (neuroimaging
expanding and being applied in different contexts, and and inflammatory markers).
there has been a call for more health economics research.
Bearing in mind that costs are of crucial importance for Participants
policy-makers, who usually consider as first-choice treat- A total of 180 FMS patients will be recruited from the
ment those interventions with the lowest cost per quality- Rheumatology service at Sant Joan de Déu Hospital (St.
adjusted life-year (QALY), economic evaluations of MBIs Boi de Llobregat, Spain). Sample size is established on
in FMS should be carried out to ensure (if cost-effective) the basis of a previous meta-analysis of controlled MBSR
their implementation in healthcare systems. Moreover, the trials [45] in which a mean effect size of d = 0.53 was
evidence for mindfulness as the causal factor in structural found. This effect size results in 1-b = 0.89 (alpha = 0.05)
and functional brain changes [27, 32] and the mechanistic for N = 60 patients per group (180 patients overall).
effects of inflammatory markers on the therapeutic ef- With 20 % maximal attrition, the power remains 1-b =
fects of mindfulness remain tenuous, so further work is 0.82. The estimated sample size for the study of bio-
needed to gain a deeper understanding of how mindful- markers (neuroimaging and cytokines) was 30 partici-
ness actually works. pants per condition, this sample size is considered
Taking these issues into consideration the aim of this adequate given that approximately 20–40 participants
12-month randomised, controlled trial (RCT) is three- (in between-group designs) are necessary to detect a
fold: firstly, to examine the effectiveness and cost-utility change of 15 % in cerebral blood flow in regions of inter-
for FMS patients of MBSR as an add-on to treatment as est (ROI) by means of pseudo-continuous Arterial Spin
usual (TAU) versus a psychoeducational programme Labeling (pCASL) [46].
(FibroQoL) that recently that has been shown to be a
cost-effective adjuvant to TAU [41]. Secondly, to exam- Eligibility criteria and Multi-stage recruitment process
ine pre-post neurobiological changes in brain structure For this study, we use a database with the medical records
and function, as well as in levels of some pro- and anti- of FMS patients referred from local general practices to
inflammatory markers in the three study arms (TAU vs the Rheumatology Service at Parc Sanitari Sant Joan de
TAU + MBSR vs TAU + FibroQoL). Thirdly, to analyse Déu to confirm diagnosis. The sample pool consists of all
the role of specific process variables (facets of mindful- FMS patients included in this database between January
ness, pain catastrophism, psychological inflexibility, and 2010 and September 2015 (Nsample pool = 531). Thus, all
self-compassion) as mediators of long-term clinical patients in the database were diagnosed with FMS (ac-
improvement. cording to the American College of Rheumatology, ACR
1990 criteria) by rheumatologists from Parc Sanitari Sant
Joan de Déu.
Methods Patients meeting the following criteria will be eligible:
Study design 1. Patients of both genders between 18–65 years-old. 2.
This RCT protocol was developed following the Standard Able to understand the Spanish language. 3. Provide
Protocol Items: Recommendations for Interventional Trials informed consent to participate. The following general
(SPIRIT) [42] and was recorded in the ClinicalTrials.gov exclusion criteria will be applied: 1. Participation in
trial register in September 2015 (NCT02561416). We de- other RCTs. 2. Presence of cognitive impairment accord-
signed a 12-month, parallel group, randomised (using a ing to the Mini Mental State Examination (MMSE < 27).
computer-generated randomisation list), single-blind, con- 3. Receiving psychological treatment during the previous or
trolled trial (RCT) with three treatment arms. The Consoli- current year. 4. Reporting previous experience in medita-
dated Standards of Reporting Trials 2010 (CONSORT) tion or other mind-body therapies. 5. Comorbidity with
[43] and the Consolidated Health Economic Evaluation severe mental or medical disorders which interfere with
Reporting Standards (CHEERS) [44] will be followed. The treatment (severe medical illness, psychotic symptoms, sub-
three treatment arms are: stance abuse). 5. Unable to attend group sessions. 6. Preg-
nancy. 7. Involved in ongoing litigation relating to FMS.
1. TAU + MBSR Usual contraindications for scanning at 3Tesla and for
2. TAU + FibroQoL measuring cytokine levels have been taken into account
3. TAU to establish the following additional inclusion/exclusion
criteria for the biomarkers sub-study:
Patients from the three study arms will receive TAU;
given that MBSR and FibroQoL were originally devel- Inclusion criteria: 1. Female gender. 2. Right-handed.
oped as complements to usual care, not as substitutes Exclusion criteria: 1. Infection/cold symptoms on the
for it. Fifty percent of the participants in each study arm day of blood extraction. 2. Needle phobia. 3. BMI >
36 kg/m2 or weight > 110Kg. 4. Neoplastic illnesses, Subsequently, two highly trained clinical psychologists
infection, cardiopulmonary, vascular, or other internal (not involved with the treatment and blind to group al-
conditions (collected from the medical history). 5. Use location) will make an appointment with those patients
of oral or local corticosteroids or anticytokine therapy. who met the inclusion criteria and agreed to participate
6. Consuming more than 7 caffeine units per day (1 in the study. The psychologists will check all inclusion/
caffeine drink will be permitted on the day of the study. exclusion criteria (both general and additional for the
8. Smoking more than 5 cigarettes per day (no smoking biomarkers study) and will perform all face-to face inter-
will be permitted on the scanning visit days prior to views. As mentioned above, study participants will be
scanning or whilst in the centre). 9. Cannot be randomised to one of the three conditions (i.e., TAU,
evaluated by means of magnetic resonance imaging TAU + MBSR, TAU + FibroQoL). Both MBSR and Fibro-
(MRI) (due to claustrophobia, metal implants, pace- QoL are conducted in a group format (up to 15 people
makers, etc.). 10. Acute pain not -related to FMS on in each group). To balance the number of participants
the day of the study (e.g. headache, lumbar pain). 11. eligible for the biomarkers sub-study across the three
Being pregnant or breastfeeding. It is important to arms, stratified randomisation will be performed. The
point out that patients presenting neuroradiological proportion of eligible participants for the biomarkers
alterations during MRI at baseline will be excluded evaluation and those only meeting criteria for the gen-
from the sub-study. Patients will be allowed to continue eral study will be pre-fixed at 1:1 in all samples. Four
with their stable medical treatment although, to reduce treatment waves (N = 45 each) will be carried out to
the effects of medications on biomarkers, they will be achieve the required final sample (N = 180).
required to refrain from taking occasional (rescue) Three-five days after the clinical evaluation, patients
analgesic drugs (e.g., non-steroidal anti-inflammatory assigned to the biomarkers sub-study will be contacted
drugs, paracetamol) 72 h prior to the MRI and for blood extraction and MRI completion. To minimise
blood extraction. Changes in pharmacological/ circadian variability in immunological markers, all whole
non-pharmacological treatment will be monitored blood samples will be collected between 8–9 am. Interven-
throughout the study and may be a cause of drop-out tions will be conducted using a parallel design to reduce
from the final analyses. seasonal variability in the study measures. The participants
will be interviewed at baseline, after treatment, and at 12-
Procedure month follow-up (56 weeks after randomisation). The
The potential FMS participants will be screened through neuroimaging tests and cytokine measurements will be
an initial telephonic interview by one of the authors performed at baseline and after treatment. A flowchart of
(A.F.S), who will provide a general overview of the study. participants is displayed in Fig. 1.
Fig. 1 Flowchart of participants in the EUDAIMON study

Interventions not directed at symptom reduction but more fundamen-

Intervention group (TAU + MBSR; see Table 1) tally towards altering how perceptible mental processes
We will use the MBSR protocol developed at the and content are experienced, towards greater awareness,
University of Massachusetts Medical School, USA. MBSR acceptance, and tolerance of the unavoidable vagaries of
[47] is intensive, structured training in mindfulness life, which facilitate enhanced psychological wellbeing,
meditation which aims to help patients increase their even in the face of continued symptoms. The eight 2 h
awareness of the present experience and to relate to their MBSR sessions (once a week) will be performed in groups
physical and psychological conditions in a more accepting (n = 15 per group) and will be led by four accredited
and non-judgmental way. The standard MBSR programme MBSR instructors (one per group) that have undergone
consists of 8 weekly sessions of around 2.5 h each and MBSR training, which will enable an analysis of possible
homework for 45 min a day, 6 days a week, even though instructor effect on the outcomes, as recommended by
several modifications in sessions, homework, and total dur- Öst [48]. A book with MBSR manual and CDs with guided
ation can be observed among distinct courses for various mindfulness practice sessions will be provided to the par-
patient populations. MBSR usually has three main compo- ticipants. In addition, we will reinforce MBSR treatment
nents including a “body scan”, which involves a gradual adherence by inviting participants to use a Mindfulness
sweeping of attention through the entire body from feet to smartphone app developed in 2014 at the University of
head, focusing non-critically on any sensation or feeling in Zaragoza, Spain. The app has been scientifically validated
body regions and using periodic suggestions of breathing by the Aragon Institute of Health Sciences. It is the first
awareness and relaxation; “sitting meditation” which in- app that tracks the state of mindfulness and provides feed-
volves both mindful attention to breathing or on the rising back on how mindful the person is during mindfulness
and falling abdomen as well as other perceptions, and a meditation sessions. It also provides instruction in several
state of non-judgmental awareness of cognitions and of mindfulness techniques by means of well-designed videos
the stream of thoughts and distractions that continuously and audio recordings.
flow through the mind; and “Hatha yoga” practice, which
includes breathing exercises, simple stretches, and pos- Treatment as Usual control group (TAU)
tures designed to strengthen and relax the musculoskeletal In Spain, treatment provided is mainly pharmacological
system. In addition to in-class mindfulness exercises, par- and adjusted to the symptomatic profile of the patients
ticipants are encouraged to engage in home mindfulness with FMS. Counselling about aerobic exercise adjusted
practice and attend an all-day intensive mindfulness medi- to patients’ physical limitations is usually provided.
tation retreat. The main premise of MBSR is that with re-
peated training in mindfulness meditation, individuals will Active control group (TAU + FibroQoL)
eventually learn to be less reactive and judgmental toward The FibroQoL is a psycho-educational programme for
their experiences, and more able to recognise, and break FMS patients based on a consensus document drawn up
free from, habitual and maladaptive patterns of thinking by the Health Department of Catalonia and shown to be
and behaviour. It is important to mention that MBSR is cost-effective in a previous study [41]. This group-based
Table 1 Session outlines for Mindfulness-Based Stress Reduction (MBSR) group treatment protocol
Session MBSRa
1 Recognising the present moment. Beginner’s Mind, Introduction to Programme, Foundations of Mindfulness, More right with you than
wrong, Introduction to Body Scan meditation, Intake.
2 Engaging with the breath. Patience, Basic Training, Working with perceptions, The Wandering Mind, Mindful Yoga.
3 Practice, practice, practice. Non-Striving, Mindfulness of Breathing Meditation, Lying Yoga, Attention vs. Disattention, Pleasant Events.
4 Stress and the flow of emotions. Stressful Events, Responding vs. Reacting, Seeing Our Patterns, Sitting Meditation, Standing Yoga, Research
on Stress & Stress Hardiness.
5 Stress and thoughts: finding another place to stand. Working with Thoughts & Emotions, Group Reflections on Halfway Point, Small & Large
Groups, Sitting Meditation, and Qigong.
6 Interpersonal mindfulness/mindful communication. Mindfulness & Communication, Avoiding Difficulty vs. Entering and Blending, Loving
kindness Meditation, Walking Meditation. Daylong Sessiona: Putting it All Together.
7 Applying mindfulness. Sitting Meditation, Qigong, Trust & Self-Reliance, Mindful Consumption, Making the Practice Your Own, Mindfulness
in Everyday Life.
8 Making mindfulness a part of your life. Sitting Meditation, Walking, The Class Never Ends: Practice for the rest of Your Life, Course
Evaluations, Group Reflection & Checking Out.
a
NOTE: Daily home practice of 30–45 min. duration, 6 days per week is encouraged (home practice guided by a workbook and audiotapes). In accordance with
the MBSR protocol developed at the University of Massachusetts Medical School, 1 day-long meditation retreat will be held between sessions 6 and 8 of
the programme
programme is divided into two parts: The first part is led – Willingness to experience: people during hypnosis,
by three general practitioners, one rheumatologist and one people are more amenable to unintentionally
psychologist. It includes updated information about patho- experience new perspectives; this feature is defined
physiology, diagnosis, and management of FMS symptoms as suggestibility.
(4 sessions). The second part is led by a psychologist and – Flexibility of Time-Space Relationship: experience of
includes training in self-hypnosis (4 sessions). In each of distortion of subjective time or temporary phenomena
these sessions, a distinct self-hypnosis technique is ex- such as regression or projection into the future.
plained and practiced. The goal of these techniques is – Alteration of sensory experience: the person may
to generate a state of deep relaxation, explore the sen- experience changes in visual perception (e.g. tunnel
sations produced by one’s own body, achieve control vision), in hearing, in physical sensations (anesthesia,
over the body and pain, and imagine the one’s life in heaviness, lightness, size and position of body parts),
the future without pain. Many authors have emphasised loss of movement, or hands and/or fingers may
the need to consider aspects of identity in order to occasionally move involuntarily (Table 2).
understand the phenomena of chronic pain [49]. There-
fore, it is especially useful to explore all the connections Study measures
between the identity of a person, the perception of his/ Study participants will complete the following instru-
her body, and attitudes towards therapy in general. If ments as part of a paper-and-pencil battery of measures
we focus on the theory that each human activity is a (see Table 3):
process of creating meaning [50], people should assem-
ble informal theories about, for instance, themselves, – Sociodemographic-clinical questionnaire. The
people or health. Their reactions to events such as bod- following information will be collected: gender, age,
ily sensations or interpersonal experiences are mediated ethnic group, marital status, living arrangements,
by their interpretations [51]. educational level, employment status, and annual
Some clinicians and scholars [51] highlight certain per- income. Relevant clinical variables, such as family
sonality traits in patients with FMS, including an exces-
sive sense of responsibility, extreme effort to please
others, personal sacrifices made for others, little time set Table 2 Session outlines for the FibroQoL group treatment
aside for themselves, and difficulty setting limits for protocol
others. These characteristics, as well as other difficulties Session FibroQoLa
showed by these patients, are discussed within the group 1 Introduction and general information. Patients’ Expectations.
and are part of the hypnotic inductions for each session. History and epidemiology of the syndrome. Common symptoms
in FM. Physiological mechanisms involved in the genesis of pain.
The group context has been considered an implementer
2 Collect information on the goals of each patient, explain
of hypnotic response since the 18th century; the fact that differences between physical and emotional pain, clarify
someone in the group evidences minimal response raises differences between hypnosis and self-hypnosis, administer
expectations among the others and this reaction can in- hypnotisability test, hypnosis “safe place”.
crease the hypnotic susceptibility of all group members. 3 Diagnosis and prognosis. Pharmacological and
The naturalistic hypnosis method requires that therapist non-pharmacological treatments. Current model of health care
in Catalonia and units specialised in the treatment of FM patients.
is well trained in observation and should have a high
degree of sensitivity when using the material provided 4 Discussion of goals and the difficulties that obstruct them,
emphasize common personality characteristics, highlight
by the patients. The reference model is Ericksonian exceptions to the problem, hypnosis “candle and bubbles”.
hypnosis [52]. According to Erickson, a patient can use
5 Strategies to increase self-esteem and regulate emotions. Pain
his/her own life experience, resources and prior learn- experience and recurrent invalidation. Social support from family
ing therapeutically. The focus of Ericksonian hypnosis and close friends.
is to breakdown non-useful patterns and/or limit be- 6 Exploration of possible changes, difference between acute and
haviours that prevent the construction of new meaning. chronic pain, hypnosis: “imagination of a journey”.
Some typical properties of hypnosis facilitate this work, 7 Reviews the goals, ask for a future possible change (the miracle
for example: question), commitment to consolidation of the changes, hypnosis:
“watch a photo album”.
8 Benefits of physical exercise in FM and closing remarks
– Experience attention absorption: the person is
a
absorbed in an aspect of context, stops paying NOTE: The current FibroQoL version contains eight 2-h sessions instead of 9.
The multidisciplinary team decided to dismantle the FibroQoL program,
attention to irrelevant stimuli. eliminating the session focused on “Holistic Medicine” because it contained some
– Changing the intensity of the experience: the information about meditation/mindfulness. Thus, both MBSR and FibroQoL
are structurally equivalent, which provides a comparison of MBSR with an
sensorial and emotional experiences, linked to intervention that matches MBSR in non-specific factors, but does not contain
memories, are stronger. mindfulness ingredients
Table 3 Study periods at which measures and data are collected

Study measures Baseline During treatment 2 months 12-months
Demographic information (gender, age, etc.) X
History of FMS (years of illness) X
Contact details X
SCID-I (depression module) X
Screening measures
MMSE (cognitive impairment) X
Primary outcome measure
FIQR (functional impairment) X X X
Secondary outcome measures
FSDC (fibromyalginess) X X X
HADS (anxiety and depression) X X X
PSS-10 (perceived stress) X X X
MISCI (subjective cognitive impairment) X X X
EQ-5D-5L (quality of life) X X
CSRI (health economic evaluation) X X
FFMQa (mindfulness facets) X X X
PCSa (pain catastrophizing) X X X
PIPSa (psychological inflexibility) X X X
a
SCS-12 (self-compassion) X X X
Other measures
Structural + Functional Neuroimaging data X X
Inflammatory data X X
CEQ (Expectation/Satisfaction with treatment) X (EXP) X (SAT)
PGIC & PSIC (Impression of change) X X
Treatment attendance form: Attendance at each scheduled MBSR/FibroQoL session X
Log of MBSR and FibroQoL practices X
Treatment fidelity (review of video-taped MBSR sessions) & monitoring of adverse events X X X
CEQ Credibility/Expectancy Questionnaire, CSRI Client Service Receipt Inventory, EQ-5D-5L EuroQoL questionnaire, FFMQ Five Facet Mindfulness Questionnaire,
FIQR Revised Fibromyalgia Impact Questionnaire, FSDC Fibromyalgia Survey Diagnostic Criteria, HADS Hospital Anxiety and Depression Scale, MISCI
Multidimensional Inventory of Subjective Cognitive Impairment, MMSE Mini-Mental State Examination, PCS Pain Catastrophizing Scale, PGIC & PSIC Patient Global
and Specific Impression of Change, respectively, PIPS Psychological Inflexibility in Pain Scale, PSS-10 Perceived Stress Scale, SCID-I Structured Clinical Interview for
DSM Axis I Disorders, SCS-12 Self-Compassion Scale
a
Secondary outcome measures that also considered process variables
Inflammatory data = Cytokines Th1: IL-6, IL-8; cytokines Th2: IL-10; + high-sensitivity CRP test
Structural and Functional Neuroimaging = Voxel-Based Morphometry, Diffusion Tensor Imaging, pCASL, and rs-fMRI
and personal medical history, years of FMS diagnosis a “probable case” of cognitive impairment when the
and comorbid conditions will also be assessed. score is less than 27 points.
– The Structured Clinical Interview for DSM Axis I
Clinical characteristics and screening measures Disorders (SCID-I) [55]. Clinical diagnosis of mood
disorders according to DSM-IV diagnostic criteria
– The Mini-Mental State Examination (MMSE) will be confirmed using the research version of the
[53, 54] is a 30-item questionnaire designed to SCID-I (mood disorders module).
measure cognitive impairment that is widely used
in older adults. The MMSE includes tests for Primary outcome measure
orientation, memory, concentration, and visuospatial
ability. In non-geriatric populations (≤65 years), – The Revised Fibromyalgia Impact Questionnaire
such as our study sample, the threshold that suggests (FIQR) [56, 57] includes 21 individual items that are
all answered on an 11-point numeric rating scale days taking the drug, the total dosage consumed,
from 0 to 10, with 10 reflecting greater impairment. the reasons for changing the drug, and adherence.
The time frame is the previous 7 days and the items 2. Service receipt. We will collect information about
are distributed into three associated domains: “physical emergency services, general medical in-patient hospital
function” (9 items); “overall impact” (2 items that admissions and out-patient health care services.
address the overall impact of FM on functioning Patients will also be asked about type and number
and symptom severity); and “severity of symptoms” of diagnostic tests administered. As shown in
(10 items; pain, energy, stiffness, quality of sleep, Table 3, the CSRI will be administered at baseline
depression, memory problems, anxiety, tenderness and at a 12-month follow-up; on both occasions,
to touch, balance problems, and sensitivity to loud the previous 12 months will be reviewed.
noises, bright lights, odours, and cold temperatures). – The EuroQoL-5D questionnaire (EQ-5D-5L) [63]
The scoring system is straightforward: the physical is a widely used health-related quality of life
function domain (0 to 90) is divided by 3, the overall instrument with a non-disease-specific classification
impact domain (0 to 20) is not transformed, and the system composed of 2 parts: Part 1 is a self-reported
severity of symptoms domain (0 to 100) is divided by description of health problems classified into five
2. The FIQR total score (0 to 100) is obtained by dimensions. Patients mark one of five degrees of
adding the three domain scores. The FIQR has been severity in each dimension. The time frame is the
shown to be a psychometrically sound instrument, is day of responding. Part 2 records the current subject’s
clinically useful as it can be completed by patients in health on a Visual Analogue Scale (VAS); a vertical
less than 2 min and scored in approximately 1 min, is 10 cm line on which the best and worst imaginable
recommended as a primary efficacy endpoint measure health states score 100 and 0, respectively.
in FMS clinical trials, and is the “gold standard” – The Hospital Anxiety and Depression Scale (HADS)
assessment measure for multidimensional functional [64, 65] was originally developed to quantify the
status in FMS patients [58]. severity of anxiety and depressive symptoms in
non-psychiatric hospital patients The HADS includes
Secondary outcome measures and process measures a total of 14 items that assess anxiety (HADS-A) and
depressive (HADS-D) symptoms, with 7 items in each
– The Fibromyalgia Survey Diagnostic Criteria (FSDC) subscale. Each item is answered on a four-point
[59, 60] is a 6-item self-report questionnaire that (0-to-3) scale so that possible scores range from
registers the key symptoms of FMS according to the 0 to 21 for both anxiety and depressive symptoms,
latest revision of the ACR. It includes assessment with higher scores indicating greater severity.
through the Widespread Pain Index (WPI) identifying – The Perceived Stress Scale (PSS-10) [66] is a 10-item,
19 body areas (jaws, shoulders, upper arms, lower self-administered instrument that measures the
arms, hips, upper legs, lower legs, neck, chest, upper degree to which situations in one’s life are considered
back, lower back and abdomen) where pain or stressful. Scores range from 0 to 72. The Spanish
tenderness was felt during the previous 7 days version of the PSS-10 has adequate reliability and
(total score 0–19). The Symptom Severity Scale validity [67].
(SS; range from 0–12) includes three major symptoms – The Multidimensional Inventory of Subjective
(fatigue, trouble thinking/remembering and waking up Cognitive Impairment (MISCI) [68] is a 10-item
tired or unrefreshed), which is scored from 0 to 3, as measure of perception of cognitive dysfunction in
well as three additional symptoms (pain or cramps FMS, developed through classical test theory and
in lower abdomen, depression, headache), which item response theory from cognitive functioning
can be coded as present (1) or absent (0). The item banks that were developed as part of the Patient
fibromyalgianess scale is defined as the sum of the Reported Outcomes Measurement Information
WPI items (0–19) and the 6-item SS scale (0–12), System (PROMIS). The MISCI showed excellent
so total scores can range from 0 to 31. internal reliability, low ceiling/floor effects, and
– The Client Service Receipt Inventory (CSRI) [61, 62] good convergent validity with a similar measure.
used for the present project will be designed to – The Pain Catastrophising Scale (PCS) [69, 70] is a
collect retrospective data on medication and service 13-item questionnaire derived partially from the
receipt: 1. Medication. A profile of the patient’s use Coping Strategies Questionnaire and other descriptions
of all prescribed medications (analgesics, non-steroidal of catastrophising. It has three dimensions: Rumination
anti-inflammatories, short- and long-acting opioids, (tendency to focus excessively on pain sensations),
etc.) will be requested, including the name of the drug, Magnification (tendency to magnify the threat value
the prescriber, the dosage level, the total number of of pain sensations) and Helplessness (tendency to
perceive oneself as unable to control the intensity are measures that have been frequently used as
of pain). The PCS total score and subscale scores indicators of meaningful overall change [on a
are computed as the algebraic sum of ratings 7-point Likert scale, from 1 = “Much better” to
made for each item. PCS items are rated in relation 7 = “Much worse”] in treatments for chronic pain,
to frequency of occurrence on 5-point scales whereas the PSIC asks about the impression of
(0 = never ~ 4 = almost always). change in more specific domains: physical and
– The Five Facet Mindfulness Questionnaire (FFMQ) social functioning, work-related activities, mood,
[71, 72] consists of 39 items that assess five facets and pain.
of mindfulness. Items are rated on a Likert scale – Adapted version of the Credibility/Expectancy
ranging from 1 (never or very rarely true) to 5 (very questionnaire (CEQ) [79]. The CEQ is a 6-item
often or always true). The factors include: Observing, questionnaire for measuring treatment expectancy
including noticing or attending to internal and and credibility for use in clinical outcome studies.
external experiences such as sensations, thoughts, The questionnaire shows overall high internal
or emotions. Describing refers to labelling internal consistency (α = 0.84–0.85). We will use an adapted
experiences with words. Acting with awareness version that evaluates Expectancy (at the end of the
involves focusing on one’s activities in the here first treatment session) and Opinion (at the end of
and now as opposed to behaving mechanically. the last treatment session) about MBSR and FibroQoL.
Non-judging of inner experience refers to taking a – Log of out-session for MBSR and psychotherapeutic
non-evaluative stance toward thoughts and feelings. practices. An ad hoc instrument for the weekly
Finally, non-reactivity to inner experience is allowing recording of formal and informal mindfulness or
thoughts and feelings to come and go, without getting FibroQoL home practice. A recent systematic
caught up in or carried away by them. In a recent review of systematic reviews and a meta-analysis
online survey answered by 4,986 FMS patients of standardised mindfulness interventions (MBSR
from all 50 US states and 30 countries, the FFMQ and MBCT) indicated that an increase in total
subscales was shown to discriminate well among minutes of mindfulness practice and class attendance
FMS patients self-identified as meditators or are associated with a reduction of stress and mood
non-meditators. Overall, FMS patients with higher complaints [80].
mindfulness scores had lower levels of FMS symptom – Adverse events of the interventions. Ad hoc measure
severity as measured with the FIQR [73]. to check for adverse events (e.g., anxiety, dizziness,
– The Self-Compassion Scale-short form (SCS-12) sleep problems, etc.) across the interventions and
[74, 75] is a shorter version (12 items) of the SCS follow-up.
(26 items). The SCS was designed to assess overall
self-compassion (total score) and components of
self-compassion across three dimensions: common Neuroimaging MRI will be performed on a 3.0 T Phillips
humanity, mindfulness and self-kindness. The SCS–SF Ingenia wide-bore MR scanner (70 cm bore size) fitted
shows good internal consistency (Cronbach’s α ≥0.86) with an 8-channel, phased-array receive-only head coil.
and very high convergence with the long form of the T1- and T2-weighted images will be acquired for radio-
scale (r ≥0.97). logic assessment and image registration. We want to
– The Psychological inflexibility in pain scale (PIPS) explore voxel-wise structural and functional changes asso-
[76, 77] is a 12-item scale designed to measure ciated with participation in the different treatments across
psychological inflexibility in pain patients. The the brain and in functionally-defined brain regions of
instrument includes two factors: avoidance and interest relating to meta-awareness, body awareness,
cognitive fusion related to pain. The items consist of memory consolidation-reconsolidation, and emotion regu-
different statements that are considered to be related lation. The main ROI for structural and functional data-
to chronic pain, psychological inflexibility, suffering sets are defined as primary and secondary somatosensory
and disability (coherent with the ACT theory). All the cortices, anterior cingulate cortex, thalamus, insula, amyg-
items are rated on a 7-point Likert-type scale that dala, hippocampus, frontal pole and orbitofrontal cortex.
ranges from “1 = never true” to “7 = always true”, with These ROI will be delineated with the aid of a neuroimag-
higher scores indicating more psychological inflexibility. ing atlas such as the WFU Pickatlas [81]. Prior to and after
MRI, all participants will be asked to rate perceived pain
Other measures intensity using a horizontal visual analog scale (100 mm
length) marked “no pain” and “maximum pain” at the
– The Patient Global Impression of Change (PGIC) endpoints. The time frame is “the day of responding” and
and Pain Specific Impression of Change (PSIC) [78] “during the MRI session”, respectively.
Brain structure Our intention is to use longitudinal the FMS patients will be instructed to remain awake
voxel-based morphometry (VBM), an automated struc- with their eyes closed.
tural MRI analysis technique, to examine whether the
three interventions (TAU, TAU + MBSR, TAU + Fibro- Inflammatory markers Blood samples will be collected
QoL) produce local changes in grey matter. We will ac- and serum will be stored at −80° for biochemical ana-
quire high-resolution T1-weighted 3-dimensional volume lyses. Levels of the following inflammatory markers will
scans pre and post treatment to assess for the presence of be assessed: IL-6, IL-8, IL-10, and high-sensitivity C-
longitudinal change following treatment. Specifically, rela- reactive protein [84]. Milliplex® assay kits (Human High
tive local increases and decreases between pre- and post- Sensitivity T Cell kit) from MerkMilliporte (commercial
treatment scans will be compared within and between firm) will be used for cytokine quantification in a Lumi-
study groups. In addition, we will use Diffusion tensor nex® platform. CRP-hs will be assessed by turbidimetry
imaging (DTI). The diffusion MR data will be analysed in an Olympus AU5400 Autoanalyser.
by using the diffusion tensor model. After a mathematical
diagonalisation process, the eigenvectors and eigenvalues Statistical analyses of study outcomes
describing the tensor ellipsoid will be determined. Then, SPSS v22.0, STATA v13.0 and Mplus v7.2 will be used for
two standard diffusion indices will be obtained: the the statistical analyses. One-way ANOVAs (with post hoc
apparent diffusion coefficient and the fractional anisot- Tukey’s HSD or Games-Howell tests) for continuous
ropy. DTI scans pre and post treatment will permit to values and χ2 tests with continuity corrections for categor-
assess changes in axial diffusivity, with lower values ical values will be computed on all baseline measures and
being interpreted as structural enhancement of white socio-demographic variables to examine pre-treatment
matter. For example, lower axial diffusivity at post- differences between groups.
treatment in MBSR participants compared to control
participants would suggest a white matter increase as Analysis of clinical efficacy
consequence of meditation training. To assess treatment effects, we will perform Intention-
to-Treat analyses, which will include all participants who
Brain function Recent evidence [82] has demonstrated undergo random allocation, using multiple imputation
the suitability of pseudo-continuous arterial spin labeling to replace missing values.
(pCASL), a perfusion MRI technique, to quantify changes To study the differences in the primary outcome and
in regional cerebral blood flow (rCBF) that relate to the in each of the secondary outcomes between groups, lin-
experience of ongoing persistent pain. In this study we will ear mixed-effects models [85] will be prepared using
assess rCBF prior to and following the three treatments. Restricted Maximum Likelihood to estimate the parame-
pCASL data acquisition, pre-processing, and analysis ters. Comparisons amongst treatment groups at post-
methodologies have been published [82, 83], as applied to treatment and at 12-month follow-up will be computed
various disease states and therapeutic regimens, using with estimates derived from the linear mixed-effect
gold-standard software packages (SPM-8 and FSL). We models (use of the Bonferroni method to adjust the sig-
will acquire pCASL images using a gradient echo single nificance level of the pairwise contrasts). Calculations of
shot echoplanar imaging readout resulting in whole-brain between-groups effect sizes using Cohen’s d with its
blood-flow maps. We will analyse pre-post rCBF differ- 95 % confidence interval will be based on the pooled
ences within and between groups, and whether pre-post standard deviation at baseline. Finally, to make the find-
rCBF differences are related to variability in subjective ings from the present RCT meaningful to clinicians, the
ongoing pain. number-needed-to-treat (NNT) [86] in the MBSR condi-
Multiple resting-state networks have been found which tion will be reported. Taking the Luciano et al. [87]
show activity during rest and during tasks. One of them NNT approach as our reference, we dichotomise partici-
is the DMN, which shows a decrease in activity during pants into responders or non-responders using three
cognitive tasks and is activated during self-referential separate cut-off criteria: (a) ≥ 20 % reduction on the
thinking. Napadow et al. [12] showed that resting con- FIQR total score from baseline to post-treatment; (b) ≥
nectivity between the insular cortex (region involved in 50 % reduction on the FIQR total score from baseline to
pain perception) and the DMN is significantly correlated post-treatment; and (c) number of patients crossing a
with clinical pain at the time of the scan in FMS pa- cut-off point (reaching no worse than mild functional
tients. In this work, we will use resting-state fMRI to impairment; FIQR total score < 39).
compare changes in insular cortex-DMN connectivity Given that some pharmacological treatments may
between study conditions as well as to analysing any interfere with cytokine levels [88], differences in cytokine
correlation between this connectivity and clinical pain. levels between patients taking vs. not taking antidepres-
During the 8-min resting state fMRI acquisition period, sants will be evaluated.
Mediational analyses by taking the number of days on sick leave and multiplying
We will examine whether the effect of treatments on out- it by the minimum daily wage in Spain. Finally, total costs
comes at 12-month follow-up are mediated through are calculated by adding direct and indirect costs. The util-
changes in “process variables” (mindfulness, pain catastro- ities represent the rating of the patients’ quality of life on a
phising, psychological inflexibility, and self-compassion) at scale from 0 (as bad as death) to 1 (perfect health). QALYs
post-treatment. Using two-stage meta-analytic structural will be calculated using Spanish EQ-5D-5L tariffs.
equation modelling, Gu and colleagues [89] identified First, we will use a micro-costing approach, which in-
moderate and consistent evidence for some of the pro- volves careful specification of training costs, staffing
posed process variables [mindfulness and rumination (di- costs, venue overheads, materials, and staff travel. Then,
mension of catastrophising)] and preliminary but still following the International Society for Pharmacoeco-
insufficient evidence for others [self-compassion and psy- nomics and Outcomes Research (ISPOR) core recom-
chological flexibility] as mediator mechanisms underlying mendations for cost-effectiveness analyses alongside
standardised MBIs (MBSR and MBCT). Following Luciano RCTs [91], we will calculate the incremental cost-utility
et al. [87], pre- to post-treatment change scores for ratios, defined as the difference in mean costs divided by
the process variable, and the pre- to follow-up change the difference in mean QALYs. As the duration of the
scores for the outcome variables will be computed. study is 12 months, neither costs nor outcomes are sub-
We will analyse the direct and indirect relationships ject to discounting. QALYs gained in each evaluation are
between treatments (TAU + MBSR vs. TAU + FibroQoL), approximated by using the area under-the-curve tech-
process variables, and study outcomes using path analysis nique. To gain insight into the uncertainty around the
models. The treatment condition is considered the inde- pooled mean ICUR, we will plot the pooled boot-
pendent variable, the pre-post change scores in the strapped cost-effect pairs on cost-utility planes. Finally,
process variables are the mediators, and pre- to follow-up acceptability curves will be presented which represent
changes in the outcome variables are the dependent vari- the probability that the intervention is cost-effective,
ables. In this way, we are taking temporality into account, given a varying threshold for the willingness to pay for
which increases the prospect of establishing conclusions each QALY gained. The robustness of the cost-utility re-
about causality. We will analyse the data of participants sults will also be tested by computing distinct sensitivity
from the MBSR and FibroQoL treatments who receive a analyses. For instance, we will perform a per protocol
sufficient dose of the intervention, defined in this case as analysis from which the FMS patients who do not attend
attendance at a minimum of 6 of the 8 weekly sessions. at least 6 MBSR or FibroQoL sessions will be excluded.
Simple and multiple mediation (simultaneously testing
multiple variables as mediators) models will be computed. Neuroimaging analyses
The direct path between study condition and clinical out- Treatment-related differences in both structural and func-
come and the indirect effect through the process variables tional MRI datasets will be assessed using mass-univariate
will be tested. voxelwise General Linear Models. Thus, repeated mea-
sures ANOVA functions available in SPSS will be com-
Cost-utility analysis puted to examine between- and within-group effects of
Taking a previous study by our group as a reference treatments. A standard threshold of p < 0.05 will be
[90], the cost-utility of TAU + MBSR compared to the applied for ROI data, correcting for multiple comparisons.
other study arms will be evaluated from healthcare and
societal perspectives. Ethical issues
Costs will be estimated from the healthcare and soci- Written informed consent will be obtained from all partic-
etal perspectives during the 12 months of follow-up. ipants before randomisation. Participants will be provided
Direct health care costs are calculated by adding costs with a general overview of the aims and characteristics of
derived from medication consumption, medical tests, the study and the interventions before signing the in-
use of health-related services, and cost of staff to run the formed consent. They will also be assured that they will
intervention. The cost of medication is calculated by deter- be participating voluntarily and can withdraw at any time
mining the price per milligram during the study, according from the study with the guarantee that they will continue
to the Vademecum International (Red Book), and including to receive the most appropriate medical treatment pre-
value-added tax. Total costs of medications are calculated scribed by their general practitioner. The study will be
by multiplying the price per milligram by the daily dose in performed in accordance with the ethical standards laid
milligrams and the number of days receiving such treat- down in the 1964 Declaration of Helsinki and its subse-
ment. The unit costs of medical tests and health services quent updates. The FSJD Research Committee Board
will be obtained from the SOIKOS health database (http:// evaluated and approved the study protocol in May 2015
www.oblikue.com/bddcostes/). Indirect costs are calculated (PIC-102-15). All patient data will be treated as
confidential and only the research team will be allowed to to the protocol in both the MBSR and FibroQoL groups.
access it after recodification of name and personal identity This RCT is intended to be as naturalistic as possible, so
number (so no individual can be directly identified). Only prescribed drugs are permitted throughout the study.
the principal investigator of the study will have access to The effects of these drugs on clinical and biological out-
the code key which will be stored separately in a safe place comes may constitute another study limitation. However,
in accordance with Spanish legislation. All data will be no baseline differences among study arms regarding
computer processed and stored. Blood samples will be medical drugs are expected (due to randomisation)
stored, encrypted, and will not be directly traceable back to and sub-analyses evaluating the potential effects of
individuals. Blood samples will be used only in ways to the main pharmacological treatments (e.g., antidepres-
which the participants consented and may only be made sants) on the outcomes will be performed. Moreover,
available to a new research project after Ethical Research received pharmacological treatment may not be stable
Committee approval and participants provide a new agree- over time (e.g., initiating antidepressant treatment due
ment. Furthermore, the participants have the right to re- to a depressive episode, changing principle/dose of
quest, without explanation, that their samples be destroyed other drugs due to variations in clinical symptoms, or
or made completely anonymous. starting individual therapy with a psychologist) so it
is probable that some patients will be excluded from
Forecast execution dates the study due to drastic changes in their treatment.
Initial recruitment of patients: January 2016 Patients will be asked at post- and follow-up assess-
Finalisation of patient recruitment: January 2017 ments for details about changes in medical treatment
Finalisation of patient monitoring period: April 2018 received and the clinicians will check the pharmaco-
Publication of results: December 2018 logical treatment history in the patients’ clinical chart.
To our knowledge, this study represents the first at-
Discussion tempt to detect structural and functional brain changes
The study described here will evaluate, for the first time, and inflammatory marker variations after MBSR in pa-
the cost-utility of MBSR for FMS patients compared tients with FMS. Indeed, few studies have focused on
with usual care and with an empirically-validated inter- exploration of the neural and inflammatory underpin-
vention (FibroQol) which proved to be cost-effective in nings of psychological treatments in chronic pain pa-
such patients in a high-quality RCT [41]. Therefore, this tients. We hope that our work will offer new advances in
is a 3-armed RCT in which we include an active control understanding the psychophysiological processes altered
condition (psycho-education) that permits us to control by mindfulness and their relationship with clinical out-
the “frustrebo response” (disappointment among control comes. Understanding of how mindfulness changes
participants at not receiving treatment) associated with these variables will in turn increase our understanding
waiting-list and TAU conditions [92]. The RCT was de- of the role of the brain and the immune system in FMS.
signed following the CONSORT recommendations, the Furthermore, determining FMS profiles according to
economic evaluation was planned following the updated psychological and brain/immune variables may also
ISPOR core recommendations for cost-effectiveness ana- allow prediction of treatment response in patients with
lyses alongside RCTs, the sample size in each study arm this diagnosis. Given that patients with FMS usually
is sufficiently large and the follow-up period is suffi- present comorbidities with psychiatric disorders (such as
ciently long to capture important costs and outcomes. If depression or anxiety) and other central sensitivity syn-
our trial results are sufficiently robust, MBSR pro- dromes (such as chronic fatigue syndrome), the results
grammes might be delivered as part of a strategic, coher- from this study may have translational value.
ent or appropriately resourced approach for patients
with FMS in the healthcare context [80, 93]. According Consent for publication
to Gotlink et al. [80], “further research should also look Not applicable.
more into the mechanisms whereby these therapies
(MBSR-MBCT) are efficacious”. In the present RCT, we Availability of data and material
are not only interested in the clinical effects of MBSR at Not applicable.
long-term, but also in the “process” psychological vari-
ables and neurobiological changes that contribute to Abbreviations
ACR: American College of Rheumatology; CEQ: Credibility/Expectancy
them, which is a current source of interest and debate in Questionnaire; CHEERS: Consolidated Health Economic Evaluation Reporting
the scientific literature [89, 94]. Standards; CNS: Central Nervous System; CONSORT: Consolidated Standards
One of the main risks in this study may be dropouts. of Reporting Trials; CSRI: Client Service Receipt Inventory; DMN: Default Mode
Network; DTI: Diffusion Tensor Imaging; EAN: Executive Attention Network;
A sensitivity analysis using a per protocol strategy will EQ-5D-5L: EuroQoL questionnaire; FFMQ: Five Facet Mindfulness
be performed to determine the impact of the adherence Questionnaire; FibroQoL: Psychoeducational programme for improving
quality of life in fibromyalgia; FIQR: Revised Fibromyalgia Impact Fabrés Anglada, DAP Delta Llobregat, Unitat Docent Costa de Ponent,
Questionnaire; fMRI: functional Magnetic Resonance Imaging; Institut Català de la Salut, Gavà, Spain. 5Primary Care Prevention and Health
FMS: Fibromyalgia syndrome; FSDC: Fibromyalgia Survey Diagnostic Criteria; Promotion Research Network (RedIAPP), Madrid, Spain. 6Rheumatology
HADS: Hospital Anxiety and Depression Scale; High-sensitivity CRP test: high Service, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain.
7
sensitivity C-reactive protein; ICUR: Incremental Cost Utility Ratio; Personal Social Services Research Unit, London School of Economics and
ISPOR: International Society for Pharmacoeconomics and Outcomes Political Science, London, UK. 8Health Psychology Section, Department of
Research; MBCT: Mindfulness-Based Cognitive Therapy; MBIs: Mindfulness-based Psychology, Institute of Psychiatry, Psychology, & Neuroscience, King’s
interventions; MBSR: Mindfulness-Based Stress Reduction; College London, London, UK. 9Department of Neuroimaging, Institute of
MISCI: Multidimensional Inventory of Subjective Cognitive Impairment; Psychiatry, Psychology & Neuroscience, King’s College London, London, UK.
10
MMSE: Mini-Mental State Examination; MRI: Magnetic Resonance Imaging; Magnetic Resonance Unit, Department of Radiology, Hospital Quironsalud
NNT: number-needed-to-treat; pCASL: pseudo-continuous Arterial Spin Zaragoza, Zaragoza, Spain. 11Department of Psychiatry, Bellvitge University
Labeling; PCS: Pain Catastrophising Scale; PGIC: Patient Global Impression Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
12
of Change; PIPS: Psychological Inflexibility in Pain Scale; PSIC: Patient Department of Psychobiology and Methodology of Health Sciences,
Specific Impression of Change; PSS-10: Perceived Stress Scale; Universitat Autònoma de Barcelona, Barcelona, Spain. 13Aragon Institute of
QALY: Quality-Adjusted Life-Year; rCBF: regional Cerebral Blood Flow; Health Sciences (I+CS), Zaragoza, Spain. 14Hospital de Sant Pau, Barcelona,
RCT: Randomised Controlled Trial; ROI: Regions of Interest; rs-fMRI: resting state Spain.
functional Magnetic Resonance Imaging; SCID-I: Structured Clinical Interview for
DSM Axis I Disorders; SCS-12: Self-Compassion Scale; SPIRIT: Standard Protocol Received: 23 January 2016 Accepted: 23 February 2016
Items: Recommendations for Interventional Trials; TAU: Treatment as Usual;
VBM: voxel-based morphometry.
References
Competing interests
1. Häuser W, Ablin J, Fitzcharles MA, Littlejohn G, Luciano JV, Usui C, Walitt B.
The authors declare that they have no competing interests.
Fibromyalgia. Nat Rev Dis Primers. 2015;1:15022.
2. Wolfe F, Häuser W. Fibromyalgia diagnosis and diagnostic criteria. Ann Med.
Authors’ contributions 2011;43:495–502.
AFS made a significant contribution to the conception and to the design of 3. Branco JC, Bannwarth B, Failde I, Abello Carbonell J, Blotman F, Spaeth M,
the study and drafted the manuscript; XB and MPG contributed to writing Saraiva F, et al. Prevalence of fibromyalgia: a survey in five European
the analysis strategy (cytokines data) and helped to draft the manuscript; countries. Semin Arthritis Rheum. 2010;39:448–53.
MTPM, ARS, and APA helped to design the study and draft the manuscript; 4. Fietta P, Fietta P, Manganelli P. Fibromyalgia and psychiatric disorders.
FDA made a substantial contribution to the analysis strategy and helped to Acta Biomed. 2007;78:88–95.
draft the manuscript; NF, CSM and MAH helped to design the study and 5. Schaefer C, Chandran A, Hufstader M, Baik R, McNett M, Goldenberg D,
draft the neuroimaging sections of the manuscript. RT, RMM and ASB Gerwin R, Zlateva G. The comparative burden of mild, moderate and severe
participated in the design of the study and revised the manuscript critically Fibromyalgia: results from a cross-sectional survey in the United States. Health
for important intellectual content; JVL initiated the study, designed the RCT, Qual Life Outcomes. 2011;9:71.
wrote part of the manuscript, and is the principal investigator of the study. 6. Leadley RM, Armstrong N, Lee YC, Allen A, Kleijnen J. Chronic diseases in
All authors have read and approved the version to be published. the European Union: the prevalence and health cost implications of chronic
pain. J Pain Palliat Care Pharmacother. 2012;26:310–25.
Authors’ information 7. Perrot S, Russell IJ. More ubiquitous effects from non-pharmacologic than
AFS, Ph. D, psychologist and biologist, postdoctoral researcher. from pharmacologic treatments for fibromyalgia syndrome: a meta-analysis
XB, Ph. D, Professor of Stress & Health. examining six core symptoms. Eur J Pain. 2014;18:1067–80.
MTPM, MD, general practitioner. 8. Cagnie B, Coppieters I, Denecker S, Six J, Danneels L, Meeus M. Central
ARS, MD, rheumatologist. sensitization in fibromyalgia? A systematic review on structural and
FD, Ph. D, economist specialising in health and social care quantitative functional brain MRI. Semin Arthritis Rheum. 2014;44:68–75.
analysis, research officer. 9. Valet M, Gündel H, Sprenger T, Sorg C, Mühlau M, Zimmer C, et al. Patients
RMM, Ph. D, Professor of Psychology as Applied to Medicine. with pain disorder show gray-matter loss in pain-processing structures:
MAH, Ph. D, Senior researcher, expert in neuroimaging of pain. a voxel-based morphometric study. Psychosom Med. 2009;71:49–56.
NF, MD, Ph. D, expert in neuroradiology. 10. Jensen KB, Loitoile R, Kosek E, Petzke F, Carville S, Fransson P, Marcus H,
CSM, Ph. D, senior researcher, expert in neuroimaging of anxiety disorders. Williams SC, Choy E, Mainguy Y, Vitton O, Gracely RH, Gollub R, Ingvar M,
MPG, MSc, psychologist, predoctoral researcher. Kong J. Patients with fibromyalgia display less functional connectivity in the
ASB, MD, Ph. D, psychiatrist, coordinator of an Emergency and Partial brain’s pain inhibitory network. Mol Pain. 2012;8:32.
Hospitalisation Unit. 11. Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic
APA, Ph. D, psychologist, predoctoral researcher. brain connectivity in fibromyalgia is associated with chronic pain intensity.
RT, MSc, psychologist, psychotherapist in private practice. Arthritis Rheum. 2010;62:2545–55.
JVL, Ph. D, psychologist, senior researcher and principal investigator of the 12. Napadow V, Kim J, Clauw DJ, Harris RE. Decreased intrinsic brain
EUDAIMON study. connectivity is associated with reduced clinical pain in fibromyalgia.
Arthritis Rheum. 2012;64:2398–403.
Funding 13. Pujol J, Macià D, Garcia-Fontanals A, Blanco-Hinojo L, López-Solà M,
The project has been funded in part by the Instituto de Salud Carlos III Garcia-Blanco S, Poca-Dias V, Harrison BJ, Contreras-Rodríguez O,
(Carlos III Institute of Health, ISCIII) of the Ministry of Economy and Monfort J, Garcia-Fructuoso F, Deus J. The contribution of sensory
Competitiveness (Spain) through the Network for Prevention and Health system functional connectivity reduction to clinical pain in fibromyalgia.
Promotion in Primary Care (redIAPP, RD12/0005/0006 & RD12/0005/0008), by Pain. 2014;155:1492–503.
a grant for research projects on health from ISCIII (PI15/00383) and co- 14. Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia
financed with European Union ERDF funds. The last listed author (JVL) has a and cytokines. Immunol Lett. 2014;161:200–03.
“Miguel Servet” research contract from the ISCIII (CP14/00087). 15. Uceyler N, Hauser W, Sommer C. Systematic review with meta-analysis:
cytokines in fibromyalgia syndrome. BMC Musculoskelet Disord. 2011;12:245.
Author details 16. Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex
1
Teaching, Research & Innovation Unit, Parc Sanitari Sant Joan de Déu, C/Dr. regional pain syndrome. Nat Rev Reumathol. 2015;11:639–48.
Antoni Pujadas 42, 08830, Sant Boi de Llobregat, Barcelona, Spain. 2Centre for 17. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine Targets in the Brain: Impact
Biomedical Research in Mental Health, CIBERSAM, Madrid, Spain. 3Stress and on Neurotransmitters and Neurocircuits. Depress Anxiety. 2013;30:297–306.
Health Research Group, Faculty of Psychology, Universitat Autònoma de 18. Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy
Barcelona, Bellaterra, Barcelona, Spain. 4Primary Health Centre Bartomeu Clin N Am. 2009;29:247–64.
19. Kim H, Chen L, Lim G, Sung B, Wang S, McCabe MF, Rusanescu G, Yang L, 42. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K,
Tian Y, Mao J. Brain indoleamine 2, 3-dioxygenase contributes to the Hróbjartsson A, Mann H, Dickersin K, Berlin J, Doré C, Parulekar W, Summerskill
comorbidity of pain and depression. J Clin Invest. 2012;122:2940–54. W, Groves T, Schulz K, Sox H, Rockhold FW, Rennie D, Moher D. SPIRIT 2013
20. Vécsei L, Szalárdy L, Fülöp F, Toldi J. Kynurenines in the CNS: recent statement: defining standard protocol items for clinical trials. Ann Intern Med.
advances and new questions. Nat Rev Drug Discov. 2013;12:64–82. 2013;158:200–07.
21. Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E. Evidence of 43. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010
central inflammation in fibromyalgia-increased cerebrospinal fluid Statement: updated guidelines for reporting parallel group randomised
interleukin-8 levels. J Neuroimmunol. 2012;242:33–8. trials. BMJ. 2010;340:c332.
22. Lakhan SE, Schofield KL. Mindfulness-based therapies in the treatment of 44. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D,
somatization disorders: a systematic review and meta-analysis. PLoS ONE. Augustovski F, Briggs AH, Mauskopf J, Loder E; CHEERS Task Force.
2013;8:e71834. Consolidated Health Economic Evaluation Reporting Standards (CHEERS)
23. Veehof MM, Oskam MJ, Schreurs KMG, Bohlmeijer ET. Acceptance-based statement. BMC Med. 2013;11:80.
interventions for the treatment of chronic pain: A systematic review and 45. Grossman P et al. Mindfulness-based stress reduction and health benefits:
meta-analysis. Pain. 2011;152:533–42. a meta-analysis. J Psychosom Res. 2004;57:35–43.
24. Bawa FL, Mercer SW, Atherton RJ, Clague F, Keen A, Scott NW, Bond CM. 46. Murphy K, Harris AD, Diukova A, Evans CJ, Lythgoe DJ, Zelaya F, Wise RG.
Does mindfulness improve outcomes in patients with chronic pain? Pulsed arterial spin labeling perfusion imaging at 3 T: estimating the
Systematic review and meta-analysis. Br J Gen Pract. 2015;65:e387–400. number of subjects required in common designs of clinical trials. Magn
25. Henke M, Chur-Hansen A. The effectiveness of mindfulness-based programs Reson Imaging. 2011;29:1382–89.
on physical symptoms and psychological distress in patients with fibromyalgia: 47. Kabat-Zinn J. An outpatient program in behavioural medicine for
A systematic review. Int J Wellbeing. 2014;4:28–45. chronic pain patients based on the practice of mindfulness meditation:
26. Lauche R, Cramer H, Dobos G, Langhorst J, Schmidt S. A systematic review theoretical considerations and preliminary results. Gen Hosp Psychiatry.
and meta-analysis of mindfulness-based stress reduction for the fibromyalgia 1982;4:33–42.
syndrome. J Psychosom Res. 2013;75:500–10. 48. Öst LG. The efficacy of acceptance and commitment therapy: an updated
27. Fox KC, Nijeboer S, Dixon ML, Floman JL, Ellamil M, Rumak SP, systematic review and meta-analysis. Behav Res Ther. 2014;61:105–21.
Sedlmeier P, Christoff K. Is meditation associated with altered brain structure? 49. Morley S, Eccleston C. The object of fear in pain. In: Asmundson GJ, Vlaeyen
A systematic review and meta-analysis of morphometric neuroimaging in J, Crombez G, editors. Understanding and treating fear of pain. Oxford:
meditation practitioners. Neurosci Biobehav Rev. 2014;43:48–73. Oxford University Press; 2004. p. 163–88.
28. Tang YY, Hölzel BK, Posner MI. The neuroscience of mindfulness meditation. 50. Feixas G, Villegas M. Constructivismo y Psicoterapia (3ª ed.) [Constructivism
Nat Rev Neurosci. 2015;16:213–25. and Psychotherapy]. Bilbao: DDB; 2000.
29. Hölzel BK, Carmody J, Vangel M, Congleton C, Yerramsetti SM, Gard T, Lazar 51. Compañ V, Feixas G, Varlotta-Domínguez N, Torres-Viñals M, Aguilar-Alonso
SW. Mindfulness practice leads to increases in regional brain gray matter Á, Dada G, Ángel Saúl L. Cognitive factors in fibromyalgia: the role of self-
density. Psychiatry Res. 2011;191:36–43. concept and identity related conflicts. J Constr Psychol. 2011;24:56–77.
30. Brewer JA, Worhunsky PD, Gray JR, Tang YY, Weber J, Kober H. Meditation 52. Erickson MH. Naturalistic techniques of hypnosis. Amer J Clin Hypn. 1958;1:3–8.
experience is associated with differences in default mode network activity 53. Folstein MF, Folstein SE, McHugh PR. “Mini Mental State”: a practical method
and connectivity. Proc Natl Acad Sci U S A. 2011;108:20254–59. for grading the cognitive state of patients for the clinician. J Psychiatr Res.
31. Jang JH, Jung WH, Kang DH, Byun MS, Kwon SJ, Choi CH, Kwon JS. 1975;12:189–98.
Increased default mode network connectivity associated with meditation. 54. Lobo A, Saz P, Marcos G, Día JL, de la Cámara C, Ventura T, Morales Asín F,
Neurosci Lett. 2011;487:358–62. Fernando Pascual L, Montañés JA, Aznar S. Revalidation and standardization
32. Marchand WR. Neural mechanisms of mindfulness and meditation: of the cognition mini-exam (first Spanish version of the Mini-Mental Status
evidence from neuroimaging studies. World J Radiol. 2014;6:471–79. Examination) in the general geriatric population. Med Clin. 1999;5:767–74.
33. Chiesa A, Serretti A, Jakobsen JC. Mindfulness: Top–down or bottom–up 55. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview
emotion regulation strategy? Clin Psychol Rev. 2013;33:82–96. for DSM-IV axis I disorders, clinician version. Washington, DC: American
34. Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, Coghill RC. Brain Psychiatric Association; 1997.
mechanisms supporting the modulation of pain by mindfulness meditation. 56. Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL. The revised
J Neurosci. 2011;31:5540–8. Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric
35. Creswell JD, Irwin MR, Burklund LJ, Lieberman MD, Arevalo JM, Ma J, Breen properties. Arthritis Res Ther. 2009;11:R120.
EC, Cole SW. Mindfulness-Based Stress Reduction training reduces loneliness 57. Luciano JV, Aguado J, Serrano-Blanco A, Calandre EP, Rodriguez-Lopez CM.
and pro-inflammatory gene expression in older adults: a small randomized Dimensionality, reliability, and validity of the revised fibromyalgia impact
controlled trial. Brain Behav Immun. 2012;26:1095–101. questionnaire in two Spanish samples. Arthritis Care Res. 2013;65:1682–9.
36. Black DS, Cole SW, Irwin MR, Breen E, St Cyr NM, Nazarian N, Khalsa DS, 58. Boomershine CS. A comprehensive evaluation of standardized assessment
Lavretsky H. Yogic meditation reverses NF-kB and IRF-related transcryptome tools in the diagnosis of fibromyalgia and in the assessment of fibromyalgia
dynamics in leukocytes of family dementia caregivers in a randomized severity. Pain Res Treat. 2012;2012:653714.
controlled trial. Psychoneuroendocrinology. 2013;38:348–55. 59. Häuser W, Jung E, Erbslöh-Möller B, Gesmann M, Kühn-Becker H,
37. Kaliman P, Alvarez-López MJ, Cosín-Tomás M, Rosenkranz MA, Lutz A, Davidson Petermann F, Langhorst J, Weiss T, Winkelmann A, Wolfe F. Validation
RJ. Rapid changes in histone deacetylases and inflammatory gene expression of the Fibromyalgia Survey Questionnaire within a cross-sectional
in expert meditators. Psychoneuroendocrinology. 2014;40:96–107. survey. PLoS ONE. 2012;7:e37504.
38. Witek-Janusek L, Albuquerque K, Chroniak KR, Chroniak C, Durazo-Arvizu R, 60. Carrillo-de-la-Peña MT, Triñanes Y, González-Villar A, Romero-Yuste S,
Mathews HL. Effect of mindfulness based stress reduction on immune Gómez-Perretta C, Arias M, Wolfe F. Convergence between the 1990 and
function, quality of life and coping in women newly diagnosed with early 2010 ACR diagnostic criteria and validation of the Spanish version of the
stage breast cancer. Brain Behav Immun. 2008;22:969–81. Fibromyalgia Survey Questionnaire (FSQ). Rheumatol Int. 2015;35:141–51.
39. Gonzalez-Garcia M, Ferrer MJ, Borras X, Muñoz-Moreno JA, Miranda C, Puig J, 61. Beecham J, Knapp M. Costing psychiatric interventions. In: Thornicroft G,
Perez-Alvarez N, Soler J, Feliu-Soler A, Clotet B, Fumaz CR. Effectiveness of Brewin C, Wing J, editors. Measuring Mental Health Needs. London: Gaskell;
mindfulness-based cognitive therapy on the quality of life, emotional status, and 1992. p. 163–83.
CD4 cell count of patients aging with hiv infection. AIDS Behav. 2014;18:676–85. 62. Vázquez-Barquero JL, Gaite L, Cuesta MJ, Garcia-Usieto E, Knapp M, Beecham J.
40. Morgan N, Irwin MR, Chung M, Wang C. The effects of mind-body therapies Spanish version of the CSRI: a mental health cost evaluation interview.
on the immune system: meta-analysis. PLoS ONE. 2014;9:e100903. Arch Neurobiol (Madr). 1997;60:171–84.
41. Luciano JV, Sabes-Figuera R, Cardeñosa E, TPeñarrubia-María M, Fernández- 63. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G,
Vergel R, García-Campayo J, Knapp M, Serrano-Blanco A. Cost-utility of a Badia X. Development and preliminary testing of the new five-level
psychoeducational intervention in fibromyalgia patients compared with version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–36.
usual care: an economic evaluation alongside a 12-month randomized 64. Zigmond AS, Snaith RP. The hospital anxiety and depression scale.
controlled trial. Clin J Pain. 2013;29:702–11. Acta Psychiatr Scand. 1983;67:361–70.
65. Luciano JV, Barrada JR, Aguado J, Osma J, García-Campayo J. Bifactor analysis group acceptance and commitment therapy for fibromyalgia: a 6-month
and construct validity of the HADS: a cross-sectional and longitudinal study in randomized controlled trial (EFFIGACT study). Pain. 2014;155:693–702.
fibromyalgia patients. Psychol Assess. 2014;26:395–406. 88. Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication
66. Cohen S, Williamson G. Perceived stress in a probability sample of the treatment on serum levels of inflammatory cytokines: a meta-analysis.
United States. In: Spacapan S, Oskamp S, editors. The social psychology of Neuropsychopharmacology. 2011;36:2452–9.
health: Claremont symposium on applied social psychology. Newbury Park: 89. Gu J, Strauss C, Bond R, Cavanagh K. How do mindfulness-based cognitive
Sage; 1988. p. 31–67. therapy and mindfulness-based stress reduction improve mental health and
67. Remor E. Psychometric properties of a European Spanish version of the wellbeing? A systematic review and meta-analysis of mediation studies.
Perceived Stress Scale (PSS). Span J Psychol. 2006;9:86–93. Clin Psychol Rev. 2015;37:1–12.
68. Kratz AL, Schilling SG, Goesling J, Williams DA. Development and initial 90. Luciano JV, D’Amico F, Cerdà-Lafont M, Peñarrubia-María MT, Knapp M,
validation of a brief self-report measure of cognitive dysfunction in Cuesta-Vargas AI, Serrano-Blanco A, García-Campayo J. Cost-utility of
fibromyalgia. J Pain. 2015;16:527–36. cognitive behavioral therapy versus U.S. Food and Drug Administration
69. Sullivan MJL, Bishop S, Pivik J. The pain catastrophizing scale: development recommended drugs and usual care in the treatment of patients with
and validation. Psychol Assess. 1995;7:524–32. fibromyalgia: an economic evaluation alongside a 6-month randomized
70. García Campayo J, Rodero B, Alda M, Sobradiel N, Montero J, Moreno S. controlled trial. Arthritis Res Ther. 2014;16:451.
Validation of the Spanish version of the pain catastrophizing scale in 91. Ramsey SD, Willke RJ, Glick H, Reed SD, Augustovski F, Jonsson B,
fibromyalgia. Med Clin (Barc). 2008;131:487–92. Briggs A, Sullivan SD. Cost-effectiveness analysis alongside clinical trials
71. Baer R, Smith GT, Lykins E, Button D, Krietemeyer J, Sauer S, et al. Construct II-An ISPOR good research practices task force report. Value Health.
validity of the five facet mindfulness questionnaire in meditating and 2015;18:161–72.
nonmeditating samples. Assessment. 2008;15:329–42. 92. Power M, Hopayian K. Exposing the evidence gap for complementary
72. Aguado J, Luciano JV, Cebolla A, Serrano-Blanco A, Soler J, García-Campayo and alternative medicine to be integrated into science-based medicine.
J. Bifactor analysis and construct validity of the Five Facet Mindfulness J R Soc Med. 2011;104:155–61.
Questionnaire (FFMQ) in non-clinical Spanish samples. Front Psychol. 2015;6:404. 93. Demarzo MM, Cebolla A, García-Campayo J. The implementation of
73. Jones KD, Mist SD, Casselberry MA, Ali A, Christopher MS. Fibromyalgia mindfulness in healthcare systems: a theoretical analysis. Gen Hosp
impact and mindfulness characteristics in 4986 people with fibromyalgia. Psychiatry. 2015;37:166–71.
Explore (NY). 2015;11:304–9. 94. Jones KD. A mindful future for fibromyalgia?: a comment on Davis and Zautra.
74. Raes F, Pommier E, Neff KD, Van Gucht D. Construction and factorial Ann Behav Med. 2013;46:253–5.
validation of a short form of the self-compassion scale. Clin Psychol
Psychother. 2011;18:250–5.
75. Garcia-Campayo J, Navarro-Gil M, Andrés E, Montero-Marin J, López-Artal L,
Demarzo MM. Validation of the Spanish versions of the long (26 items) and
short (12 items) forms of the Self-Compassion Scale (SCS). Health Qual Life
Outcomes. 2014;12:4.
76. Wicksell RK, Renofalt J, Olsson GL, Bond FW, Melin L. Avoidance and cognitive
fusion-central components in pain related disability? Development and
preliminary validation of the psychological inflexibility in pain scale
(PIPS). Eur J Pain. 2008;12:491–500.
77. Rodero B, Pereira JP, Pérez-Yus MC, Casanueva B, Serrano-Blanco A,
Rodrigues da Cunha Ribeiro MJ, Luciano JV, Garcia-Campayo J. Validation of
a Spanish version of the psychological inflexibility in pain scale (PIPS) and an
evaluation of its relation with acceptance of pain and mindfulness in sample
of persons with fibromyalgia. Health Qual Life Outcomes. 2013;11:62.
78. Scott W, McCracken LM. Patients’ impression of change following treatment
for chronic pain: global, specific, a single dimension, or many? J Pain. 2015;
16:518–26.
79. Devilly GJ, Borkovec TD. Psychometric properties of the credibility/
expectancy questionnaire. J Behav Ther Exp Psychiatry. 2000;31:73–86.
80. Gotink RA, Chu P, Busschbach JJ, Benson H, Fricchione GL, Hunink MG.
Standardised mindfulness-based interventions in healthcare: an overview of
systematic reviews and meta-analyses of RCTs. PLoS ONE. 2015;10(4):e0124344.
81. Maldjian JA, Laurienti PJ, Burdette JB, Kraft RA. An automated method for
neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data
sets. NeuroImage. 2003;19:1233–9.
82. Howard MA, Sanders D, Krause K, O’Muircheartaigh J, Fotopoulou A, Zelaya
F, Thacker M, Massat N, Huggins JP, Vennart W, Choy E, Daniels M, Williams
SC. Alterations in resting-state regional cerebral blood flow demonstrate
ongoing pain in osteoarthritis: an arterial spin-labeled magnetic resonance
imaging study. Arthritis Rheum. 2012;64:3936–46. Submit your next manuscript to BioMed Central
83. Gregory S, ffytche D, Simmons A, Kumari V, Howard M, Hodgins S, and we will help you at every step:
Blackwood N. The antisocial brain: psychopathy matters. Arch Gen
Psychiatry. 2012;69:962–72. • We accept pre-submission inquiries
84. Sturgill J, McGee E, Menzies V. Unique cytokine signature in the plasma of • Our selector tool helps you to find the most relevant journal
patients with fibromyalgia. J Immunol Res. 2014;938576.
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85. Gueorguieva R, Krystal JH. Move over ANOVA: progress in analyzing
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86. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures
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Feliu-Soler et al.

BMC Complementary and Alternative Medicine (2016) 16:81

STUDY PROTOCOL Open Access

Cost-utility and biological underpinnings of

(Continued from previous page)

Background connectivity were associated with pain reduction in FMS

Fig. 1 Flowchart of participants in the EUDAIMON study

Interventions not directed at symptom reduction but more fundamen-

Table 3 Study periods at which measures and data are collected

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