Open access Protocol Efficacy, cost-­utility and physiological effects of Acceptance and Commitment Therapy (ACT) and Behavioural Activation Treatment for Depression (BATD) in patients with chronic low back pain and depression: study protocol of a randomised, controlled trial including mobile-­technology-­based To cite: Sanabria-­Mazo JP, Forero CG, Cristobal-­Narváez P, ecological momentary assessment (IMPACT study) et al. Efficacy, cost-­utility and physiological effects of Acceptance and Commitment Therapy (ACT) and Behavioural Activation Treatment for Depression (BATD) in patients Juan P Sanabria-­Mazo ‍ ‍,1,2,3 Carlos G Forero,2 Paula Cristobal-­Narváez,3,4 with chronic low back pain Carlos Suso-­Ribera,5,6 Azucena García-­Palacios,5,6 Ariadna Colomer-­Carbonell,1,3 and depression: study protocol of a randomised, controlled Adrián Pérez-­Aranda,1,7 Laura Andrés-­Rodríguez,1 Lance M McCracken,8 trial including mobile-­ Francesco D'Amico,9 Pere Estivill-­Rodríguez,3 Bernat Carreras-­Marcos,3 technology-­based ecological Antonio Montes-­Pérez,7 Olga Comps-­Vicente,7 Montserrat Esteve,6,10,11 momentary assessment (IMPACT study). BMJ Open Mar Grasa,6,10,11 Araceli Rosa,4,12 Antonio I Cuesta-­Vargas ‍ ‍,13,14 Michael Maes,15 2020;10:e038107. doi:10.1136/ Xavier Borràs ‍ ‍,1 Silvia Edo,1 Antoni Sanz,1 Albert Feliu-­Soler,1,3 bmjopen-2020-038107 Juan R Castaño-­Asins,7 Juan V Luciano ‍ ‍3 ►► Prepublication history and additional material for this paper are available online. To view these files, please visit ABSTRACT pretreatment, post-­treatment and at 12 months follow-­up, the journal online (http://​dx.​doi.​ Introduction The IMPACT study focuses on chronic low being pain interference the primary outcome measure. org/​10.​1136/​bmjopen-​2020-​ back pain (CLBP) and depression symptoms, a prevalent The following physiological variables will be considered at 038107). and complex problem that represents a challenge for pretreatment and post-­treatment assessments in 50% of JPS-­M and CS-­R are joint first health professionals. Acceptance and Commitment the sample: immune-­inflammatory markers, hair cortisol authors. Therapy (ACT) and Brief Behavioural Activation Treatment and cortisone, serum cortisol, corticosteroid-­binding AF-­S, JRC-­A and JVL are joint for Depression (BATD) are effective treatments for patients globulin and vitamin D. Polymorphisms in the FKBP5 senior authors. with persistent pain and depression, respectively. The gene (rs3800373, rs9296158, rs1360780, rs9470080 objectives of this 12 month, multicentre, randomised, Received 27 February 2020 and rs4713916) will be analysed at baseline assessment. controlled trial (RCT) are (i) to examine the efficacy Revised 30 May 2020 Moreover, we will include mobile-­technology-­based and cost-­utility of adding a group-­based form of ACT Accepted 11 June 2020 or BATD to treatment-­as-­usual (TAU) for patients with ecological momentary assessment, through the Pain CLBP and moderate to severe levels of depressive Monitor app, to track ongoing clinical status during ACT symptoms; (ii) identify pre–post differences in levels of and BATD treatments. Linear mixed-­effects models using © Author(s) (or their some physiological variables and (iii) analyse the role of restricted maximum likelihood, and a full economic employer(s)) 2020. Re-­use polymorphisms in the FKBP5 gene, psychological process evaluation applying bootstrapping techniques, acceptability permitted under CC BY-­NC. No measures and physiological variables as mediators or curves and sensitivity analyses will be computed. commercial re-­use. See rights moderators of long-­term clinical changes. Ethics and dissemination This study has been approved and permissions. Published by BMJ. Methods and analysis Participants will be 225 patients by the Ethics Committee of the Fundació Sant Joan de with CLBP and moderate to severe depression symptoms Déu and Hospital del Mar. The results will be actively For numbered affiliations see recruited at Parc Sanitari Sant Joan de Déu (St. Boi de disseminated through peer-­reviewed journals, conference end of article. Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), presentations, social media and various community Correspondence to randomly allocated to one of the three study arms: TAU vs engagement activities. Juan V Luciano; TAU+ACT versus TAU+BATD. A comprehensive assessment Trial registration number NCT04140838 ​jvluciano@​pssjd.​org to collect clinical variables and costs will be conducted Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 1 Open access thus HPA function too) and its interaction with distal and Strengths and limitations of this study proximal stressors has not been previously examined in ►► This is thought to be the first study comparing the efficacy and cost-­ comorbid chronic pain and depression. This interaction utility of Acceptance and Commitment Therapy and Behavioural could be key for understanding the etiological mecha- Activation Treatment for Depression in addition to treatment as usu- nisms involved in such conditions, as well as for identi- al (TAU) versus TAU alone for the management of comorbid chronic fying potential therapeutic mechanisms.20–26 In addition, low back pain (CLBP) and depression. hair cortisol reflecting long-­term HPA activity has recently ►► The IMPACT protocol combines assessment with classical legacy emerged as a potential predictor of treatment response in measures and ecological momentary assessment to obtain more anxiety and depression.19 precise information on the dynamics of the variables to be assessed. The therapeutic options available for chronic pain ►► Besides self-­report measures, this study will include physiological management are very extensive. Interestingly, a number variables such as cortisol, cytokines and vitamin D levels, in order of psychological treatments have shown positive effects to know the impact of treatments on these stress-­related biological variables. at the psychological, neuroendocrine and immune levels ►► As far as we know, this study represents the first attempt to explore in a wide range of pain-­related conditions, as well as for the predictive role of FKBP5 gene and distal or proximal stressful depression.27 These generally comprise forms of Cogni- experiences in response to psychological treatments for CLBP and tive Behavioural Therapy (CBT), including treatments depression. that focus on mindfulness, and Acceptance and Commit- ►► Blinding of patients and therapists will not be possible. This rep- ment Therapy (ACT). In a meta-­analysis of 11 clinical resents a fundamental problem in randomised controlled trials with trials in patients with chronic pain,28 ACT was better than psychological treatments. the control conditions in improving pain acceptance, functional impairment, anxiety, depression and pain intensity. In addition, another form of CBT, Behavioural INTRODUCTION Activation Treatment for Depression (BATD), has proved Recent systematic reviews have estimated that more to be as effective as classical CBT in reducing depressive than 10% of the general population worldwide suffers symptoms in a meta-­analysis.29 chronic pain.1 2 Among chronic pain conditions, chronic Both treatments, ACT and BATD, are potentially cost-­ low back pain (CLBP) is one of the most prevalent and effective for the management of chronic pain and depres- costly.3 4 Depression is by far the most common psychi- sion, respectively, according to a recent systematic review atric problem associated with CLBP.5 6 carried out by the team of the present project.30 In our The relationship between pain and depression is bidi- opinion, it is important to demonstrate their cost-­utility rectional.7 Some theories postulate that pain and depres- for the management of a complex problem as relevant sion share common physiopathological mechanisms as comorbid CLBP and depression, to characterise the and that one can lead to the other via activation of these psychological and physiological mechanisms through mechanisms. This could include mediators of the inflam- which they exert their therapeutic effect, and identify matory and immune response and the role they play in potential predictors of treatment response. endogenous nociceptive regulation and affective regu- The objectives of the IMPACT (Improving Pain and Depres- lation.8 In particular, cytokines appear to have a crucial sion with ACT and BATD) study are (i) to examine the efficacy role in chronic pain conditions, so that a high expression and cost-­utility of adding ACT or BATD to treatment-­as-­ of proinflammatory mediators can alter the physiopa- usual (TAU) in the management of patients with CLBP thology of chronic pain.9 At the same time, inflammatory and moderate to severe depression for improving pain mediators of innate immunity and cell-­mediated immu- interference (primary outcome) and depressive, anxious nity cooperate in the onset and expression of depres- and stress symptoms, pain catastrophising and quality of sion.10 On the other hand, a clear correlation between life (secondary outcomes); (ii) to identify pre–post differ- vitamin D deficiency and the presence of chronic pain ences in levels of different physiological variables (immune-­ and depression has been described in recent years.11 inflammatory markers, hair cortisol and cortisone, serum Vitamin D substantially modulates the inflammatory cortisol, corticosteroid-­ binding globulin (CBG) and response by controlling cytokine expression, inhibiting vitamin D) and correlate these changes with those observed proinflammatory, and increasing anti-­inflammatory ones. at self-­report measures and (iii) analyse the role of polymor- Vitamin D deficiency could affect the response of patients phisms in the FKBP5 gene, psychological process measures with chronic pain to the treatments applied.12–15 and physiological variables as mediators or moderators of Chronic stress appears to play a pivotal role in mental and long-­term clinical changes. physical health and leads to hypothalamic–pituitary–ad- renal axis (HPA) dysregulation which in turn impairs the stress response.16 17 Genetic, epigenetic and early stress METHODS AND ANALYSIS exposure, among other factors, shape individual resil- Trial design ience and vulnerability, as well as HPA activity.18 19 In this The RCT protocol has been developed following the regard, the FKB506 binding protein 51 gene (FKBP5) is a Standard Protocol Items: Recommendations for Inter- critical regulator of glucocorticoid receptor activity (and ventional Trials.31 For reporting, we will follow the 2 Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 Open access guidelines of the Consolidated Standards of Reporting Potential participants will be excluded according to the Trials (CONSORT)32 and the Consolidated Health following exclusion criteria (based on previous RCTs):36 Economic Evaluation Reporting Standards statement.33 the presence of cognitive impairment; previous (last year) IMPACT is a 12-­month multicentre RCT with three treat- or current psychological treatment; presence of severe ment arms: TAU, TAU+ACT and TAU+BATD. Therefore, psychiatric disorder (eg, psychotic disorder), substance patients in three arms will receive TAU, and ACT and dependence/abuse or presence of degenerative medical BATD will be complementary treatments to the standard disease (eg, Alzheimer’s dementia); patients involved in one provided in the Spanish National Health System. litigation with the health system; patients with scheduled surgical intervention or other interventions and inability Recruitment strategy to attend group treatment sessions. For the biomarkers Potential participants are those patients with CLBP diag- substudy (50% of patients in each study arm), the nosis seeking services currently or in the last 3 years at following exclusion criteria will be added: cold/infection Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, symptoms on the day of blood collection; needle phobia; Spain) or Hospital del Mar (Barcelona, Spain). These BMI>30 kg/m2 or weight >110 kg; consumption >8 units patients will be screened to evaluate their current pain of caffeine per day (maximum one drink with caffeine on intensity and the Patient Health Questionnaire (PHQ-9) the day of testing); smoker >5 cigarettes a day; hair length will be administered to confirm the presence of moderate <3 cm, use of glucocorticoid medication or anticytokine to severe active depression. drugs and being pregnant or breastfeeding. Procedure and randomisation Sample size A list of potential participants (with contact telephone Sample size was estimated considering a target power number) will be presented to the study team at each centre. of 80%, an alpha level of 0.05 and was calculated taking This list will pass to the clinicians, so that they carry out the primary outcome measure into account (Brief Pain the telephone screening and set an appointment for the Inventory-­ Interference Scale (BPI-­ IS)). The estimate first face-­to-­face interview (performed by health psychol- was based on a one-­way analysis of variance (followed ogists) with all those who agree to participate and meet by Dunn–Bonferroni post-­hoc tests) for between-­group the eligibility criteria. After obtaining informed written differences in the change from baseline to subsequent consent, the evaluators will conduct the baseline inter- assessment, assuming no systematic baseline or other view using battery of computer-­administered measures. covariate group differences after randomisation. The Patients will be contacted again after 3–5 days to obtain minimal clinically significant difference for the BPI-­IS is 1 peripheral blood and hair samples. These extractions will point (SD of improvement of 2 points).34 This calculation be performed at a preset time (8.00–9.00 AM) to reduce yielded a suggested sample size of 64 patients per study circadian variability in the levels of the immune and endo- arm. Allowing for a potential attrition rate of 15% our crine markers evaluated. In order to limit the effects of final sample size was 75 participants per group. medication on the study variables, patients will be asked to refrain from taking analgesic or anti-­ inflammatory Eligibility criteria drugs within 72 hours prior to obtaining the biological All participants will meet the following inclusion criteria: samples. male or female aged 18–70 years; diagnosis of CLBP (>3 Random assignment of participants to study arms will months) according to medical history; pain intensity >4 be executed after baseline assessments as recommended points out of 10 points on a numeric pain rating scale in by the CONSORT guidelines.32 Randomisation will be the past week; moderate to severe depressive symptoms planned and executed by a statistician with no involve- according to PHQ-9 (total score ≥10); fluent in Spanish ment in screening, enrolment or treatment processes. language and provision of written informed consent to Once written consent and baseline assessment have been participate (a copy of the consent form is provided as an completed, study participants will be given a unique (online supplementary document). Only participants personal code and randomised by means of an online with a score of at least 60% on the question ‘Which situ- randomisation programme. The computer-­ generated ation describes your pain over the past 4 weeks the best? randomisation will apply a permuted block design to 100% of the pain in the low back; 80% of the pain in ensure that the groups are balanced taking biomarkers the low back and 20% in the leg(s); 60% of the pain in substudy eligibility criteria into account. The randomi- the low back and 40% in the leg(s); 50% of the pain in sation list will remain with the clinical trials committee the low back and 50% in the leg(s); 40% of the pain in of Fundació Sant Joan de Déu (FSJD) for the full dura- the low back and 60% in the leg(s); or 20% of the pain tion of the RCT. This list will be stored in an encrypted in the low back and 80% in the leg(s)’ will be included. file on a password-­ protected computer in the clinical With this question, we will be able to differentiate domi- trials supervisor’s office to assure concealment of alloca- nant leg pain from dominant CLBP, avoiding the likeli- tion. Participants’ assignments will be communicated to hood of recruitment of participants suffering dominant administrative personnel of each centre by the clinical radiculopathy.35 trials supervisor via e-­mail. Patients will be informed of Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 3 Open access their group allocation by the administrative personnel, Treatment-as-usual+Acceptance and commitment therapy who will send a notification in sealed, opaque numbered The ACT treatment component includes, as the envelopes. name implies, methods to promote acceptance (non-­ Two subsequent face-­to-­face assessments will be carried avoidance) of unwanted experiences, and engagement out at the end of the 8 weeks of treatment (post-­treatment) in goal-­directed and values-­ based action. Alternatively, and at 12 months follow-­up (56 weeks after randomisa- ACT is focused on promoting psychological flexibility, tion). To obtain the biological samples at post-­treatment, or the ability to develop behaviour patterns open, aware the same procedure as in the baseline assessment will be and engaged37 (see table 1). Patients suffering from pain followed. See figure 1 for patients’ flow chart. recurrently use avoidance as a coping strategy, and at its most basic level, this therapy is designed to address that by providing a broader set of skills. There is now consid- Treatments erable evidence for the therapeutic model underlying Treatment-as-usual ACT38 and for the treatment approach itself as applied to In Spain, chronic pain management is mainly carried out chronic pain. Recent meta-­analyses supported the effec- by general practitioners (GPs) in regular consultations, tiveness of ACT in patients with chronic pain.28 39 commonly consisting of face-­to-­face visits (5–10 min) to monitor the physical and emotional status of the patient. Treatment-as-usual+Behavioural activation treatment for GPs usually provide advice, and prescribe pharmaco- depression therapy (pain medications, hypnotics and antidepres- BATD is based on the application of learning principles sants) or make onward referrals to pain units in hospitals to the pattern of withdrawn or reduced behaviour activity when more specialised pain management procedures are associated with depression (see table 2). Its objective is to required. The frequency of consultations is based on the counteract depressive symptoms and, as a consequence, to type and stage of disease of each patient. For this study, ensure that patients regain a productive and emotionally usual care will be the same as in routine daily practice, satisfying life. Its methodology essentially consists in ‘acti- without any modifications. vating’ subjects with depression through programming Figure 1 Flowchart of the IMPACT study based on the Consolidated Standards of Reporting Trials guidelines. ACT, Acceptance and Commitment Therapy; BATD, Brief Behavioural Activation Treatment for Depression; CLBP, chronic low back pain; EMA, ecological momentary assessment; ITT, intention-­to-­treat; TAU, treatment as usual. 4 Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 Open access Table 1 Outline of ACT group treatment sessions Session ACT 1 Participants’ and clinician’s presentation. Psychoeducation and introduction to ACT (ACT basics; scientific advances in chronic pain and depression management; psychological theories of pain, suffering and stress; stressors, fears and indicators; identification of values; breathing exercises). 2 Value analysis I. Problems of experiential avoidance. Creative hopelessness through metaphors: control is the problem and not the solution. Anxiety, fight and flight, and its effects. Accepting the risk of the life’s journey: experiences, feelings and emotions. 3 Value analysis II. Objectives. Laws of thought and consequences of language. Mind and deactivation of thought (cognitive defusion): creating distance with thoughts. Learning meditation techniques and effects. Practicing meditation exercises. 4 Value analysis III. Psychological barriers and obstacles. Emotional distress and its consequences. Emotional phenomena, personality variables and health states. Discovering commitments with committed actions. 5 Values and feelings. Taking the initiative with a ‘Plan of action and willingness’. Psychological flexibility, resilience and self-­motivation. Expansion and body scan exercises. Learning to relax. 6 Taking a direction. The self as context, process and content. Awareness of the present: ‘here and now’. The brain and emotions: managing situations and overwhelming emotional responses. 7 Dare and change: willingness and determination. Self-­awareness, assertiveness and self-­esteem. Experiential expansion exercises: felt sensations. Happiness according to positive psychology. Benefits of physical exercise: movement. At the beginning of each session, time will be taken to briefly go over what was discussed in the previous session and every person’s weekly records will be collected and briefly commented on. ACT, Acceptance and Commitment Therapy. and conduct of behaviours that are likely to increase the Both psychological treatments (ACT and BATD) will experiences of directly positively reinforcing qualities be administered in a group format of 8 weekly 1.5 hour in their current context. A meta-­analysis supported the sessions. In RCTs of psychological treatment, it is recom- effectiveness of behavioural activation in patients with mend that more than one therapist deliver each treatment depression.29 to create a more realistic and generalisable impression of Table 2 Outline of BATD group treatment sessions Session Description 1 Participants’ and clinician’s presentation. Collection of information related with areas of activity and interaction contexts. Delivery of activity log to obtain an accurate assessment of the patient’s daily activities, which is useful for: providing a baseline measure and comparing their progress when their activity level increases later in the treatment. 2 Identification of information related to depressive behaviours. Exploration of problematic behaviours and identification of patients’ objectives regarding treatment. 3 Obtaining complementary information regarding the characteristics of the history of patient interactions and any contexts and interactions that reinforce depressive behaviours. Establishment of short-­term, medium-­term and long-­term goals. 4 Explanation of the hypotheses of factors associated with the origins, maintenance and therapeutic change of problematic behaviour. In this session, 10 personalised activities are selected according to each person’s own needs and desires, without any particular order. With the selected activities, a ranking is then generated that goes from the least difficult to the most difficult activity. 5 Once the 10 target activities have been identified, a record is made to track their progress weekly, including the number of times they would like to complete the activity in a period of 1 week (the ideal frequency). The number of activities varies each week, but they always range between three and five activities. 6 Discussion of what was obtained from the records in general. Exploration of the satisfaction with the activities. 7 Coping abilities. How to approach emotions and reactions to events and responses associated with depression. Relationship between avoidance behaviours and maintenance of difficulties. 8 Examination of new behaviours to be incorporated. Discussion about the goals achieved and the barriers to maintain the weekly activity plan. Farewell. BATD, Brief Behavioural Activation Treatment for Depression. Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 5 Open access effectiveness,40 so each therapy will be conducted by at Study measures least three different therapists. In addition to prior expe- All participants will be assessed with a computer-­ rience delivering ACT or BATD, all therapists will do a administered battery of measures, using the software 3-­hour ‘refresher’ training prior to starting the RCT with Research Electronic Data Capture (REDCap) (see the aim also to assure simultaneous fidelity to the manual table 3). with flexibility within sessions. Finally, to monitor treat- ment fidelity within ACT and BATD, research assistants Measures for sociodemographic characteristics, clinical will video-­tape all sessions. Two independent experts in features and screening both treatments have been selected for his expertise in Sociodemographic Questionnaire. Information about gender, the delivery of these therapies. They will rate adherence to date of birth, marital status, living arrangements, educa- treatment using videotapes of therapy sessions. A random tional level, income level and employment status. sample of tapes, stratified by therapist and therapy session Clinical data. Ad hoc interview collecting data about will be rated using the instruments described below. history and duration of CLBP and depression symptoms, Table 3 Time points at which measures and data are collected Measures Pre During Post 1-­year follow-­up Sociodemographic, clinical and screening measures  Sociodemographic data (gender, date of birth, marital status) X        Clinical data (years of evolution, comorbidities) X        PHQ-9 (depression symptoms) X        CIDI (diagnosis of depression) X        CTQ-­SF (childhood trauma) X       Primary outcome measure  BPI-­IS (pain interference) X   X X Secondary outcome measures  NRS (pain intensity) X   X X  DASS-21 (anxiety, depression and stress) X   X X  PCS (pain catastrophising) X   X X Process measures          CPAQ-8 (pain acceptance) X   X X  BADS-­SF (behavioural activation for depression) X   X X Other measures          EQ-­5D-­5L (quality of life) X   X X  CEQ (credibility and expectations regarding treatments) X   X    CSRI (medication consumption and service receipt) X     X  AET (negative effects of psychological treatments)     X    PGIC and PSIC (impression of change)     X    ACT-­FM (fidelity measure)   X X    QBAS (fidelity measure)   X X    Pain Monitor app   X     Physiological variables  Immune-­inflammatory markers X   X    HPA and vitamin D markers X   X    FKBP5 polymorphisms X       ACT-­FM, Acceptance and Commitment Therapy Fidelity Measure; AET, Adverse Effects of Treatments checklist; BADS-­SF, Behavioural Activation for Depression Scale (short form); BPI-­IS, Brief Pain Inventory-­Interference Scale; CEQ, Credibility/Expectancy Questionnaire; CIDI, Composite International Diagnostic Interview—depression section; CPAQ-8, Chronic Pain Acceptance Questionnaire (8-­item version); CSRI, Client Service Receipt Inventory; CTQ-­SF, Childhood Trauma Questionnaire−Short Form; DASS-21, Depression Anxiety Stress Scales-21; EQ-­ 5D-­5L, EuroQoL; HPA, hypothalamic–pituitary–adrenal; NRS, Numerical Pain Rating Scale; PCS, Pain Catastrophising Scale; PGIC, Patient Global Impression of Change; PHQ-9, Patient Health Questionnaire; PSIC, Pain Specific Impression of Change; QBAS, Quality of Behavioral Activation Scale. 6 Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 Open access and family history of medical/mental illness. Information patients with chronic pain and the psychometric proper- regarding comorbidity with other diagnosed physical–psy- ties are well-­established (α>0.80).48 chiatric conditions and the type and dose of current drugs will be consulted in medical records. Secondary outcome measures The Patient Health Questionnaire (PHQ-9).41 42 Each of The Numeric Rating Scale (NRS).49 The NRS is a unidimen- the nine PHQ items corresponds to one of the DSM-­IV sional measure of pain intensity mainly used for adults. Diagnostic Criterion A symptoms for major depressive The most used version is an 11-­point numeric scale (a disorder. Response options are ‘not at all’, ‘several days’, horizontal bar or line) with 0 representing ‘no pain’ and ‘more than half the days’ and ‘nearly every day’, scored 10 representing ‘worst pain imaginable’. Time frames as 0, 1, 2 and 3, respectively. In addition, the PHQ-9 has vary between studies. In the present work, respondents a functional impairment question (item 10) that asks will be asked to report average pain intensity over the last how much the symptoms they endorse in the first nine week. items interfere with daily functioning. The questionnaire The Depression Anxiety Stress Scales-21 (DASS-21).50 The can be used algorithmically for the probable diagnosis DASS-21 is a self-­report measure developed to differen- of a depressive disorder, or as a continuous measure of tiate between features of depression (low positive affect), scores ranging from 0 to 27, with cut-­off points of 5, 10, anxiety (physical arousal) and stress (psychological 15 and 20, which set the levels of symptoms of depres- tension/agitation) in clinical and non-­clinical samples. In sion as mild, moderate, moderately severe or severe. In addition, the DASS has been validated in clinical chronic the present work, if potential participants obtain a score pain samples.51 Responders are required to indicate the ≥2 at item 9 (risk of suicide), additional assessment will presence of a symptom over the previous week. Each item be undertaken to explore the real risk of suicide. The is scored from 0 (‘did not apply to me at all over the last telephone-­ administered version of the PHQ-9 showed week’) to 3 (‘applied to me very much or most of the adequate reliability (α=0.82),43 therefore it seems highly time over the past week’). There are seven items on each recommendable for our telephone-­ based screening of of the three subscales (Depression, Anxiety and Stress). concomitant depression symptomatology. Therefore, total scores in each scale can range from 0 to The Composite International Diagnostic Interview—depres- 21. Higher scores indicate more severe levels of depres- sion section (CIDI V.3.0).44 The CIDI is a fully structured sion, anxiety and stress. The Spanish version obtained diagnostic interview developed and validated by the adequate internal consistency (0.84, 0.70 and 0.82 for the WHO to be used with the general population by trained depression, anxiety and stress scales, respectively).52 lay interviewers. The interview will be used to confirm the The Pain Catastrophising Scale (PCS).53 The PCS will be presence of major depression. The psychometric proper- used to assess the pain catastrophising thoughts. It is a ties of the CIDI have been examined extensively and are 13-­item measure that captures three dimensions: rumina- highly sound.44 tion over pain, magnification of pain and helplessness in The Childhood Trauma Questionnaire−Short Form (CTQ-­ the face of pain symptoms. Each item is answered on a SF).45 The CTQ-­SF is a 28-­item retrospective question- rating scale of 5 points (0 = ‘never’, 4 = ‘almost always’). naire designed to capture five dimensions of childhood Total scores on each scale can range from 0 to 52, with maltreatment (each scale includes five items): physical higher scores indicating more pain catastrophising abuse; emotional abuse; sexual abuse (SA); physical thoughts. The Spanish PCS has shown good internal neglect and emotional neglect (EN). Additionally, there is a three-­ item minimisation/denial scale. Items are consistency (α=0.79) and test–retest reliability (r=0.84).54 scored from 1 to 5 in order to reflect the frequency of maltreatment experiences (‘never true’ to ‘very often Process measures true’). Higher scores indicate greater child abuse and The Chronic Pain Acceptance Questionnaire (CPAQ-8).55 The neglect. The Spanish CTQ-­ SF obtained Cronbach’s α CPAQ-8 is a self-­report measure reflecting engagement in values ranging from 0.66 for EN to 0.94 for SA.46 important activities with pain and willingness to experi- ence pain. The eight items are rated on a 7-­point scale (0= Primary outcome measure ‘never true’, 6= ‘always true’). Higher total scores reflect The Brief Pain Inventory-­Interference Scale (BPI-­IS).47 The greater acceptance. The Spanish CPAQ‐8 has adequate BPI-­IS is a seven-­item self-­report measure that assesses internal consistency, a Cronbach α values of 0.75.56 the extent to which pain interferes with general activity, The Behavioural Activation for Depression Scale—short walking, work outside and inside the home, sleep, mood, form (BADS-­SF).57 58 Behavioural activation is conceptual- enjoyment of life and relationships, each rated on a 0 ised as a key therapeutic process in BATD. The BADS-­SF (‘does not interfere’) to 10 (‘completely interferes’) assesses this construct by means of a 9-­item scale. Items scale. Scoring is done by computing the arithmetic mean are answered on a Likert scale of 7 points ranging from of all items, such that higher scores indicate greater pain 0 (‘not at all’) to 6 (‘completely’). Higher scores indicate interference. A reduction of 1 point on the BPI-­ IS is greater behavioural activation in depressed individuals. considered as a clinically meaningful change. The BPI-­IS The BADS-­SF has shown adequate internal consistency is highly recommended as an outcome in clinical trials of (α=0.82).57 Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 7 Open access Other measures of meaningful change in treatments for chronic pain. The EuroQoL (version EQ-­5D-­5L).59 The EQ-­5D-­5L is a The most frequently used scale is a 7-­point numerical health-­related quality of life questionnaire that consists scale (from 1= ‘Much better’ to 7= ‘Much worse’). The of two parts: in the first part, the individual’s difficul- PGIC is one item referred to the perception of global ties concerning mobility, self-­care, pain/discomfort and improvement, whereas the PSIC asks about the impres- anxiety/depression are evaluated; and in the second sion of change in more specific domains: physical and part, the current state of perceived health is assessed by a social functioning, work-­ related activities, mood and Visual Analogue Scale (VAS) ranging from 0 to 100. The pain. These scales will be completed by the participants EQ-­5D-­5L scores will be used to calculate the Quality-­ who are assigned to ACT and BATD. Adjusted Life Years (QALYs) during the follow-­up period, The Acceptance and Commitment Therapy Fidelity Measure adjusting the duration of time affected by the health (ACT-­FM).63 The ACT-­FM is a recently developed 25-­item outcome by the value of the utility. measure that captures four areas: therapist stance, The Credibility/Expectancy Questionnaire (CEQ).60 The open response style, aware response style and engaged CEQ is a quick and easy to complete measure widely response style (each split into ACT consistent and ACT used to assess credibility and expectations regarding inconsistent items, making eight sections in all). Items treatments. The CEQ contains six items: three of them are rated on a 4-­point scale from 0 (‘behaviour never focused on therapy credibility (the extent to which the treat- occurred’) to 3 (‘therapist consistently enacts this ment appears logical; the extent to which the treatment behaviour’). appears useful and the confidence with which the patient The Quality of Behavioural Activation Scale (QBAS).64 The would recommend the treatment to a friend having the same problem) and three items assessing expectations (the QBAS is a 14-­item scale designed to assess ability in imple- extent to which the patient thinks an improvement will menting behavioural activation. Items are rated using a occur; the extent to which the patient feels that therapy 7-­ point Likert-­type scale with higher scores indicating will help him/her and the extent to which the patient higher implementation quality (total score range 0–96). feels an improvement will occur). The CEQ has demon- A score of 3 on each item corresponds to satisfactory skill strated satisfactory psychometric properties.60 in implementing the BA component delineated by that The Client Service Receipt Inventory (CSRI).61 The CSRI item. Preliminary psychometric analysis of this instru- will be used to collect retrospective data on medication ment yielded adequate inter-­rater reliability (intraclass consumption and service receipt. Regarding medication correlation coefficient=0.72). intake, patients are asked to bring their daily medication prescriptions and the following information for pain-­ Ecological momentary assessment (EMA) related drugs (ie, analgesics, anti-­inflammatories, opioids, Pain severity and other pain-­related variables included in muscle relaxants, antidepressants) is recorded: the name the study (eg, mood symptoms and health-­related quality of the drug, the dosage, the total number of prescrip- of life, to name some examples) can fluctuate during the tion days and the daily dosage consumed. Concerning day and across days depending on many factors, such service receipt, patients are asked about the total visits as environmental stressors. Additionally, retrospective to accident and emergency services, the total number evaluation is known to be susceptible to memory bias.65 of general inpatient hospital admissions, the number of Retrospective evaluation can lead to overestimation of diagnostic tests administered and the total visits to health- the symptomatology, which can be avoided by frequent care professionals for pain management, including family evaluations of the present symptomatology. Moreover, the physicians, nurses, social workers, psychologists, psychia- prospective and repeated evaluation over time substan- trists, group psychotherapy and other community health- tially improves the accuracy, reliability and quality of care professionals, specifying in each case if these services research.66 While EMA has been difficult for decades were provided by the public or by the private sector. The due to the problems associated with paper diaries, the CSRI will be administered on two occasions: at baseline availability of smartphones and the explosion of apps and at 12-­month follow-­up, both referring to the previous is making EMA easiest than ever.67 There is growing 12 months. Medical records will be checked to verify the accuracy of the collected data. evidence indicating that well-­designed smartphone can Ad-­hoc measure of Adverse Effects of Treatments. It was be very easy to use and well accepted even in relatively old developed in a previous RCT36 and will be used to check pain populations, and compliance rates with daily assess- the presence of negative effects of ACT and BATD. The ment have been as high as 75%.66 In the present study, we item reads as follows: Have you experienced, during the course will use the Monitor del Dolor (Pain Monitor) app, which of the psychological treatment, any unwanted symptom that you has been recently validated in an empirical study68 that think might be directly or indirectly associated with the psycholog- assessed a number of biopsychosocial constructs twice a ical intervention? day during 4 weeks. In the present work, we will assess The Patient Global Impression of Change (PGIC) and the daily (twice a day: once in the morning and once in the Pain Specific Impression of Change (PSIC).62 Patient impres- evening, at convenient times) the items listed in table 4 sion of change measures are frequently used as indicators during the 8-­week treatment period. 8 Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 Open access will be taken, packed in foil to avoid light impact and Table 4 List of items administered via pain monitor app stored at room temperature. For the hormones deter- Items Morning Evening mination only the 1 cm of hair closest to the scalp will Pain intensity X X be analysed. The extraction of hormones will be done Fatigue X X from pre–post samples in the Nutrition and Obesity Perceived control over pain X X Laboratory of the Biochemistry and Molecular Medi- cine Department (University of Barcelona, UB), as they Openness to thoughts and feelings X X are obtained. The protocol consists, after hair samples Focused in the present moment X X weighing, of a previous wash with 5 mL of isopropanol to Guided by goals and values X X remove accumulated dirt and sweat, detergent residue or Perceived competence X X cosmetic products. Then, hair samples are dried at 37°C Activity level X X and minced. Cortisol and cortisone are extracted in 2 mL liquid chromatography with tandem mass spectrometry Perceived stress X X (LC–MS) grade methanol and stirring overnight at room Perceived social support X X temperature in the presence of deuterated Cortisol-­d4 Rumination X X and Cortisone-­ d8 (Sigma Aldrich solution C-113 and Magnification X X 900170). The methanol is transferred to test tubes and Helplessness X X evaporated in a dry bath at 50°C under a stream of N2. The dried tubes are stored at −20°C until the quantification of Sleep disturbance X   cortisol and cortisone by LC-­MS/MS at the Scientific and Interference with leisure activities X X Technological Centres of the UB (CCiTUB). The levels Interference with work-­related activities X X of vitamin D and cortisol in serum will be determined by Rescue medications X X ELISA (DRG EIA-5396, EIA-­1887R and EIA-3647) and CBG by RIA125I (IBL KIP1809) in a radioactive facility The Pain Monitor app informs patients automatically when to respond (by default, at 11 AM and 7 PM) using a push notification situated at the UB. system, but patients can change the assessment times with a Polymorphisms in the FKBP5 gene. A blood sample of 4 mL flexibility of 2 hours from given times. Collected data are stored on will be collected in a vial with EDTA anticoagulant (BD a secure server at the Jaume I University, Spain. The app and the Vacutainer; BD, NJ, USA). Specifically, the analysis of the data are stored on different servers with different domain names genetic variants of the FKBP5 gene will be carried out in and connected locally only (the server containing the data does not have Internet access).69 the Molecular Genetics Laboratory of the Anthropology Unit (UB). The samples will be coded, preserved and the DNA will be extracted with the Real Extraction DNA kit Physiological variables (Durviz S.L.U., Valencia, Spain). Quality of the DNA will Immune-­inflammatory markers. After drawing the blood, it be tested using the Nanodrop D1000 (Thermoscientific, will be allowed to coagulate for a minimum of 30 min at Wilmington, DE). The genotyping of the five proposed room temperature and then centrifuged for 10 min at SNP polymorphisms in the FKBP5 gene will be carried out 1000 g. The resulting serum will be stored at −80°C during using TaqMan 5′ exonuclease assay (Applied Biosystems) the same morning of extraction until it is ready to be anal- technology at the Scientific and Technological Centres of ysed. All samples (pre and post) will be analysed in a single the UB (CCiTUB): rs3800373 (SNP1), rs9296158 (SNP2), analytical batch to reduce inter-­assay variability (approx. rs1360780 (SNP3), rs9470080 (SNP4) and rs4713916 15%). The serum levels of cytokines IL-6, CXCL-8, IL-10, (SNP5). The PCR reaction will be carried out on the ABI TNF-α, IL-1β and high-­sensitivity C-­reactive protein will PRISM 7900HT instrument thermal cycler and geno- be evaluated. For the quantification of the cytokines, the type analysis will be carried out using SDS V.2.1 software Milliplex reagents from the company MerckMillipore (Applied Biosystems). For accuracy of genotyping, 15% of will be used and analysed using a Luminex platform. the samples, randomly selected, will be genotyped twice. The high sensitivity multiplex kit will be used: Human Finally, the estimation of haplotypes will be conducted High Sensitivity T Cell, catalogue number: HSTCMAG- in order to increase the power to detect genetic associa- 28SPMX11 adapted to the aforementioned cytokines. tions.69 Linkage disequilibrium between the five polymor- The hs-­PCR will be quantified using turbidimetry in an phisms in the FKBP5 gene will be examined by pair-­wise Olympus AU5400 auto-­analyser. comparisons of r2 and D’ using Haploview V.4.2.70 Estima- Hair cortisol and cortisone, blood cortisol, CBG and vitamin tion of FKBP5 haplotype combination per subject will be D. Hair samples will be obtained from the middle-­lower conducted using a Bayesian approach implemented with back area of the head as it is less exposed to environ- PHASE software.71 mental conditions such as sunlight, which affect the hormone levels in hair and as close as possible to the Statistical analysis scalp. No products such as gels, lacquers or softeners will The main analysis will compare the effect of the treat- be used during the 3 days prior to obtaining the sample. ments on the primary outcome (pain interference at A strand about 10 mm thick from the posterior vertex 12 months follow-­up). All data analyses will be carried out Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 9 Open access following an intention-­to-­treat (ITT) principle, that is, the start of the treatments will be calculated by the area regardless of protocol adherence. Then, we will compute under the curve. analysis of the primary outcome post-­treatment and anal- The direct costs will be calculated by adding together ysis of the secondary and treatment process outcomes the costs derived from the medication and the use of the at post-­treatment and at 12-­month follow-­up. The anal- health services. The cost of medications will be calcu- yses will be replicated from a per-­ protocol approach. lated by multiplying the price per milligram by the total Multi-­level, linear mixed models will be created using daily dose consumed (in milligrams) and the number of the restricted maximum likelihood method for the esti- days that the treatment is received. The cost arising from mation of parameters. The effect sizes will be calculated the use of the health services (primary care, specialist according to Cohen’s d. No interim analysis is planned for and accident and emergency consultations and hospital this RCT. A 5% significance level will be used in all two-­ admissions) will be obtained from the eSalud database tailed tests, applying the Benjamini-­Hochberg correction (http://www.​oblikue.​com/​en/​esalud.​html). The indi- for multiple comparisons (to reduce the risk of false posi- rect costs will be calculated based on the days off work, tives). For these analyses, we will use SPSS V.24.0. which will be multiplied by the official minimum wage To examine whether the effects of ACT and BATD during the study period. The effect of the treatments will in addition to usual care on primary and secondary be estimated using ordinary least squares multivariate outcomes at 12-­month follow-­up are mediated through regression, adjusting for the baseline differences between pre–post changes in pain acceptance (CPAQ-8), and groups. In order to manage uncertainty in the sampling behaviour activation (BADS-­ SF), respectively, we will distribution of the ICUR, non-­parametric bootstrapping calculate pre–post changes in the total scores of the will be applied, with 1000 replications in each compar- CPAQ-8 and the BADS-­ SF and pre-­ follow-­up change ison. Cost-­utility analyses will be conducted with STATA scores in the primary and secondary outcomes. Then, V.16.0. bivariate Pearson correlations will be computed between the pre–post change in the process variables and the Patient and public involvement pre-­follow-­up change in the outcomes to detect poten- tial significant relationships. Finally, we will explore Patients or the public were not involved in the design, or the direct and indirect associations between the treat- conduct, or reporting or dissemination of our research. ment condition (TAU+ACT vs TAU and TAU +BATD vs TAU as independent variable), CPAQ-8 and BADS-­SF (mediators), and primary and secondary outcomes ETHICS AND DISSEMINATION (dependent variables) using path analyses. The direct All procedures performed in this study will be in accor- paths between the treatment condition and clinical dance with the 1964 Helsinki declaration and its last outcomes and the indirect effect path through CPAQ-8, amendments (seventh revision, adopted by the 64th and BADS-­SF will be tested in all models. Regression World Medical Association General Assembly, Fortaleza, coefficients (B) of bias-­corrected bootstrapped indirect effects will be calculated as well as their SEs and 95% Brazil). Signed informed consent will be obtained from CIs. Parameters of indirect effects are considered statis- all patients once they have been informed of the study tically significant when the 95% CI does not include 0. procedures, potential risks and their right to withdraw The MPlus V.7.4 will be used to compute the mediation at any time from the RCT. The FSJD Ethics Committee models. Board evaluated and approved the study protocol in Regarding analyses of the EMA data, Group September 2019 (PIC-178-19). The Hospital del Mar (TAU+ACT vs TAU+BATD vs TAU), Time (each of the Ethics Committee Board evaluated and approved the EMA measurement points; up to two assessments per day study protocol in November 2019 (2019/8866/I). Only × 60 days) and the Group × Time interaction will be the the principal investigator (JVL) will have full access to the primary fixed effects of interest. final trial data set. Regarding the economic evaluation, when the cost-­ Once the RCT is completed, we will publish our results utility of two or more therapeutic options is compared, in international peer-­reviewed biomedical journals and it is necessary to calculate the relationship between the present them at national and international confer- costs of each treatment and its consequences in the form ences. In addition, we will send participating patients of QALYs, a measure designed for assessing both quantity a short report of our findings. A copy of the report of life (years) and health-­related quality of life (ie, a year will also be sent to Institute of Health Carlos III (main lived with the maximum quality of life would be trans- funding body). The principal investigator will organise formed into 1 QALY; a year lived with half the maximum an end-­ of-­ study knowledge translation seminar. The quality of life would be transformed into 1/2 QALY). main objective of this activity will be to share the study This relative value will be called the incremental cost-­ findings with stakeholders in order to discuss how to utility ratio (ICUR), and it will express the relationship maximise uptake of the findings in patient treatment between the costs and the effects of one option compared and clinical practice, and to determine future research with another. The QALYs obtained in the 12 months after directions. 10 Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 Open access DISCUSSION excluded, but the analyses will be limited to the classical The present manuscript describes the design and protocol assessments. Finally, we have to note the lack of blinding of an RCT that aims to assess the efficacy, cost-­utility and of patients and therapists, a typical bias in RCTs of psycho- physiological effects of adding ACT or BATD to TAU for logical treatments. the management of CLBP and moderate to severe levels of depressive symptoms. If the results are strong enough in Author affiliations 1 Department of Basic, Developmental and Educational Psychology, Autonomous terms of cost-­utility, in one or both of the evaluated treat- University of Barcelona, Barcelona, Spain ments (ACT and BATD), they could be considered for inclu- 2 Department of Medicine, International University of Catalunya, Barcelona, Spain sion in the public healthcare system to treat patients with 3 Parc Sanitari Sant Joan de Deu, Sant Boi de Llobregat, Catalunya, Spain CLBP and depression, and could be used to treat similar 4 Network Centre for Biomedical Research in Mental Health (CIBERSAM), Institute of conditions if such general applicability is demonstrated. Health Carlos III, Madrid, Spain 5 Department of Basic and Clinical Psychology and Psychobiology, Universitat Jaume The fact that these treatments are performed in groups can I, Castelló de la Plana, Spain make them more cost-­effective, and therefore of interest 6 Biomedical Research Centre in Physiopathology of Obesity and Nutrition for health managers.72 Additionally, if the results are posi- (CIBERobn), Institute of Health Carlos III, Madrid, Spain tive, these treatments could also be tested in similar chronic 7 Consorci Parc de Salut MAR de Barcelona, Barcelona, Catalunya, Spain 8 conditions (eg, fibromyalgia, irritable bowel syndrome, or Psychology Department, Uppsala University, Uppsala, Sweden 9 Personal Social Services Research Unit, London School of Economics and Political chronic fatigue syndrome) that also frequently present with Science, London, UK comorbid depression symptoms. 10 Department of Biochemistry and Molecular Biomedicine, University of Barcelona, This study has some strengths that should be high- Barcelona, Spain lighted. The inclusion of a large sample and the inclu- 11 Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain 12 sion of a comprehensive set of measures will allow us Department of Evolutionary Biology, Ecology and Environmental Sciences, University of Barcelona, Barcelona, Spain to explore important pain-­related outcomes and treat- 13 Faculty of Health, Queensland University of Technology, Brisbane, Queensland, ment mediators. Our study will both focus on the clin- Australia ical effects of ACT and BATD as add-­on treatments in 14 Department of Physiotherapy, University of Malaga & Biomedical Research the long-­term, and also on the psychological constructs Institute of Malaga (IBIMA), Malaga, Spain 15 and physiological variables that may be involved in the Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand changes experienced by patients after treatment. On the Twitter Bernat Carreras-­Marcos @psicolegclinic whole, our study explores genetic, neuroendocrine (HPA axis) and immune-­ inflammatory (cytokines) pathways Contributors JVL, AF-­S and JRC-­A designed the major outlines of the study. PC-­N, CS-­R, AG-­P, AC-­C, AP-­A, LA-­R, LMMcC, FD'A, PE-­R, BC-­M, AM-­P, OC-­V, ME, MG, with a combination of technologies which may lead to a AR, AIC-­V, MM, XB, SE, AS and AF-­S contributed to the study design. PE-­R, JRC-­A, characterisation of biochemical markers and targets rele- AM-­P and OC-­V will include patients in the study. JVL, CGF and FD'A carried out the vant to increase our understanding of both chronic pain sample size calculation. JPS-­M wrote the first draft of the manuscript together with and depression, new therapeutic interventions to manage JVL, AF-­S, JRC-­A and CS-­R. All authors read and approved the final version of the manuscript. these disorders, and a better prediction of treatment results based on individual variations of these biomarkers Funding This study has been funded by the Institute of Health Carlos III (ISCIII; PI19/00112 & PI16/00165 have been cofinanced with European Union ERDF funds). in the line of personalised medicine. In addition, this JVL has a 'Miguel Servet Type II' contract from the ISCIII (CPII19/00003). ISCIII did study will use a smartphone app to monitor the treat- not have any role in the analysis and interpretation of data, in the writing of the ments’ effects ecologically, which is a novel approach into manuscript and in the decision to submit the paper for publication. the pain literature exploring the effectiveness of psycho- Competing interests None declared. logical interventions. Patient and public involvement Patients and/or the public were not involved in It is important to mention that we will analyse five the design, or conduct, or reporting or dissemination plans of this research. different polymorphisms in the FKBP5 gene whose Patient consent for publication Not required. interest relies on its implication in HPA axis stress Provenance and peer review Not commissioned; externally peer reviewed. response regulating glucocorticoid receptor affinity and Open access This is an open access article distributed in accordance with the signalling. Previous gene-­environment studies have found Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which associations between the variability of this gene and early permits others to distribute, remix, adapt, build upon this work non-­commercially, trauma with depression73 74 and anxiety.75 Based on these and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use findings, our main aim is to explore, for the first time, the is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. moderator role of the interaction between FKBP5 gene polymorphisms and childhood trauma on the response to ORCID iDs Juan P Sanabria-­Mazo http://​orcid.​org/​0000-​0003-​1688-​435X psychological treatments for chronic pain and depression. Antonio I Cuesta-­Vargas http://​orcid.​org/​0000-​0002-​8880-​4315 There are some potential limitations that should be Xavier Borràs http://​orcid.​org/​0000-​0003-​3972-​1385 acknowledged. First, there may be a higher than expected Juan V Luciano http://​orcid.​org/​0000-​0003-​0750-​1599 dropout rate due to the length of the study (1 year). Second, there is a risk that not all recruited patients have a smartphone or that completion rates may be unsatis- factory, so EMA might not be possible or effective for all participants. Participants who do not engage will not be Sanabria-­Mazo JP, et al. BMJ Open 2020;10:e038107. doi:10.1136/bmjopen-2020-038107 11 Open access REFERENCES 28 Hughes LS, Clark J, Colclough JA, et al. Acceptance and 1 Mansfield KE, Sim J, Jordan JL, et al. A systematic review and meta-­ commitment therapy (act) for chronic pain: a systematic review and analysis of the prevalence of chronic widespread pain in the general meta-­analyses. 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