Randomized Controlled Trial of Internet-delivered Exposure-based Cognitive Behavior Therapy vs. Internet-delivered Traditional Cognitive Behavior Therapy for Patients With Fibromyalgia
Phase: NA
Conditions: Fibromyalgia
Sponsor: Karolinska Institutet

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
RANDOMIZED CONTROLLED TRIAL OF INTERNET-DELIVERED 
EXPOSURE-BASED COGNITIVE BEHAVIOR THERAPY VS. INTERNET-
DELIVERED TRADITIONAL COGNITIVE BEHAVIOR THERAPY FOR 
PATIENTS WITH FIBROMYALGIA 
 
 
 
Document date: 2021-06-11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
1 
Study protocol 
 
Randomized controlled trial of internet-delivered exposure-based cognitive behavior therapy 
vs. internet-delivered traditional cognitive behavior therapy for patients with fibromyalgia 
Summary 
Fibromyalgia (FM) is a common medical condition characterized by chronic generalized 
musculoskeletal pain, fatigue, and a series of additional somatic and psychiatric problems that 
give rise to distress, functional impairment, and substantial societal costs. The most extensively 
evaluated treatment for FM is traditional cognitive behavior therapy (T-CBT) which typically 
appears to have small to moderate effects when compared to waitlist, attention control, 
treatment as usual or other active nonpharmacological therapies. Internet-delivered exposure-
based cognitive behavior therapy (Exp-CBT) where the patient willingly and systematically 
engages with stimuli associated with pain and pain-related distress has shown promising 
controlled effects versus a waiting-list but has never been compared to T-CBT in a randomized 
controlled trial. In this randomized controlled trial, self-recruited adults with FM (N=260) are 
randomly assigned (1:1) to 10 weeks of internet-delivered Exp-CBT or internet-delivered T-
CBT and complete self-report questionnaires to measure symptoms and therapeutic processes 
up to 12 months after treamtent. Primary outcome is the relative effect of Exp-CBT and T-CBT 
on FM severity as modelled using linear mixed models fitted on weekly Fibromyalgia Impact 
Questionnaire sum scores over the treatment period, testing the hypothesis of Exp-CBT 
superiority based on the coefficient for the time × group interaction. Cost-effectiveness and 
mediational processes are investigated in secondary analyses. We expect this trial to be of 
notable clinical significance as it will provide valuable information about the value of Exp-CBT 
in helping patients with FM as compared to using other interventions.  
 
Overview of the field 
 
Fibromyalgia: a common, disabling, and costly chronic pain condition 
Fibromyalgia (FM) is a chronic pain syndrome affecting approximately 2-4% of the general 
population, and most typically (90%) women (Queiroz, 2013). The condition is characterized 
by chronic muskuloskeletal pain, stiffness, fatigability, and decreased pain threshold (Smith, 
Harris, & Clauw, 2011). Diangostic criteria for FM according to the American College of 
Rheumathology are the following: 1) generalized pain defined as pain in at least four out of five 
regions (left and right upper region, left and right lower region; axial region), 2) the symptoms 
have persisted for at least 3 months, and 3) either at least 7 points on the Widespread Pain Index 
(WPI) and at least 5 points on the Symptom Severity Scale (SSS) or at least 4 points on the 
WPI and at least 9 points on the SSS (Wolfe et al., 2011). Individuals with FM also commonly 
experience other somatic and psychiatric symtoms such as disturbed sleep, tension headache, 
migraine, fatugie, gastrointestinal problems, cognitive impairment, dizziness, low mood, 
anxiety, and increased sensitivity to stress (Wolfe, Ross, Anderson, Russell, & Hebert, 1995). 
The condition is associated with functional impairment, substantially lowered quality of life 
(Hauser et al., 2015), and also notable societal consts due to its effects on health care 
expenditure, sick leave, and work status (Rivera, Rejas, Esteve-Vives, Vallejo, & ICAF, 2009).  
 
The avoidance of pain is predictive of poor health outcomes 
The experience of pain relies on a complex interaction of biological, psychological, and social 
factors (Gatchel, Peng, Peters, Fuchs, & Turk, 2007). A number of psychological factors have 
been found to be especially important, including attentional, emotional, and cogitive processes. 
An important factor in the maintenance of pain over time is pain-related avoidance, i.e., that the 
patient starts avoiding situations and activities where pain might occur, whereby the avoided 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
2 
situations and activities by classical and operant conditioning become associated with pain and 
pain-related distress. Pain-related avoidance often implies a reduction in meaningful activites 
such as social interaction and work, and often leads to a viscious cycle where a shrinking 
behavioral repertoire feeds the impact of pain on everyday life, which leads to more avoidance, 
more attention devoted to pain instead of meaningful activites, and so on (Wicksell et al, 2008). 
Numerous studies have indicated that pain-related avoidance is predictive of increased pain, 
increase attention to pain, and increased functional impairment (Geisser, Haig, & Theisen, 
2000; Goubert, Crombez, Eccleston, & Devulder, 2004; McCracken, Eccleston, & Bell, 2005; 
Philips & Jahanshahi, 1985; Prkachin, Schultz, & Hughes, 2007). 
 
Importance of psychological treatment 
While pharmacological treatment for FM with antidepressants and anticonvulsants (Arnold, 
2006; Goldenberg, Burck, Hardt, Crofford, 2004) can reduce pain and other FM-related 
symptoms, of those who recieve pharmacological treatment for FM, only about 40% experience 
clinically singificant improvement (Arnold, 2006) and the utility of pharmacological treatment 
has been therefore questioned (Nüesch, Hauser, Bernardy, Barth, & Jüni, 2013). Non-
pharmacological treatments are commonly at least as efficacious (Rossy et al., 1999). 
 
Traditional cognitive behavior therapy 
Traditional cognitive behavior therapy (T-CBT) is the most widely evaluated psychological 
treatment for FM with over 40 randomized controlled trials. In the majority of these trials, T-
CBT protocols have been composite interventions, based on a combination of treatment 
components such as relaxation, problem solving, psychoeducation, stress management 
practices, and cognitive restructuring techniques. A widely used treatment component with 
relatively robust support has been pacing: the systematic dosing of activity level to achieve 
energy conservation. The patient is encouraged to use particular strategies before, during, and 
after activites in order to moderate pain (Hammond, 2004). 
 
Bernardy and colleagues published a 2013 systematic Cochrane review and meta-analysis of 
randomized controlled trials of cognitive-behavioral interventions (including acceptance and 
commitment therapy) for FM (Bernardy, Klose, Busch, Choy, & Hauser, 2013). Their 
conclusion was that such treatments give a small but significant added effect on pain, mood, 
and functional impairment as compared to waitlist control, attention control, treatment as usual 
or other nonpharmacological therapies. An update was published in 2017 including trials 
conducted between 2013-2017 (Bernardy, Klose, Welsch, & Hauser, 2017). In this review, CBT 
was found to provide a clinical benefit over control interventions in reducing some core 
symptoms and disability at the end of treatment, but did not change the major findings from the 
original review.  
 
Exposure-based cognitive behavior therapy 
Exposure is among the most widely employed treatment components in psychological 
treamtents for common anxiety disorders (Koran et al., 2007; National Collaborating Centre for 
Mental Health, 2005, 2006, 2011, 2013; Ursano et al., 2004) and has also been evalued with 
promising results for several somatic conditions (Bonnert et al., 2016; Craske et al., 2011; 
Ljótsson, Hedman, et al., 2011). Exposure therapy is based on repeated and maintained 
confrontation with stimuli that give rise to unwanted responses, and is conducted with the aim 
of achieving therapeutic effects, usually conceptualized as some sort of new learning. Exposure 
for somatic conditions implies that the patient systematically engages in exposure exercises, 
such as by provking discomfort or feared symptoms, approaching avoided activities and 
situations in a new manner without resorting to distraction. Exposure also implies refraining 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
3 
from so called safety- and avoidance behaviors intended to reduce unwanted emotions or 
discomfort in the short term. The mechanism of action by which exposure works is not fully 
understood, but it is commonly hypothesized that repeated exposure leads to an increased 
tolerance of unwanted emotions or discomfort, and that the patient gradually developes a 
stronger belief in his or her ability to manage symptoms and situations previously feared or 
avoided (Tryon, 2005). 
 
Considering that avoidance behavior contributes to maintain pain over time, exposure has been 
suggessted as a key intervention for patients suffering from chronic pain, and has also been 
evaluated for chronic pain conditions in a few randomized controlled trials (den Hollander et 
al., 2016; Leeuw et al., 2008; Linton et al., 2008; Woods & Asmundson, 2008). Our research 
group has previously developed and evaluated exposure-based treatment for patients with FM 
in a pilot study and subsequent large-scale RCT (Hedman-Lagerlöf et al., 2018; Brjánn Ljótsson 
et al., 2014), both with promising results as detailed below. Considering that pain-related 
avoidance behavior exists in many forms including covert processes such as distraction, 
resisting, and checking, exposure treatment can be tailored to a wide spectrum of individuals 
with fibromyalgia including those who do not exhibit avoidance that is visible to the eye 
 
Delivering psychological treatment via the internet 
Treating patients with psychological methods via the internet has become increasingly common 
in recent years (Andersson, 2009). Use of the internet to deliver interventions has several 
advantages, including high cost-effectiveness since the intervention commonly demands less 
time from the therapist and can be more easily distributed compared to face-to-face treatment. 
A systematic review by Carlbring and colleagues (2018), demonstrates that therapist-guided 
treamtent often results in effects similar to those of conventional face-to-face treament. Internet-
delivered T-CBT for FM has been evaluated in two RCTs with mixed results (Friesen et al., 
2017; Vallejo, Ortega, Rivera, Comeche, & Vallejo-Slocker, 2015). 
 
Our research group has evaluted expousure-based cognitive behavior therapy (Exp-CBT) for 
FM in two clinical trials. First, in 2012, we completed a pilot trial (regional ethics review board 
of Stockholm identifier 2011/1499-31/4) where 41 participants with FM took part in a 10-week 
internet-delivered psychological treatment program that emphasized systematic exposure. 
Results were indicative of substantial change from pre- to post-treatment (p<0.001) in all 
outcome domains, with moderate to large standardized effects (d=0.65-1.21)(Brjánn Ljótsson 
et al., 2014). In the subsequent RCT, 140 participants were randomized to 10 weeks of Exp-
CBT or a waiting-list, resulting in large waitlist-controlled effects on FM-symptoms, pain, 
fatigue, functional impairment and pain-related anxiety. The study also indicated that Exp-CBT, 
compared to no treatment, is highly cost-effective, and that a reduction in FM-related avoidance 
was associated with a larger treatment effect. A clear limitation in the current body of 
knowledge, however, is that exposure-based treatment for FM has not been compared to an 
active control group. Our knowledge of treatment moderators and mechanisms is also limited. 
 
Summary of background 
In conclusion, FM is a common problem with substantial negative consequences. The most 
widely evaluated psychological treatment for FM is T-CBT which usually has small to moderate 
controlled effects on pain, mood and functional impairment. Based on one pilot study and one 
wailist-controlled RCT, Exp-CBT appears to have promising effects on FM but this treatment 
has not yet been compared to an active control condition. The present study aims to compare 
internet-delivered Exp-CBT to internet-delivered T-CBT in a randomized controlled trial. In 
addition to clinical efficacy, we will also investigate cost-effectiveness and mediational 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
4 
processes. Primary hypothesis is that Exp-CBT will be more efficacious than T-CBT in reducing 
FM severity, i.e., a composite score indicative of symptoms and functional status, as assessed 
using the primary outcome Fibromyalgia Impact Questionnaire (FIQ). 
 
Overarching aim of the study 
The overarching aim of the study is to evaluate the clinical efficacy of internet-delivered 
exposure-based cognitive behavior therapy (Exp-CBT) compared to internet-delivered 
traditional cognitive behavior therapy (T-CBT) for patients with fibromyalgia (FM) in a large-
scale randomized controlled trial.  
 
Primary research question 
Does Exp-CBT, compared to T-CBT, produce a larger reduction in FM severity over the 10-
week treatment period? Hypothesis: Yes. 
Secondary research questions 
1) Does Exp-CBT, as compared to T-CBT, produce larger controlled effects on A) pain, B) 
fatigue, C) quality of life, D) functional impairment, E) depression, and F) anxiety? Exploratory. 
2) Is Exp-CBT more cost-effective than T-CBT? Hypothesis: Yes. 
3) What factors moderate the treatment outcome? Hypotheses will be fully formulated and 
registered prior to the analysis, when the precise modeling approach has been chosen. 
4) What factors mediate the treatment outcome? Hypotheses will be fully formulated and 
registered prior to the analysis, when the precise modeling approach has been chosen. 
 
Methods 
 
Design 
This is a randomized controlled trial with repeated measurments and two conditions: the 
experimental group (Exp-CBT) and an active control group (T-CBT). Based on previous trials, 
we expect an Exp-CBT within-group effect of approximately 16.9 points (Hedman-Lagerlöf et 
al., 2018) and a corresponding T-CBT within-group effect of no more than 9 points (Castel, 
Salvat, Sala, & Rull, 2009; King, Wessel, Bhambhani, Sholter, & Maksymowych, 2002; 
Redondo et al., 2004) on the Fibromyalgia Impact Questionnaire (Burckhardt, Clark, & 
Bennett, 1991). Given this scenario, Monte Carlo simulation (n=1000) of multi-level linear 
regression analyses with 11 weekly measurements and an expected data loss of 10% at every 
measurement point after baseline indicated that 130 participants will be needed per arm (Exp-
CBT vs. T-CBT) for 80% power in testing the time × group coefficient (alpha=.05).  
 
Eligibility criteria 
The study will be open for adults of at least 18 years diagnosed with FM living in Sweden, with 
access to the internet and with a completed pre-treatment assessment. Concurrent psychotrophic 
medication is allowed if the dose has been stable for at least 4 weeks before randomization and 
the participant agrees to keep it constant during treatment. Exclusion criteria are the following: 
A) severe depression (≥ 30 on the Montgomery Åsberg Depression Rating Scale—Self Rated 
[MADRS-S] at screening), B) suicidal ideation (≥ 4 on the suicide item of the MADRS-S at 
screening), C) psychosis, D) alhocol or substance use disorder as primary diagnosis or likely to 
severely interfere with treatment, E) ongoing psychological treatment, F) pregnancy (>29 wk 
gestation), G) another somatic condition that requires immediate treatment and/or is deemed to 
be the primary condition, and H) insufficient knowledge of the Swedish language or insufficient 
computer skills to benefit from the text-based online treatment. 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
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Outcome measures 
• 
Composite FM severity: symptoms and functional status (primary outcome). The 
Fibromyalgia Impact Questionnaire, FIQ (Burckhardt, Clark & Bennett, 1991). This is 
a validated and disease-specific instrument known to be reliable and responsive to 
change (R. Bennett et al., 1996). 
• 
Pain. The Fibromyalgia Impact Questionnaire, FIQ-Pain subscale (Burckhardt, Clark 
& Bennett, 1991) and Brief Pain Inventory-Short Form, BPI-S (Mendoza, Mayne, 
Rublee, & Cleeland, 2006) 
• Fatigue. Fatigue Severity Scale, FSS (Krupp, LaRocca, Muir-Nash, & Steinberg, 1989). 
• Anxiety and depression. The GAD-2 (Kroenke, Spitzer, Williams, Monahan, & 
Löwe, 2007) and Patient Health Questionnaire-2, PHQ-2 (Kroenke, Spitzer, & 
Williams, 2003) 
• Functional impairment and quality of life. The WHO Disability Assessment 
Schedule 2.0, WHODAS 2 (Üstün et al., 2010), Brunnsviken Brief Quality of Life 
Inventory, BBQ (Frykheden, 2014), and EQ-5D (Rabin & Charro, 2009) 
• 
Pain-related avoidance behavior. The Psychological Inflexibility in Pain Scale-
avoidance subscale, PIPS (Wicksell, Lekander, Sorjonen, & Olsson, 2010) 
• 
Pacing and overdoing behavior: Patterns of Activity Measure – Pain: pacing and 
overdoing subscales, POAM-P-p/o (Cane, Nielson, McCarthy, & Mazmanian, 2013) 
• Pain-related castastrophizing. Pain Catastrophizing Scale, PCS (Sullivan, Bishop, & 
Pivik, 1995)  
• Hypervigilance. Pain Vigilance and Awareness Questionnaire, PVAQ (Roelofs, 
Peters, McCracken, & Vlaeyen, 2003) 
• Physical activity. The Godin-Shephard leisure-time physical activity questionnaire 
(Godin, 2011) 
• Global measure of perceived change. Patient Global Impression of Change, PGIC 
(Hurst & Bolton, 2004) 
• 
Resource use including health care consumption and sick leave. Trimbos and 
Institute of Medical Technology Assessment Cost Questionnaire for Psychiatry, TIC-P 
(Haakart-van Roijen, 2002) 
• 
Treatment credibility. Credibility/Expectancy Questionnaire, CEQ (Devilly & 
Borkovec, 2000) 
• 
Working alliance. Working alliance inventory – short version, WAI-S (Hatcher & 
Gillaspy, 2006)  
• 
Patient satisfaction. Client satisfaction questionnaire, CSQ-8 (Kelly et al., 2018) 
• 
Adverse events. Free-text reports of adverse events and rating of the aversiveness of 
these events on a 4-point Likert scale as used in previous trials, AE (Hedman-Lagerlöf 
et al., 2018; Brjánn Ljótsson et al., 2014) 
 
Procedure 
 
Recruitment 
Participants are self-recruited. The study will be advertised in newspapers, and information will 
be spread via patient organizations and health care clinics and clinicians in Stockholm Region. 
Considering that the study does not involve a medical assessment, applicants will be required 
to already have been diagnosed with FM by a physician. Those interested will apply to 
participate by completing an online form to provide informed consent after having been 
presented with the obligatory patient information. Here, applicants confirm that they have been 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
6 
given an FM diagnosis and subsequently complete a series of self-report screening 
questionnaires including routine questions concerning sociodemographic characteristics, FM, 
medical status, and symptoms. Complete applications are reviewed and followed by a structured 
telephone interview to inform about the study, collect key clinical data, and assess the study 
eligibility criteria. Applicants who meet all eligibility criteria are informed that they will be 
included and randomized after they have completed the pre-treatment assessment. The 
eligibility interview is conducted by a licenced psychologist, resident psychologist, or 
psychologist- or psychotherapist student under supervision of a licensed psychologist with 
knowledge of FM and common psychiatric comorbidities. Individuals who are excluded are 
informed about the reason for this, and referred to routine care services as necessary.  
 
Randomization 
Randomization is conducted 1:1 using the www.random.org service, on a cohort-by-cohort 
basis, by an external person who is blind to participant characteritsics. 
 
Table 1. Measurements 
Questionnair
e 
Outcome 
Reference 
SN 
PRE 
WK 
PO
ST 
6M
FU 
12M
FU 
Efficacy outcomes 
FIQ 
Composite FM 
severity 
(Burckhardt et al., 1991) 
x 
x 
x 
x 
x 
x 
FIQ subscale 
Pain, primary 
measure 
 
x 
x 
x 
x 
x 
x 
FSS 
Fatigue 
(Krupp et al., 1989) 
 
x 
 
x 
x 
x 
BPI-S 
Pain, secondary 
measure 
(Mendoza et al., 2006) 
 
x 
 
x 
 
 
GAD-2* 
Anxiety 
(Kroenke et al., 2007) 
 
x 
 
x 
x 
x 
PHQ-2* 
Depression 
(outcome) 
(Kroenke et al., 2003) 
 
x 
 
x 
x 
x 
WHODAS 2 
Functional 
impairment 
(Üstün et al., 2010) 
 
x 
 
x 
x 
x 
BBQ 
Quality of life 
(Lindner et al., 2016) 
 
x 
 
x 
x 
x 
PGIC 
Impression of 
change 
(Hurst & Bolton, 2004) 
 
 
 
x 
 
 
Screening only 
MADRS-S 
Depression 
(screening) 
(Svanborg & Asberg, 
1994) 
x 
a 
a 
a 
a 
a 
AUDIT 
Alcohol use 
(Saunders, Aasland, 
Babor, de la Fuente, & 
Grant, 1993) 
x 
 
 
 
 
 
DUDIT 
Drug use 
(Berman, Bergman, 
Palmstierna, & Schlyter, 
2005) 
x 
 
 
 
 
 
Primarily used to investigate processes 
PIPS-avoid 
Avoidance 
(Wicksell et al., 2010) 
 
x 
x 
x 
x 
x 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
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POAM-P-p/o 
Pacing and 
overdoing 
(Cane et al., 2013) 
 
x 
x 
x 
x 
x 
PCS 
Catastrophizing 
(Sullivan et al., 1995) 
 
x 
x 
x 
x 
x 
PVAQ 
Hypervigilance 
(Roelofs et al., 2003) 
 
x 
x 
x 
x 
x 
C/E 
Credibility, 
expectancy 
(Devilly & Borkovec, 
2000) 
 
 
w. 2 
 
 
 
WAI-S 
Therapeutic 
alliance 
(Hatcher & Gillaspy, 
2006) 
 
 
w. 2 
 
 
 
 
GSLTPAQ 
Physical activity 
(Godin, 2011) 
 
x 
x 
x 
 
 
Primarily used for health economic analyses 
EQ-5D 
HR quality of life 
(utility) 
(Rabin & Charro, 2009) 
 
x 
 
x 
x 
x 
TIC-P 
Resource use 
(societal) 
(Haakart-van Roijen, 
2002) 
 
x 
 
x 
x 
x 
Other outcomes 
CSQ-8 
Patient 
satisfaction 
(Kelly et al., 2018) 
 
 
 
x 
 
 
AE 
Adverse events 
(Hedman-Lagerlöf et al., 
2018; Brjánn Ljótsson et 
al., 2014) 
 
 
 
x 
 
 
6MFU = 6-month follow-up; 12MFU = 12-month follow-up; FM = fibromyalgia; HR = health-related; POST = 
post-treatment; PRE = pre-treatment; SN = screening / application; WK = weekly assessment (week 1-9). *In this 
study, we will employ a cut-off of 3 points to identify clinically significant anxiety and depression on the GAD-2 
and PHQ-2 respectively. a) Only suicidality item administered; patients contacted if flagged and referred to routine 
care as needed. 
 
Data management 
Personal data will be managed confidentially and each participant is granted a personal code. 
Personal data and the personal key (“kodnyckel”) will be stored on a secure server, access to 
which requires double authentication, as employed in previous projects (regional ethics review 
board of Stockholm identifier 2014/1944-31/5). These data will only be accessed by researchers 
in the project. All correspondence between participants and therapists will take part via a secure 
messaging system that employs double authentication, and to which the participant is granted 
a personal password. Data is stored and managed in accordance to Swedish and European Union 
data protection and privacy legislation including the Swedish National Board of Health and 
Welfare guidelines for management of personal data (2 kap. 5 § SOSFS 2008:14). Data derived 
from self-report questionnaires will be reported in such a way as to not enable the identification 
of individuals. 
 
Treatment conditions 
General structure of internet-delivered treatment 
Participants in Exp-CBT and T-CBT are encouraged to work with self-help texts and complete 
regular homework exercises via a secure treatment platform. Both treatments are 10 weeks 
long, equally exhaustive, and involve approximately the same level of therapist support. 
Throughout the treatment, participant communicate with a therapist, who guides the 
participants through the intervention by means of email-like text messages. Therapists are 
assigned to only one treatment protocol to prevent contamination. Therapists are licensed 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
8 
psychologists, resident psychologists, last-year students of the Swedish master-level 
psychologist program, or student of the advanced-level Swedish psychotherapist program. All 
therapists are given thorough education in the treatment protocol and work under the 
supervision of a licensed psychologist. 
Internet-delivered exposure-based cognitive behavior therapy (Exp-CBT) 
The Exp-CBT treatment manual is the same as developed and tested previously, as detailed 
above (Hedman-Lagerlöf et al., 2018). The primary treatment component is exposure to stimuli 
(situations and activities) that give rise to pain, distress, and unwanted emotional responses. 
The treatment proceeds in accordance with functional analysis (Haynes & O'Brien, 1990). 
Exercises are tailored for the patient so that, for example, individuals whose main coping 
strategy is to be overly active (i.e., persistence behavior) are encouraged to sit down and observe 
pain and other aversive bodilty sensations as they arise. The protocol also includes regular 
exercises where the participant is encouraged to observe and name physical sensations without 
acting on them. 
 
Internet-delivered traditional cognitive behavior therapy (T-CBT) 
The T-CBT treatment manual has been developed and tested for chronic back pain (Buhrman, 
Fältenhag, Ström, & Andersson, 2004). This treatment is based on components typical of T-
CBT for FM, including relaxation, activity planning or pacing, cognitive restrucutring 
techniques, stress management strategies, and assertiveness training.  
 
Statistical analysis 
To evaluate the effect of treatment, data is analyzed using linear mixed-effects regression 
according to the intention-to-treat principle. For the primary analysis, linear mixed models are 
fitted on the weekly FIQ sum scores over the treatment period, testing the hypothesis of Exp-
CBT superiority based on the coefficient for the time × group interaction. In a secondary 
analysis, we will aslo investigate the proportion of participants in Exp-CBT and T-CBT who 
achieve a clinically relevant improvement in FM severity, defined as a FIQ sum score reduction 
of at least 14% (R. M. Bennett, Bushmakin, Cappelleri, Zlateva, & Sadosky, 2009). A health-
economic analysis will be concerned with the incremental cost-effectiveness of Exp-CBT as 
compared with T-CBT using the same definition of clinically relevant improvement as efficacy 
outcome. Cost-utility will also be assessed as based on quality-adjusted life years derived from 
utility scoring of the EQ-5D. 
 
Previous experiences 
 
Communication with patients via the internet has become increasingly common in recent years 
and can be used to successfully treat numerous somatic and psychiatric health problems. Use 
of the web as treatment platform entails several advantages. It is health economically attractive 
since treatment can be offered more widely, including to geographically remote areas. Access 
to effective treatment is hence not limited to urbanized areas or particular clinics. 
 
The pilot study that we completed in 2012 investigated the effects of Exp-CBT for 41 
individuals with FM (regional ethics review board of Stockholm identifier 2011/1499-31/4). 
Results were indicative of moderate to large within-group effects on FM symptoms. The 
randomized controlled trial completed in 2016 (regional ethics review board of Stockholm 
identifier 2015/1528-31/1) was indicative of large between-group effect sizes in terms of FM 
symptoms (including pain), fatigue, functional impairment, pain-related anxiety and 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
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psychological flexibility in pain. 
 
Primary investigator for this project is Maria Hedman-Lagerlöf, licensed psychologist and PhD 
at Karolinska Institutet (KI), Stockholm, Sweden. She initated the pilot study completed in 2012 
and led the large-scale RCT that was completed in 2016.  
 
Brjánn Ljótsson, licensed psychologist and associate professor at KI has completed several 
trials of exposure-based treatment for irritable bowel syndrome (Ljótsson, Andersson, et al., 
2011; Ljótsson, Andréewitch, et al., 2010; Ljótsson, Falk, et al., 2010; Ljótsson, Hedman, et al., 
2011; B Ljótsson et al., 2014). Taken together, these studies indicate that exposure can be 
effective as administered either via the internet or in a group format. This treatment has 
documented effects on gastrointestinal symptoms, symptom-related anxiety, avoidance 
behaviors, quality of life, and comorbid psychiatric problems. The effects of this treatment have 
also been found to be maintained over time (Ljótsson, Andersson, et al., 2011) and to be 
associated with socioeconomic gains (Andersson et al., 2011). Brjánn Ljótsson has also taken 
part in internet treatmenet studies for panic disorder (Bergström et al., 2010), obsessive-
compulsive disorder (Andersson et al., 2012), social anxiety disorder (Hedman, Andersson, 
Ljótsson, et al., 2011), and health anxiety (Hedman, Andersson, Andersson, et al., 2011). 
 
Erik Hedman-Lagerlöf, licensed psychologist at Gustavsberg primary care clinic and professor 
in psychology at the department of clinical neuroscience at KI. Professor Hedman-Lagerlöf’s 
research has primarily focused on Internet-delivered treatment and the implementation of 
psychological treatment in a primary care. Erik Hedman-Lagerlöf has worked alongside Brjánn 
Ljótsson in all projects mentioned above. 
 
Erland Axelsson, licensed psychologist and PhD at Liljeholmen primary care clinic, affiliated 
with KI. His primary research and clinical interests are in behavioral medicine, and the 
relationship between psychological processes and physical complaints. Dr Axelsson exhibits 
extensive competence in scientific and statistical methods, has been involved in over 10 
randomized controlled trials of psychological interventions indcluding the 2016 RCT of Exp-
CBT for FM (Hedman-Lagerlöf et al., 2018), and has – under EHL – led the largest published 
RCT of Exp-CBT for health anxiety.  
 
Monica Buhrman, PhD, licensed psychologist and associate professor, senior lecturer at 
Uppsala University has led and completed several randomized controlled trials evaluating 
psychological interventions for chronic pain (Buhrman et al., 2012; Buhrman et al., 2004; 
Buhrman, Nilsson-Ihrfeldt, Jannert, Strom, & Andersson, 2011; Buhrman et al., 2013) and 
developed the T-CBT protocol intended to constitute the control condition in the present trial. 
Dr. Buhrman is also appointee of the Swedish national expert group for the development of 
guidelines for the treatment of FM.  
 
Ethical considerations 
This project will be conducted in accordance with the declaration of Helsinki, and Swedish and 
European Union legislation pertaining to the management of personal data. The RCT will also 
be preregistered at ClinicalTrials.gov.  
 
Participants confirm via an online form that they have been diagnosed with FM by a physician. 
Informed consent will be a prerequisite for data collection and inclusion in the study. If the 
applicant meets exclusoin criteria, he or she is informed of this and referred to routine care 
services as needed. At the post-treatment assessment as well as weekly during treatment, 

Exposure-based CBT vs. traditional CBT for patients with fibromyalgia 
Study protocol intended for expert review 
 
10
patients are given the opportunity to provide free-text written reports of adverse events. In the 
case of acute deterioration, an individual assessment will be conducted by a licensed 
psychologist or resident psychologist under supervision, and the participant will be referred to 
rutine care services as needed. 
 
Previous data suggest that Exp-CBT is associated with few negative effects (Hedman-Lagerlöf 
et al., 2018; Brjánn Ljótsson et al., 2014). The control intervention (T-CBT) has been previously 
found to be efficacious for chronic pain (Buhrman et al., 2004) and is easily matched to Exp-
CBT in terms of readability, image content, and length so as to achieve a fair control condition. 
Risks associated with this project are thus deemed small in relation to the potential gains. In 
order to ensure safe mangement of data, communication via the internet is encrypted access to 
the treatment web platform requires two factor authentification (electronic identification). 
Personal passwords are confirmed via SMS. All data will be presented in a manner that does 
not make it possible to identify specific participants.  
 
Our experience from having conducted several studies at the Internet psychiatry unit for somatic 
conditions such as irritable bowel syndrome as well as psychiatric conditions usch as panic 
disorder and health anxiety is that text-based online communication, which enables more 
regular interaction than conventional face-to-face treamtent, generally functions well to monitor 
the health and wellbeing of pariticipants, and to ensure that serious adverse events do not arise. 
 
We expect that a positive outcome of this trial would ultimately contribute to a large patient 
group being able to access effective treatment with excellent scalability. We thus consider the 
potential harms to to be acceptible when considered in relation to the potential gains of 
delivering an effective form of Exp-CBT to this patient group. 
 
Clinical implications 
Individuals with FM suffer much from their disease which leads to impairment and typically 
lowered mood and quality of life. Even if T-CBT has been found to be efficacious in a number 
of studies this treamtent is not widely available. In previous Swedish research projects, there 
are several examples of online treamtents delivered in a similar format as Exp-CBT that have 
successfully, and relatively swiftly, been implemented in a routine care setting, such as that of 
the Internet psychiatry unit where 10,000 patients have completed treatment since 2008. Thus, 
in our experience, this type of treatment can benefit patients and lead to notable societal gains 
by increasing access to evidence-based care. 
 
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