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Juvenile fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder in children and adolescents for which there are no evidence-based treatments. The objective of this multisite, single-blind, randomized clinical trial was to test whether cognitive–behavioral therapy (CBT) was superior to fibromyalgia (FM) education in reducing functional disability, pain, and symptoms of depression in juvenile FMS.
Participants were 114 adolescents (ages 11–18 years) with juvenile FMS. After receiving stable medications for 8 weeks, patients were randomized to either CBT or FM education and received 8 weekly individual sessions with a therapist and 2 booster sessions. Assessments were conducted at baseline, immediately following the 8-week treatment phase, and at 6-month followup.
The majority of patients (87.7%) completed the trial per protocol. Intent-to-treat analyses showed that patients in both groups had significant reductions in functional disability, pain, and symptoms of depression at the end of the study, and CBT was significantly superior to FM education in reducing the primary outcome of functional disability (mean baseline to end-of-treatment difference between groups 5.39 [95% confidence interval 1.57, 9.22]). Reduction in symptoms of depression was clinically significant for both groups, with mean scores in the range of normal/nondepressed by the end of the study. Reduction in pain was not clinically significant for either group (<30% decrease in pain). There were no study-related adverse events.
In this controlled trial, CBT was found to be a safe and effective treatment for reducing functional disability and symptoms of depression in adolescents with juvenile FMS.
Juvenile fibromyalgia syndrome (FMS) is a chronic pain condition that is estimated to affect 2–7% of school-age children (1–3), primarily adolescent girls. As in adult fibromyalgia (FM), juvenile FMS is characterized by persistent and widespread musculoskeletal pain, sleep difficulty, fatigue, and mood disturbances (3). Patients with juvenile FMS experience substantial impairment in physical, school, social, and emotional functioning (4–6), and the majority of them continue to have ongoing symptoms and functional disability into late adolescence and early adulthood (7). Although progress has been made in the understanding and treatment of adult FM (8), there are few studies of juvenile FMS. Two recent meta-analytic reviews of cognitive–behavioral therapy (CBT) clinical trials for FM arrived at slightly different conclusions, with one supporting the effectiveness of CBT (9) and the other reporting no significant effect on pain and function (10). However, both reviews indicated significant improvement in coping and emphasized the need for higher quality trials of CBT.
It is unclear whether findings from the 2 meta-analytic reviews, based mainly on adult FM patients, are applicable to pediatric patients. In a recent meta-analysis of psychological therapies for pediatric chronic pain (mostly headache and abdominal pain), Palermo et al (11) reported a large positive effect for pain reduction. It is possible that behavioral interventions found to be promising for adults with FM can be even more effective in juvenile FMS because they are implemented at an early age when pain coping and lifestyle factors are more malleable. There are no rigorously controlled studies of CBT for juvenile FMS at present. Early evidence for possible efficacy of CBT for improving function and decreasing pain and symptoms of depression in children and adolescents with juvenile FMS was shown in 2 small-scale studies (12,13). Unfortunately, neither study controlled for the nonspecific therapeutic effects of attention and support from health professionals, which by themselves could have resulted in improved outcomes. Therefore, the specific effects of CBT that go beyond providing emotional support and include intensive training in behavioral pain coping skills targeted at improving functioning by increasing patients' psychological coping and confidence in pain self-management skills have not yet been tested in a controlled study.
We performed a multisite, randomized controlled trial in a sample of children and adolescents with juvenile FMS to rigorously assess the safety and efficacy of an 8-session, individually delivered CBT intervention compared to an 8-session supportive FM education program in reducing functional disability, pain severity, and depressive symptoms. The CBT treatment protocol was developmentally tailored for older school-age children and adolescents and included parental instruction to ensure family support for the behavioral interventions. We hypothesized that 1) CBT would be significantly more effective than FM education in reducing functional disability (primary outcome) in youth with juvenile FMS and 2) CBT would be significantly more effective than FM education in reducing pain severity and symptoms of depression (secondary outcomes). Unlike a “no-treatment” placebo control, the FM education condition was designed to be an “attention control” condition in which the nonspecific psychological benefits of the therapeutic relationship and educational information provided were expected to lead to some improvement in the short term (posttreatment assessment). However, we hypothesized that CBT would lead to sustained benefit and be demonstrably superior to FM education in reducing disability, pain, and symptoms of depression 6 months after the end of active treatment (end-of-study assessment).
Selection of the outcome domains of function, pain severity, and symptoms of depression was consistent with the Pediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (PedIMMPACT) guidelines for measurement of outcomes in clinical trials of pediatric chronic pain (14). Functional disability was selected as the primary outcome because the goal of CBT is to reduce pain-related disability by teaching patients both coping and self-management behaviors (and providing parental guidance in behavior management) to improve function, while secondarily reducing pain severity and symptoms of depression. Other outcomes of interest such as tender point sensitivity, health-related quality of life (HRQOL), sleep quality, and physician's global assessment were also measured at each assessment.
The study was conducted at 4 pediatric rheumatology centers in the Midwestern US. The enrollment period was between December 2005 and December 2009. Treatment and followup of all patients were completed in June 2010. Children between ages 11 and 18 years were eligible if they 1) met juvenile FMS classification criteria as determined by a pediatric rheumatologist (3), 2) were receiving stable medications for 8 weeks and were willing to continue receiving stable medications for the duration of the study, 3) reported average pain severity ≥4 on a 0–10-cm visual analog scale (VAS) based on 1 week of daily pain diaries, and 4) obtained a score >7 on the Functional Disability Inventory (FDI) (15), indicating at least mild disruption in daily activities due to juvenile FMS symptoms. Exclusion criteria were 1) other rheumatic disease, such as juvenile arthritis or lupus; 2) documented developmental delay; 3) current panic disorder or major depression, or lifetime bipolar disorder or psychosis; and 4) use of opioids. The study protocol was approved by the Institutional Review Boards at each of the 4 sites. Written informed consent was obtained from parents of the patients, and written assent was obtained from the patients. An independent Data and Safety Monitoring Board assembled by the study sponsor (the National Institutes of Health) and composed of an adult rheumatologist, pediatric rheumatologist, pediatric psychologist, biostatistician, physician medical/safety monitor, and bioethicist monitored the conduct of the trial.
At the first (screening and baseline) study visit, patients underwent thorough medical and psychiatric evaluations including a tender point examination and a comprehensive psychiatric interview (the Kiddie Schedule of Affective Disorders and Schizophrenia) (16).
All primary and secondary outcome measures were completed at baseline, posttreatment (week 9), and 6 months following the end of the treatment phase (end of study). The primary outcome was functional disability at the end of the study as assessed by the FDI, a well-validated measure recommended by the recently published PedIMMPACT consensus statement to assess functional disability in pediatric pain trials (14). The FDI is a 15-item self-report inventory that assesses children's ability to perform a variety of daily physical, social, and recreational activities. For children with chronic pain, the clinical reference points are 0–12 = no/minimal disability, 13–29 = moderate disability, and 30+ = severe disability (17). Secondary outcomes were assessed with the Children's Depression Inventory (CDI), a validated instrument used to assess symptoms of depression in children and adolescents (18), and VAS to assess pain severity based upon the mean of ratings in a 7-day daily diary in which patients rated their average pain severity on a 0–10-cm scale of “no pain” to “worst possible pain.” VAS are validated for use in school-age children and adolescents (14).
Other outcomes that were evaluated at each assessment were tender point sensitivity as measured with a standardized 18-point tender point examination using dolorimetry, physician's global assessment on a 0–10-cm VAS (higher scores indicate doing better), HRQOL using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and PedsQL Rheumatology Module (19,20), and sleep quality (average 0–10-cm VAS rating from a 1-week daily diary).
Eligible patients were randomly assigned to 1 of the 2 treatment arms (CBT or FM education) based upon a computer-generated randomization list. Randomization was stratified by site.
The study used a single-blind design. When a patient was enrolled, the study therapist contacted the biostatistician to obtain the subject identification number and treatment allocation. The principal investigator (PI), study physicians, study coordinator, and assessment staff were all blinded to the patients' treatment condition throughout the trial. Patients were asked not to divulge what treatment they were receiving to their study physician.
Patients in the CBT and FM education treatment arms received 8 weekly individual sessions in the active treatment phase. Treatment sessions were carried out by 5 therapists with postdoctoral training in pediatric psychology that included training in CBT. Therapists received 6–8 hours of training from the PI in the standardized implementation of the manualized treatment protocols used in this study, along with ongoing supervision (in a blinded manner) throughout the study. All therapists were trained in both CBT and FM education and delivered interventions according to the patients' group assignment. All sessions (CBT and FM education) were individual one-to-one 45-minute sessions with the child/adolescent, and parents were included in 3 of the 8 sessions.
The CBT protocol was a refined version of the CBT manual for adolescents with juvenile FMS used in our pilot study (13) and modeled after well-tested CBT protocols for pain management in adults (21). The sessions included education about the rationale for behavioral pain management as well as training in muscle relaxation, distraction, activity pacing, problem solving, using calming statements, and relapse prevention strategies. Instructions for home practice were reviewed with patients at each session to encourage use of coping skills in their everyday lives. All patients in the CBT treatment arm completed weekly ratings of whether they practiced the skills they had been taught in session. Parent training in behavioral management techniques (22) was included in 3 of the 8 sessions to ensure that behavior change was supported in the home environment. Parents were asked to encourage their children to manage their pain independently, maintain a normal routine, refrain from frequent status checks and offers of assistance, and praise their children whenever they were observed to be using adaptive coping such as pacing, distraction, or calming themselves. Individualized examples and problem solving accompanied each of these guidelines.
FM education sessions included education and discussion about FM, pain medications, general lifestyle issues such as diet, sleep, and exercise, and impact of juvenile FMS on the patients' lifestyle. In lieu of skills practice, patients were provided educational information about healthy lifestyle habits to review at home. Parents attended 3 of the 8 educational sessions with the patient but did not get specific training in behavioral management. The purpose of FM education sessions was to provide the same number of therapist contact hours in a supportive environment, without providing any specific guidelines or instruction regarding behavior change.
All sessions were audiotaped, and treatment integrity was reviewed during the course of the trial by independent monitors (psychology fellows not involved with the trial) who reviewed 20% of randomly selected sessions and completed checklists of adherence to the manual. Independent monitors were used to preserve blinding while ensuring accuracy of treatment delivery by the therapists.
At the end of the 8-week active treatment phase, participants and their parents completed a 4-item treatment credibility checklist on which they rated 1) how logical they thought the treatment was for managing their juvenile FMS symptoms, 2) how confident they were that the treatment would help them reduce their symptoms, 3) how confident they were that the treatment would help them deal with their symptoms, and 4) how likely they would be to recommend the treatment to a friend with juvenile FMS. Each item was rated on a 0–8 scale (from no confidence to high confidence). An average credibility rating (0–8) was computed for parent and child for the FM education and CBT treatment arms.
Patients were seen for medical safety visits by the study rheumatologist every 4 weeks during the treatment phase. In the 6 months following treatment, all patients were seen for 2 booster/maintenance sessions and medical safety visits at 8-week intervals and a final end-of-study assessment at the end of 6 months. All adverse events, regardless of whether they were study-related, were monitored throughout and reviewed at each study assessment, medical safety visit, and therapy session.
The primary aim was to test if patients in the CBT group would show greater reduction in FDI scores by the end of the study compared to those in the FM education group. Both groups were expected to show some improvement immediately post-treatment, but the CBT group was expected to show significantly better outcomes than the FM education group by the end of the study (a group-by-time interaction effect). A priori power analyses were conducted using nQuery software, version 5.0 (Statistical Solutions) to estimate sample sizes required to detect the group-by-time interaction effect. Estimated means and SDs for FDI scores were based upon our prior published pilot study (13) showing a large effect size (0.8) for CBT on FDI scores. Within-person correlation was set equal to 0.7. The calculations showed that a sample size of 114 was required to yield a minimum of 47 patients per group (with 18% dropout) for intent-to-treat analyses with 99% power for the interaction effect. Power to detect between-group effects was 80%, and power to detect time effect was 99%.
The primary statistical analysis was intent-to-treat analysis on all patients who were randomized and attended at least 1 CBT or FM education session. Prior to analysis, data were examined for completeness, and reasons for any missing data were documented. Means, ranges, SDs, and descriptive measures were computed for each continuous variable as well as frequencies for categorical variables. For the final analyses, we used mixed modeling for repeated measures with the fixed factors being group, time, and group-by-time interaction for the primary end point (functional disability) as well as the 2 secondary outcome variables (pain severity and symptoms of depression). Akaike's information criterion was examined to determine the best variance–covariance structure to use in the analyses. The variance–covariance structure used in the final analysis was autoregressive. The subject was treated as a random effect in the model.
Published norms using clinical reference points for disability on the FDI (no/mild disability, moderate disability, and severe disability) (17) and cutoff scores for symptoms of depression (depressed, nondepressed) on the CDI (18) were used to interpret clinical significance. For pain intensity, a reduction of ≥30% in pain ratings was considered to be minimally clinically significant as suggested by Farrar et al (23).
Descriptive data were computed on baseline to end-of-treatment scores for tender point sensitivity, sleep quality, HRQOL, and physician's global assessment. The primary intent was to include an assessment of associated symptoms (muscle tenderness/sensitivity and sleep) as well as more broad-band measures (PedsQL and physician global ratings) to examine whether these outcomes also improved in the expected direction. Due to the modest sample size with limited power to test multiple within- and between-group differences, statistical significance tests were not deemed appropriate for these additional measures.
A total of 114 patients with juvenile FMS were enrolled and randomized (57 in each group). The sample was composed primarily of white females (mean age 15 years). There were no significant baseline differences between the CBT and FM education groups with regard to age, sex, race, socioeconomic status, disease duration, or the number of medications used at a stable dose (including analgesics, nonsteroidal antiinflammatory drugs, anticonvulsants, and antidepressants) for juvenile FMS symptoms prior to enrollment in the trial (Table 1). Adolescents in the CBT and FM education groups also did not differ on baseline measures of functional disability, pain severity, or symptoms of depression. There were no significant site differences in age, disease duration, or number of medications used. The participant flow chart is presented in Figure 1. Of the 114 participants randomized, 112 were included in the intent-to-treat analyses (2 patients dropped out prior to attending any sessions). One hundred patients (87.7% retention) completed the treatment and followup phases per protocol with no differential dropout in the 2 treatment arms. Due to the high retention, missing data were minimal and no imputation procedures were deemed necessary for the intent-to-treat analyses. Age was examined as a potential covariate and was found to have no significant effect on outcomes.
Intent-to-treat analysis showed that both the CBT and FM education groups had significant reductions in functional disability (main effect for time F = 10.85; P < 0.0001); however, the CBT group showed significantly greater improvement than the FM education group (group-by-time interaction F = 5.15; P = 0.007). The difference between the average baseline to end-of-study scores for the 2 groups was significant, with an average difference between means of 5.39 (95% confidence interval [95% CI] 1.57, 9.22). The effect size was large for the CBT intervention (0.90) in contrast to the much lower effect size for the FM education intervention (0.26) by the end of the study. Improvement in mean FDI scores was 37% for the CBT group compared to 11.8% for the FM education group (Figure 2). In terms of clinical significance, mean FDI scores were in the moderate range at baseline (mean across both groups 20.27). By the end of the study, the mean FDI score of the CBT group (13.41) was approaching the range of minimal disability (0–12) compared to a mean FDI score for the FM education group (16.96) that remained in the moderate range (Table 2).
Pain severity showed small but statistically significant reductions in both groups by the end of the study (main effect for time F = 4.43; P = 0.01), with no significant differences between the CBT and FM education treatment arms (group-by-time interaction F = 0.71; P = 0.49). Pain severity was reduced by 14.0% in the CBT group and by 8.6% in the FM education group. The average difference between groups in baseline to end-of-study means was 0.33 (95% CI −0.55, 1.21) (Table 2).
Repeated measures analyses indicated that both CBT and FM education were associated with significant reductions in symptoms of depression by the end of the study (main effect for time F = 17.92; P < 0.001), with CBT being significantly more effective than FM education (group-by-time interaction F = 3.14; P = 0.04). In percentage terms, the CBT group had a 34.6% improvement in symptoms of depression compared to a 27.5% improvement for the FM education group, but when the mean baseline to end-of-study scores of the CBT and FM education groups were compared, the difference between groups was not found to be significant (average difference between means 1.05 [95% CI −1.65, 3.75]). Using clinical reference points for the CDI (18), the mean CDI score of both groups (13.05) was in the range of mild depression at baseline, but the mean CDI score for each group was within the range of normal/nondepressed (<10) by the end of the study (8.68 for the CBT group, 9.32 for the FM education group).
Descriptive information on each of the other evaluated outcomes is presented in Table 3. In keeping with the findings showing generally positive effects of behavioral treatment, there appeared to be improvements in both groups on physician's global assessment and all aspects of HRQOL based upon the PedsQL Generic Core Scales and Rheumatology Module. Improvements in tender point sensitivity and sleep quality were negligible.
None of the adverse events reported (the most common being asthma flare-ups, sinus infections, strep throat, gastrointestinal infections, and abdominal pain) were study-related. Nine patients had brief hospitalizations (4 for asthma flare-ups, 2 for elective surgeries, 1 for abdominal pain, 1 for low potassium levels, and 1 psychiatric hospitalization) that were also not study-related. (The psychiatric hospitalization was for further assessment of a patient who revealed possible psychotic symptoms at the first treatment session.) There were no differences in adverse events between the groups.
In the course of the trial, 9 patients (4 in the CBT group and 5 in the FM education group) were prescribed a new (antidepressant) medication due to medical necessity. Fourteen patients (7 in each group) discontinued all medications on their own by the end of the study.
On a 0–8 scale, adolescents' mean ratings were 6.5 for the CBT intervention and 5.5 for the FM education intervention. Parents' mean ratings were 6.7 for the CBT intervention and 5.7 for the FM education intervention.
Psychological intervention in the form of CBT was shown to be a well-tolerated, effective, and safe intervention for adolescents with juvenile FMS when added to stable usual medical care in this multisite, randomized clinical trial. The study had a high rate of retention with almost 90% of participants completing the treatment and followup phases. The CBT intervention was seen as a very credible approach for managing and dealing with juvenile FMS symptoms by both adolescents with juvenile FMS and their parents. The study design rigorously controlled for the nonspecific effects of therapist attention/support and patient education (FM education treatment arm). As anticipated, we found improvement with both interventions, but CBT was demonstrably superior to FM education in reducing disability. Treatment effects for CBT were most evident at the end of the 6-month followup, showing that patients continued to improve even after the active weekly treatment sessions were discontinued. Effect sizes for reduction in functional disability were large, with adolescents being able to function better due to the reduced impact of juvenile FMS symptoms on their daily lives by the end of the study. In fact, average scores on the functional disability measure approached the range of minimal impairment in the CBT group by the end of the study, demonstrating the clinically significant effect of the treatment.
Interestingly, both groups showed reductions in symptoms of depression, and their scores fell within the range of normal/healthy by the end of the study. This implies that attention and support from health care providers via intensive weekly individual sessions can in and of themselves reduce emotional distress. These nonspecific positive effects were also observed in both groups on more global measures of patient-reported HRQOL and physicians' (blinded) global assessments, which may have been a reflection of the patients' improved well-being. However, CBT clearly had the additional benefit of significantly improving daily functioning over and above the positive effects on overall well-being.
In contrast to the relatively strong effect sizes found in this study, recent meta-analyses reported small effect-size improvements in adult FM trials of CBT (9,10). One potential reason might be that adults with FM may have had the symptoms for many years and experienced more longstanding dysfunction related to their symptoms. Also, the inclusion of parents in the treatment of adolescents may have served to increase support in the family environment to enhance or maintain treatment effects. Early identification and effective interventions for FM symptoms that emerge in adolescence might mitigate long-term problems with disability found in adults with FM (24,25), and further longitudinal followup studies are needed to examine longer term effects of CBT.
Although the effects of CBT for the reduction of disability and symptoms of depression were robust, the effect on pain severity was less impressive and was similar to effect sizes for pain reduction reported in the 2 recent meta-analyses of CBT trials (9,10). While the findings were statistically significant, pain ratings were reduced by only ~14% in the CBT group (average of 1 point on a 0–10-point scale), which is lower than the ≥30% reduction in pain thought to be clinically meaningful (23). These findings are contrary to findings of significant pain reduction in pediatric non–juvenile FMS pain CBT trials (11) and suggest that pain associated with juvenile FMS may be more refractory than headaches or abdominal pain in pediatric patients. The effects on improving sleep quality also appeared to be very small, and tender point sensitivity was mostly unchanged. Nevertheless, it is encouraging that marked improvement in the patients' ability to engage in previously avoided activities such as going to school, doing chores, going out with friends, and the like was achieved without increasing pain or interfering with sleep. One future direction for research is to test whether CBT can be used to increase tolerance for more vigorous physical activity, and whether combining CBT with exercise-based approaches can lead to both improved functioning and reduced pain severity (both VAS pain ratings and tender point sensitivity). Also, inclusion of specific behavioral training in sleep hygiene as part of the CBT protocol might be useful.
One limitation of this study, as in other CBT trials, was that medications prescribed as part of usual medical care were not strictly controlled. However, in contrast to prior CBT studies, we required that all patients be receiving stable medications for at least 8 weeks prior to study entry, requested them to continue taking stable medications, and monitored medication use. Medication changes were allowed if deemed medically necessary, and we found no differential medication changes in the treatment arms. Newer medications that have recently been approved for the management of adult FM have yet to be tested in children and adolescents with juvenile FMS. A promising area for future research is whether a combination of CBT with one of the new pharmacologic therapies can be used to treat juvenile FMS with even more positive results.
The manualized CBT protocol used in this study is amenable to dissemination, although it requires a trained psychologist for proper implementation. Fortunately, most pediatric psychologists already have training in CBT approaches and can easily integrate the pain-specific CBT techniques into their treatment with a small amount of additional training. With rapidly evolving technology, efforts are also under way to test internet-based CBT approaches for the management of pediatric pain (26) which could be modified for use in juvenile FMS patients. There were no adverse effects of CBT, and the self-management skills were durable over at least 6 months after the end of active treatment. Patients were quite easily engaged in the treatment and willing to attend clinic-based sessions, and retention in this study was high. Much of the high retention could probably be attributed to the strong relationship that participants and parents developed with the therapists, as evidenced by their anecdotal reports and high treatment credibility ratings at the end of the study. This study presents the first rigorously tested evidence supporting the use of CBT for juvenile FMS. Findings demonstrated that when added to usual medical care, CBT was clearly the superior choice for the treatment of juvenile FMS because of the marked reduction in disability, the strong reduction in symptoms of depression, and the improvement in overall well-being.
We would like to thank research staff who served as study therapists: Ivy Ho, PhD, Irina Parkins, PhD, and Stacy Flowers, PsyD. We would also like to thank study coordinators and assistants: Raegan Malblanc, MA, Sonya Crook, RN, Megan Johnston, BA, Emily Verkamp, BA, and Daniel Strotman, BA.
ClinicalTrials.gov identifier: NCT00086047.
Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01-AR-050028 to Dr. Kashikar-Zuck).
AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kashikar-Zuck had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Kashikar-Zuck, Arnold, Bean, Powers, Graham, Schikler, Banez, Lovell.
Acquisition of data. Kashikar-Zuck, Ting, Graham, Passo, Schikler, Hashkes, Spalding, Lynch-Jordan, Banez, Richards, Lovell.
Analysis and interpretation of data. Kashikar-Zuck, Arnold, Bean, Powers, Banez, Lovell.