Fibromyalgia syndrome (FMS) is a major clinical problem in adults and has been diagnosed in 3.5% of women and 0.5% of men in the US, representing ∼5 million persons and total annual health care costs exceeding $16 billion (1, 2). Although FMS is known to cause significant morbidity in adults, its impact in the pediatric population has only recently been addressed. Previous studies have revealed that many children continue to experience persistent pain many years after being diagnosed with juvenile primary FMS (JPFMS) (3), and that 28% of adult patients with FMS reported that their pain symptoms began in childhood (4). Perhaps if the specific interactions between physiologic and psychological factors were better understood, the developmental course of the syndrome, including possible trajectories from childhood to adulthood, could be influenced to minimize the durability and pervasiveness of its effects.
It is generally recognized that JPFMS is similar to FMS in that it is a pain amplification syndrome that includes musculoskeletal discomfort in predictable tender points, as well as sleep disturbance, fatigue, and mood problems (5). In adults, FMS is a major cause of work disability, and in children, JPFMS often causes considerable school absenteeism. In light of this constellation of symptoms, and the fact that no objective physical findings (e.g., joint inflammation) are associated with FMS, questions arise about the authenticity of the syndrome and whether FMS and JPFMS are truly rheumatic disorders (6).
The Cartesian dichotomy of pain being either in the mind or in the body is inaccurate, because chronic pain is a complex entity requiring a psychobiologic perspective that includes an array of psychological, social, and biologic factors that impact on mechanisms of pain transmission and pain modulation (7). Lifespan developmental models of chronic pain have been used to observe biologic changes over time, as well as factors such as temperament, stressor load, and family environment (8). Such a model is quite consistent with the gate control theory of pain, because it provides a framework through which a broad range of factors may be unified to define a pain response (9). For example, individual differences in temperament (usually described as a psychological variable) are apparent in autonomic nervous system functioning, hypothalamic–pituitary–adrenal (HPA) axis activation, and central processing (usually conceptualized as physiologic variables), all of which affect pain (10–12).
The aim of this study was to investigate specific psychobiologic factors that might contribute to pain amplification responses that typify the onset and maintenance of JPFMS. It was hypothesized that in comparison with children with arthritis and healthy controls, patients with JPFMS would have increased perceptual sensitivity to pain and other stimuli, heightened physiologic responses to stress, a specific cluster of temperamental features that minimize pain inhibition, greater affective symptomatology, poorer parental psychological adjustment, and increased family conflict.
PATIENTS AND METHODS
Subjects represented 3 distinct groups: children with JPFMS (11 girls, ages 10.5 years to 17.7 years [mean ± SD age 14.25 ± 2.46 years], and 5 boys, ages 7.4 years to 17.4 years [mean ± SD age 13.60 ± 4.50 years]), children with arthritis (9 with juvenile rheumatoid arthritis [JRA] and 7 with spondylarthropathy; 10 girls, ages 9.7 years to 17.8 years [mean ± SD age 13.60 ± 2.60 years], and 6 boys, ages 8.4 years to 14.4 years [mean ± SD age 11.60 ± 2.60 years]), and healthy controls (8 girls, ages 7.7 years to 17.1 years [mean ± SD age 13.20 ± 2.60 years], and 8 boys, ages 8.1 years to 15.8 years [mean ± SD age 12.30 ± 3.10 years]).
There were no significant age differences between the groups. Although there was an apparent overrepresentation of girls in both the JPFMS (68.8%) and the arthritis (62.5%) groups, the observed difference failed to reach statistical significance and is deemed typical of these clinical populations (12).
All consecutive patients with JPFMS or arthritis were recruited from the pediatric rheumatology clinic at Hackensack University Medical Center; the time since diagnosis in these patients ranged from 0 to 1.91 years and from 0 to 1.85 years, respectively. Patients in the JPFMS group reported experiencing symptoms 3–36 months before diagnosis (the average duration of symptoms prior to diagnosis was 12 months). Two of the 16 patients with JPFMS reported that pain began following an infection, and 1 patient reported the onset of symptoms following an accident. The remaining 13 patients reported no infection, trauma, or other triggering event. Patients with a diagnosis of JPFMS and those with arthritis met relevant American College of Rheumatology diagnostic criteria (13, 14). Healthy control subjects were recruited from a local pediatrician's office; thus, control subjects and patients were drawn from the same demographic population. All subjects in the study were white and English-speaking, represented a wide range of religious and socioeconomic backgrounds, and did not have any other known organic disease or cognitive deficits. The period of recruitment was 1 year. Refusals to participate were reported to be attributable to time constraints.
Eight of the patients with JPFMS were receiving tricyclic antidepressants and 1 was receiving a selective serotonin reuptake inhibitor at the time they were recruited. All subjects had been prescribed psychotropic medication at a low dose for pain and/or sleep restoration. Eleven of the 16 patients with JPFMS were being treated with a nonsteroidal antiinflammatory drug (NSAID). Physical therapy intervention had been prescribed for 4 of these 16 patients. The patients with JRA were receiving NSAIDs (n = 15), methotrexate (n = 1), sulfasalazine (n = 3), and hydroxychloroquine (n = 2).
Subjects and their parents (mothers in all but one case) completed several self-report instruments, each of which was chosen based on its demonstrated psychometric properties and applicability to this clinical population.
The Sensitivity Temperament Inventory for Pain (STIP) (15).
The STIP assesses basic styles of responding to painful stimuli, either augmenting (pain sensitive) or reducing (pain tolerant). Both the STIP for children and that for parents were designed so that higher scores represent more pain sensitivity. The 4 factors are 1) sensation seeking/pain tolerance, 2) perceptual sensitivity, 3) symptom reporting, and 4) insulate/avoid sensation.
Dimensions of Temperament Survey-Revised (DOTS-R) (16).
The DOTS-R is a self- and parent-report measure of children's and adolescents' temperament. It contains 54 items measuring several salient dimensions of temperament or behavioral style, consistent with parameters identified by Thomas and Chess (17). The scale pertains to 9 attributes: 1) activity level, general; 2) activity level, sleep; 3) approach–withdrawal; 4) flexibility–rigidity; 5) mood; 6) rhythmicity, sleep; 7) rhythmicity, eating; 8) daily habits; and 9) task orientation.
Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) (18, 19).
The CBCL is an extensively used measure designed to assess child behavior problems and social competencies. The CBCL is a 118-item questionnaire completed by parents. Profiles include total behavior problems, internalizing and externalizing behavior problems, as well as more specific scales, including withdrawn, somatic complaints, anxious/depressed, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior. The YSR is a parallel form for use with adolescents between the ages of 11 years and 18 years.
Family Environment Scale (FES) (20).
The FES assesses 10 social environmental characteristics of the family, including the 3 underlying domains of relationships, personal growth, and system maintenance. Subjects ages 13 years and older and parents used the standard scale, a 90-item true–false measure, while younger children used the Children's Family Environment Scale (21), which comprises 30 pictures with associated multiple-choice statements.
Children's Depression Inventory (CDI) (22).
The CDI is a 27-item self-report instrument designed to assess depressive symptoms in children between the ages of 7 years and 17 years. Items on the CDI are categorized into 5 scales: negative mood, interpersonal problems, ineffectiveness, anhedonia, and negative self-esteem.
State-Trait Anxiety Inventory for Children (STAIC) (23).
The STAIC is a 40-item measure of anxiety that was used for subjects between the ages of 7 years and 13 years. The items measure perceived feelings of worry, tension, and fear at a particular time (state) and as a general characteristic (trait). The STAI (24) is a 40-item measure used for individuals older than age 13 years.
Symptom Checklist-90-Revised (SCL-90-R) (25).
The SCL-90-R is a 90-item, self-report inventory designed to assess the psychological symptoms of psychiatric and medical patients. The inventory measures somatization, depression, anxiety, phobic anxiety, psychoticism, paranoid ideation, hostility, and global indices of psychopathology. It was administered to the parents of children in the study, as a measure of their own general psychological adjustment.
Determination of salivary cortisol levels.
In several previous studies, salivary cortisol has been used as a measure of physiologic responsiveness to acute stressors (26). Cortisol, the primary glucocorticoid of the HPA system in humans, is a stress-related hormone that affects almost every organ and tissue in the body. A primary effect is to increase the energy available for action. The typical methodology is to obtain a saliva sample before and then ∼20 minutes after use of the stressor, because this is when salivary cortisol levels peak (27).
This study was approved by the Institutional Review Board of Hackensack University Medical Center. The principal investigator approached subjects during a scheduled appointment at the rheumatology clinic or during a routine visit to the pediatrician's office. Informed consent was obtained from parents, and informed assent was obtained from children ages 9 years and older. Data on medical history and medication administration were gathered from patient records.
Children and their parents were instructed to complete the questionnaires independently. The majority of subjects and their parents opted to complete questionnaires at home and mail them back. Among those who completed the questionnaires in the clinic setting, an average of 45–60 minutes was needed to do so. Upon completion of all questionnaires, subjects received a $5.00 gift certificate to Blockbuster Video.
After being seen by their physicians, subjects underwent venipuncture for clinical diagnostic purposes. Insertion of the needle was used as the focal acute stressor for studies of changes in the level of salivary cortisol. Thus, saliva samples were obtained immediately before and 20–30 minutes after venipuncture. Saliva was obtained by placing a dental cotton roll in each subject's mouth (against the cheek) for about 30 seconds. The cotton roll was then placed in a syringe, and the saliva was extracted into a collecting vial, topped, labeled, and frozen at −70°C until ready for shipment for analysis. All saliva samples were analyzed at the Behavioral Endocrinology Laboratory at Pennsylvania State University and were run in a single batch to maximize reliability.
Differences between groups were analyzed by one-way analysis of variance (ANOVA). When results were significant, post hoc comparisons were conducted using Tukey's test. Salivary cortisol data, in which the focus was differences in scores before and after exposure to a stressor, were analyzed with a repeated-measures ANOVA.
One-way ANOVAs were used to establish that the age, sex, and time since diagnosis had no significant relationship to key independent variables and outcome measures.
ANOVAs revealed significant differences between groups on DOTS-R scales, reflecting lower mood, irregularity of daily habits, lower task orientation, and higher distractibility in the JPFMS group compared with the arthritis group and healthy controls. Post hoc comparisons revealed that significant differences were consistently observed between children with JPFMS and healthy controls, but not between other groups. An identical pattern was shown for parental ratings of mood and task orientation (see Table 1).
Table 1. Results of Dimensions of Temperament Survey-Revised*
|Child report|| || || || || |
| Mood||25.06 ± 3.3||22.56 ± 4.3||26.50 ± 2.3||5.42||0.01|
| Rhythmicity, daily habits||12.81 ± 2.3||9.93 ± 2.7||11.18 ± 3.0||4.65||0.01|
| Task orientation||22.93 ± 3.8||18.81 ± 6.2||21.43 ± 3.6||3.16||0.05|
| Distractibility||13.56 ± 2.9||10.75 ± 3.8||12.12 ± 2.5||3.29||0.04|
|Parent report|| || || || || |
| Mood||24.44 ± 5.0||20.63 ± 5.5||25.00 ± 4.3||3.25||0.05|
| Task orientation||21.75 ± 4.8||19.31 ± 5.4||24.06 ± 4.9||3.54||0.03|
As shown in Table 2, YSR data showed that adolescents with JPFMS reported significantly more behavior problems than did the other 2 groups, as demonstrated by the total problems composite, as well as scores for internalizing behaviors, somatization, and attention problems. However, on withdrawal and anxiety/depression scales, differences were found only between the group with JPFMS and the group with arthritis. On the CBCL, parents of children with JPFMS reported more attention problems, withdrawal, thought problems, somatic complaints, and delinquent behavior, as well as more internalizing, externalizing, and overall behavior problems than did parents of children in the other groups.
Table 2. Results of Youth Self-Report and Child Behavior Checklist*
|Youth Self-Report|| || || || || |
| Withdrawal||53.25 ± 5.1||59.15 ± 9.8||50.33 ± 8.8||5.95||0.01|
| Somatization||54.50 ± 5.9||66.62 ± 9.8||56.83 ± 7.6||8.79||0.001|
| Anxious/depressed||53.50 ± 5.2||60.00 ± 9.9||51.58 ± 3.2||5.28||0.01|
| Attention problems||53.00 ± 4.2||61.23 ± 11.9||52.00 ± 3.2||5.48||0.01|
| Internalizing||47.50 ± 12.7||62.07 ± 11.1||47.83 ± 8.8||7.3||0.002|
| Total||47.25 ± 11.9||60.54 ± 9.6||46.75 ± 9.9||7.05||0.002|
|Child Behavior Checklist|| || || || || |
| Attention problems||51.44 ± 3.2||56.38 ± 7.9||52.50 ± 3.9||3.63||0.03|
| Withdrawn||51.44 ± 3.8||57.75 ± 6.5||50.25 ± 1.0||13.29||0.0000|
| Thought problems||50.44 ± 1.7||55.75 ± 6.5||52.25 ± 5.0||4.98||0.01|
| Somatization||53.94 ± 5.9||62.81 ± 8.1||57.44 ± 10.9||4.34||0.02|
| Delinquent behavior||51.75 ± 3.10||55.31 ± 6.6||51.81 ± 3.1||3.19||0.05|
| Externalizing||42.56 ± 9.2||51.75 ± 10.4||43.81 ± 9.2||4.30||0.01|
| Internalizing||45.50 ± 11.1||58.88 ± 8.3||46.25 ± 12.7||7.68||0.001|
| Total||41.50 ± 11.2||55.94 ± 9.4||44.75 ± 12.1||7.05||0.001|
On the CDI, patients with JPFMS reported significantly higher levels of anhedonia, negative mood, ineffectiveness, negative self-esteem, and total overall depression than did both healthy controls and children with arthritis (Table 3). On the STAI, patients with JPFMS scored significantly higher on both the state and trait scales than did healthy controls and children with arthritis.
Table 3. Results of Children's Depression Inventory and State-Trait Anxiety Inventory*
|Children's Depression Inventory|| || || || || |
| Anhedonia||43.88 ± 6.5||59.31 ± 12.2||46.19 ± 6.0||14.60||0.0000|
| Negative mood||44.19 ± 6.6||54.44 ± 11.7||46.56 ± 5.5||6.57||0.0030|
| Ineffectiveness||40.13 ± 2.9||48.69 ± 8.6||41.69 ± 4.6||9.57||0.0003|
| Negative self-esteem||42.56 ± 4.3||49.50 ± 8.1||42.62 ± 5.0||6.99||0.0023|
| Total depression||41.38 ± 5.9||54.88 ± 11.6||42.69 ± 4.1||14.23||0.0000|
|State-Trait Anxiety Inventory|| || || || || |
| State||43.00 ± 11.7||52.50 ± 11.90||40.31 ± 5.6||6.35||0.003|
| Trait||45.53 ± 9.7||55.50 ± 12.00||42.87 ± 5.8||7.53||0.001|
Children with JPFMS reported significantly less family cohesion and lower levels of family organization than did children in the other groups. The same differences were found for parental ratings of family cohesion and expressiveness in the family (Table 4).
Table 4. Results of Family Environment Scale*
|Child Report|| || || || || |
| Cohesion||54.20 ± 16.4||43.63 ± 15.3||56.73 ± 9.9||3.74||0.03|
| Organization||55.00 ± 13.0||47.37 ± 11.5||56.80 ± 6.9||3.34||0.04|
|Parent Report|| || || || || |
| Cohesion||58.00 ± 12.4||44.38 ± 20.2||60.44 ± 8.2||5.70||0.01|
| Conflict||40.00 ± 9.1||47.50 ± 11.1||47.56 ± 9.9||3.00||0.05|
| Intellectual/cultural||53.31 ± 9.8||43.56 ± 15.9||57.38 ± 11.2||5.10||0.01|
Parental psychological adjustment.
On the SCL-90-R, parents of children with JPFMS reported greater anxiety and depression and had higher total global symptom scores compared with parents of healthy controls but not parents of children with arthritis (Table 5).
Table 5. Results of Symptom Checklist-90-Revised*
|Anxiety||46.88 ± 9.7||56.75 ± 10.7||50.19 ± 12.0||3.41||0.04|
|Depression||45.88 ± 9.7||56.25 ± 10.6||51.75 ± 8.5||4.66||0.01|
|Global symptom checklist||47.31 ± 9.5||57.31 ± 12.2||51.31 ± 11.7||3.23||0.04|
Results of the STIP showed that patients with JPFMS had higher perceptual sensitivity, more symptom reporting, and greater total pain sensitivity compared with both children with arthritis and healthy controls. Parents of children with JPFMS indicated more pain and symptom reporting and greater total pain sensitivity in their children than did mothers of children in the other 2 groups (Table 6).
Table 6. Results of Sensitivity Temperament Inventory for Pain (STIP)*
|Child report|| || || || || |
| Perceptual sensitivity||31.06 ± 4.7||34.56 ± 5.5||29.87 ± 4.5||3.87||0.030|
| Symptom reporting||9.25 ± 3.5||13.50 ± 2.2||11.00 ± 2.5||9.30||0.000|
| STIP total||75.50 ± 13.6||90.87 ± 6.5||79.60 ± 9.4||9.53||0.000|
|Parent report|| || || || || |
| Pain and symptom reporting||19.50 ± 3.9||24.75 ± 3.9||19.87 ± 4.2||8.41||0.001|
| STIP total||67.06 ± 11.2||78.1 ± 10.8||67.75 ± 8.1||5.99||0.010|
Repeated-measures ANOVA showed no main effects for group status or for changes over time (before and after venipuncture), nor for interaction effects between group status and time.
The purpose of this study was to describe key psychobiologic elements that differentiate between children with JPFMS, children with arthritis, and healthy controls. Results showed that compared with children with arthritis and control subjects, children with JPFMS demonstrated significantly greater temperamental instability, as evidenced by significantly lower mood, irregularity of daily habits, low task orientation, and high distractibility. Furthermore, children with JPFMS had greater levels of anxiety and depression than did children in the other groups, resulting in an interesting triangle of temperamental factors, affective responses, and chronic pain. Although these 3 sets of factors interact, it is very difficult to demonstrate specific antecedent–consequence or causal relationships.
Temperamental characteristics are stable essentially from birth and have been shown to affect multiple areas associated with adaptive or maladaptive functioning (28, 29). For example, temperamental style impacts on coping with stressors (30), including an individual's response to invasive procedures and postoperative pain (31–34). Thus, it is very likely that specific temperamental factors antecede the manifestation of problematic pain syndromes. The fact that children with JPFMS reported higher levels of anhedonia and ineffectiveness, however, raises questions about the specific sequence of events in the development of the observed triad. Thus, temperament could a) be the common element that underlies poor psychological adjustment and difficulties coping with pain, b) principally affect psychological adjustment, which then impacts on coping with chronic pain, or c) sensitize an individual to pain responses, thereby taxing coping and affecting psychological adjustment. Only through prospective longitudinal studies may we determine which factors are primary and which serve as mediating variables leading to other problematic outcomes.
Previously reported data on the prevalence of psychopathology among children and adolescents with JPFMS have been inconsistent. Reid et al (35) observed no significant group differences in psychological functioning between patients with JPFMS, those with arthritis, and healthy controls or their parents, while Yunus and Masi (36) and Mikkelsson et al (37) reported relatively high rates of psychopathology in pediatric patients with JPFMS. Data from the present study are consistent with those from latter studies and may even represent somewhat of an underestimate of true effects, given that some of the patients with JPFMS were receiving antidepressant medication to facilitate sleep and pain relief. Further systematic studies controlling for relevant variables are needed to identify cause–effect relationships.
Parental and familial influences provide important contextual information but potentially cloud the picture even more. Parents of children with JPFMS demonstrated higher levels of anxiety and depression, as well as poorer psychological adjustment overall, compared with parents of children with arthritis and parents of healthy control subjects. Whether this is in response to dealing with a child experiencing chronic pain or whether parental anxiety and depression antecede a child's difficulties has not been shown. Similarly, results from the current study show that families of children with JPFMS function more poorly compared with other families (i.e., cohesion and organization are diminished and conflict is increased), corroborating data from a previous study (38). The question remains as to whether maladaptive families produce children with problematic pain syndromes or whether such syndromes are extremely disruptive and help break down family systems.
An interesting question focuses on the manner in which ontogenetic and environmental factors affect children's specific pain experiences. In this study, patients with JPFMS demonstrated significantly greater perceptual sensitivity and more symptom reporting, as well as higher total pain sensitivity levels, than did the other subjects. Parents of children with JPFMS reported that the level of pain sensitivity in their children was greater than that reported by parents of children in the other groups. Although such characteristic pain responses have been linked to coping with acute pain (39), the present findings are unique in that clear differences in pain responsiveness were shown for children with chronic pain syndromes.
We had hypothesized that basic physiologic reactions to stressful events would be different between the 3 groups, thereby further supporting the notion that psychological and physiologic stress and pain responses are inextricably related. However, differences between the 3 groups in cortisol levels before and after venipuncture were not significant. The lack of difference may be attributable to methodology, because the situation may not have been sufficiently stressful for any of the subjects to mount a major response. In addition, initial saliva samples were gathered just before venipuncture; these 2 events may have been too temporally proximate, in which case the stress response was already launched. Finally, factors such as circadian rhythm (27) and individuals' baseline responsiveness (40) may have a major impact on salivary cortisol levels, and such factors were not considered in the present study.
The present study has other limitations. Although the sample size provided enough power to show group differences, it was not sufficient to conduct the multivariate analyses needed to delineate specific relationships among variables within the groups. Given the relatively low prevalence of pediatric FMS, multicenter studies would be needed. The current research sample comprised white families. Although the incidence of JPFMS and arthritis is higher in whites than in nonwhites (35), and the racial distribution in the current study was relatively consistent with the epidemiology of specific rheumatologic illnesses, the contribution of ethnic, sociocultural, and socioeconomic factors could not be appreciated. This limits the generalizability of our findings.
With any cross-sectional study design, it is impossible to demonstrate directionality or infer causality. The causal relationship between temperament, pain sensitivity, and psychological and family functioning is impossible to determine without using longitudinal data. The ideal methodology would involve following up a cohort of children over a period of years so that antecedent and consequent relationships in this complicated model may be identified.
Finally, it is difficult to assess the impact of prescription medications on self-report measures and salivary cortisol levels. Due to the nature of JPFMS and arthritis, dosages and medications change frequently. In addition, subjects reported that they either were taking the medication infrequently or were not taking it at all at the time when saliva was collected for measurement of cortisol. To truly account for medication effects, one would have to track specific usage over a period of time, which was not done in the present study.
The current study offers support for a psychobiologic model with factors that interact to place a child at increased risk of developing a pain disorder. Interventions should target the identified risk factors, such as augmenting a child's ability to cope with pain and increasing his or her daily activities (41). Reports from preliminary studies of children with JPFMS (42–44) and adults with FMS (45, 46) have suggested that cognitive–behavioral treatments, with emphasis on self-regulatory strategies and pain perception, are effective. The findings of this study, combined with results of previous studies, suggest that interventions to enhance coping and adjustment in children with JPFMS might best include both children and their parents. Family therapy may facilitate a reduction in family conflict, as well as an increase in cohesion and organization. Specifically, an increase in family cohesion might function as a protective factor for those children at risk for psychological adjustment problems.
The ultimate goal of research on chronic pain syndromes in both children and adults is to account for the array of physiologic and psychological variables that come into play, and to integrate them into a holistic model that may be applied to both research and clinical paradigms. Data from the present study make it clear that a constellation of stable individual differences in temperament, social/ecologic variables (e.g., parental and family characteristics), and pain reactivity are all linked in manners yet to be defined. Nonetheless, these and other factors should be pursued, both in the clinical setting and in basic and applied research.