Associations between sickness behavior, but not inflammatory cytokines, and psychiatric comorbidity in chronic pain.

OBJECTIVES: Approximately one in five adults experiences chronic pain, often in co-occurrence with depression, insomnia, anxiety, and lower self-rated health. Elevated levels of cytokines, e.g. tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10), have been identified in patients with chronic pain. Depression, insufficient sleep, poor self-rated health, and pain intensity have also been associated with inflammatory biomarkers. This study aimed to investigate the interrelationships between inflammatory biomarkers and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity in patients with chronic pain. METHODS: Self-report questionnaires and blood samples analyzed for plasma levels of inflammatory biomarkers were collected from 80 adult patients with chronic pain. Associations between inflammatory biomarkers (TNF-α, IL-6, IL-8, IL-10, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity, were analyzed using bivariate Spearman rank correlation coefficients and regression analyses. RESULTS: Participants were mainly women (72.5 %), with a mean age of 50.8 years, and a reported mean pain duration of 16.7 years. There were significant correlations between insomnia and CRP (rs =.26, p <.05); sex and ESR (rs =.29, p <.05); age and IL-6 (rs =.29, p <.05) and IL-8 (rs =.30, p <.05); BMI and IL-6 (rs =.50, p <.001), CRP (rs =.63, p <.001) and ESR (rs =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (ß =.32 and ß =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (ß =.37) explaining 31 % of the total variance in insomnia ratings. Inflammatory biomarkers, however, did not contribute significantly to the models. CONCLUSIONS: Participants reported high levels of symptoms, yet the associations between these ratings and the inflammatory biomarkers were either absent or weak. Also, despite high levels of self-reported sickness behavior, overall the inflammatory status remained within the normal range. Ratings of sickness behavior contributed more than inflammatory markers in explaining ratings of depression and insomnia. The present results point to the complexity of chronic pain, and the challenges of identifying biomarkers that explain symptomatology.

Child and Parent Risk and Resilience Factors as Predictors of Long-term Recovery in Youth Undergoing Spinal Fusion Surgery.

OBJECTIVES: Undertreated pediatric postsurgical pain negatively affects health-related quality of life (HRQOL) and functioning and may lead to chronic postsurgical pain (CPSP). Predictors of recovery have been identified but more research is needed, particularly regarding resilience, social factors, and long-term effects. The aim of the present study was to investigate child and parent risk and resilience factors as predictors of long-term postsurgical recovery for adolescents. METHODS: Participants were patients with Adolescent Idiopathic Scoliosis (AIS), 12 to 18 years old, undergoing spinal fusion, and their parents. Recruitment occurred at the orthopedic units at 4 hospitals in Belgium. Data were collected before surgery (T0), at 3 (T1) and 6 weeks (T2), 6 months (T3), and 1 year (T4) post surgery. Multiple regression models were used to evaluate the predictive effect of pain intensity, pain catastrophizing, psychological flexibility, and pain acceptance on long-term functioning, HRQOL, and pain. RESULTS: The sample comprised 100 adolescents and 61 parents. Pain at T0, T1, and T3 and adolescent pain catastrophizing (T0) predicted health-related quality of life, functioning, and pain at T4 (while pain at T2 predicted HRQOL and pain). Parent pain catastrophizing predicted pain at T4. Adolescent and parental psychological flexibility predicted HRQOL, and parent psychological flexibility also predicted pain at T4. Adolescent acceptance at T1 predicted pain, and acceptance at T2 predicted HRQOL, at T4. DISCUSSION: The study identified pain and adolescent pain catastrophizing as risk factors, and adolescent and parental psychological flexibility and adolescent pain acceptance as resilience factors, for long-term recovery in youths undergoing spinal fusion. Postsurgical pain management targeting these factors may therefore promote recovery for these adolescents.

Exploration of Functional Connectivity Changes Previously Reported in Fibromyalgia and Their Relation to Psychological Distress and Pain Measures.

Neural functional connectivity changes in the default mode network (DMN), Central executive network (CEN), and insula have been implicated in fibromyalgia (FM) but stem from a sparse set of small-scale studies with limited power for the investigation of confounding effects. We investigated whether anxiety, depression, pain sensitivity, and pain intensity modulated functional connectivity related to DMN nodes, CEN nodes, and insula. Resting-state functional magnetic resonance imaging data were collected from 31 females with FM and 28 age-matched healthy controls. Connectivity was analysed with a region-based connectivity analysis between DMN nodes in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex, CEN nodes in the intraparietal sulcus (IPS), and bilateral insula. FM patients displayed significantly higher levels of anxiety and depressive symptoms than controls. The right IPS node of the CEN showed a higher level of connectivity strength with right insula in FM with higher pain intensity compared to controls. More anxiety symptoms in FM correlated with higher levels of connectivity strength between the vmPFC DMN node and right sensorimotor cortex. These findings support the theory of altered insular connectivity in FM and also suggest altered IPS connectivity in FM. Interestingly, no change in insular connectivity with DMN was observed.

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms.

BACKGROUND: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations. METHODS: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (ß-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-ß-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions. RESULTS AND CONCLUSIONS: Only ß-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-ß-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-ß-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

An observational study on risk factors for prolonged opioid prescription after severe trauma.

BACKGROUND AND AIMS: Trauma is one of the most common causes of morbidity and mortality in people of working age. Following surgery, approximately 10% of patients develop persistent postsurgical pain. Chronic pain is a complex phenomenon that can adversely affect quality of life and is associated with psychiatric conditions such as anxiety and depression. Pharmacological treatment is normally insufficient to fully alleviate chronic pain and improve functional capacity, especially in the long term. The appropriateness of opioid treatment in chronic non-cancer pain has become increasingly examined with high numbers of serious side effects including drug dependency and death. The present study was based on clinical observations suggesting that a problematic opioid use can be initiated during trauma care, which implies the importance of evaluating opioid therapy and its effect on trauma patients. Specific attention is given to patients with known psychiatric conditions which may render them more vulnerable to develop problematic opioid use. The aim of this observational study was to broadly characterize patients referred to a pain specialist after severe trauma regarding their trauma type, psychiatric co-morbidity, and opioid prescription pattern. This was done to tentatively investigate possible risk factors for long-term opioid use following trauma. METHODS: Trauma patients referred to the Pain Center at Karolinska University Hospital, Sweden (n=29) were recruited for the study over a period of 2 years. Demographic information, trauma-related data as well as psychiatric diagnoses and pharmacological prescriptions were retrieved from the registry SweTrau and electronic medical records. RESULTS: Among the 29 participants (age range 21-55 years, median=34; 76% male), 14 (48%) were prescribed opioids at least once during the 6-months period preceding the trauma. For 21 patients (72%) opioids were prescribed 6 months after the trauma. One year after the trauma, 18 patients (62%) still had prescriptions for opioids corresponding to daily use or more, and two other patients used opioids intermittently. Twenty patients (69%) had psychiatric diagnoses before the trauma. According to the medical records, 17 patients (59%) received pharmacological treatment for psychiatric conditions in the six months period preceding the trauma. During the follow-up period, psychiatric pharmacological treatment was prescribed for 27 (93%) of the patients. CONCLUSION AND IMPLICATIONS: For most of the participants opioids were still being prescribed one year after trauma. The majority presented with psychiatric co-morbidity before trauma and were also prescribed psychiatric medication. Findings support the notion that patients with a complex pain situation in the acute phase following trauma are at risk for prolonged opioid prescription. These results, although tentative, point at psychiatric co-morbidity, opioid use before trauma, high injury severity, extensive surgery and extended hospital stay as risk factors for prolonged opioid prescription after severe trauma. This study is purely observational, with a small sample and non-controlled design. However, these data further emphasize the need to identify patients at risk for developing problematic long-term opioid use following trauma and to ensure appropriate pain treatment.

Approach as a key for success: Reduced avoidance behaviour mediates the effect of exposure therapy for fibromyalgia.

Fibromyalgia (FM) is a prevalent chronic pain disorder associated with large suffering and substantial societal costs. Pain-related avoidance behaviour and hypervigilance to bodily symptoms are common in FM and contribute in maintaining and exacerbating the disorder. Exposure therapy targeting avoidance behaviours and hypervigilance has shown promise in the treatment of FM. The present study investigated mediators of treatment outcome in exposure therapy for FM. We used data from a randomised trial, where 140 participants were allocated to 10-week internet-delivered exposure therapy or to a waiting-list control condition. The main outcome variable (FM symptoms) and the hypothesized mediators (FM-related avoidance behaviour, mindful non-reactivity and FM-related worry) were measured weekly throughout treatment. Mediation analyses were conducted using linear mixed effects models with bootstrap replication and time-lagged analysis. Results indicated that all three process variables were significant mediators of FM severity. However, in the time-lagged analyses, only FM-related avoidance behaviour displayed a unidirectional relationship over time with FM symptoms, suggesting a causal effect. Thus, results illustrate that changes in avoidance behaviour mediate the outcome of exposure on FM symptoms, which implies that avoidance behaviour is an important treatment target in exposure therapy.

Cost-Effectiveness and Cost-Utility of Internet-Delivered Exposure Therapy for Fibromyalgia: Results From a Randomized, Controlled Trial.

Fibromyalgia (FM) is a prevalent and debilitating chronic pain disorder associated with a substantial economic burden. Although there are several studies investigating the effectiveness of psychological treatments such as cognitive-behavioral therapy for FM, studies on cost-effectiveness are scarce. The aim of the present study was to investigate the cost-effectiveness of Internet-delivered exposure therapy (iExp) for FM. We used health economic data from a recently conducted randomized, controlled trial, where 140 participants were randomized to either iExp or a waitlist control (WLC) condition. Economic data were collected at pre-treatment, post-treatment, and at the 1-year follow-up. Treatment effectiveness in relation to costs were analyzed using both a societal perspective (including all direct and indirect costs) and a health care unit perspective (including only the direct treatment costs). Bootstrapped net benefit regression analyses were also conducted, comparing the difference in costs and effects between iExp and WLC, within different willingness-to-pay scenarios. Results showed that the incremental cost-effectiveness ratio was -$15,295, indicating that iExp was highly cost-effective as each successfully treated case (treatment responder) was associated with a substantial net reduction in costs. The robustness of the results was tested in 2 different sensitivity analyses, where iExp remained cost-effective, even in a willingness-to-pay-scenario of $0. We conclude that iExp is a cost-effective treatment that generates large societal cost savings. PERSPECTIVE: Health-economic evaluations of psychological interventions for FM are scarce. This study is a cost-effectiveness analysis of Internet-delivered exposure therapy for patients with FM. Results showed that iExp was highly cost-effective compared with no treatment, where each successfully treated case generated a substantial societal cost saving.

Internet-Delivered Exposure Therapy for Fibromyalgia: A Randomized Controlled Trial.

BACKGROUND: Fibromyalgia (FM) is a common and disabling chronic pain disorder, for which existing pharmacological and psychological treatments have yet yielded insufficient effects. Previous literature has shown that exposure therapy may be an effective treatment for chronic pain. This study constitutes the first randomized controlled trial evaluating exposure therapy for FM. METHODS: A total of 140 participants with diagnosed FM were randomized to a 10-week Internet-delivered exposure treatment (iExp; n=70) or a waitlist control condition (WLC; n=70). Primary outcome measure were FM symptoms and impact, and secondary outcome measures were fatigue, disability, quality of life, pain-related distress and avoidance behaviors, insomnia, depression, and anxiety. RESULTS: Data retention was high (100% data completion at posttreatment for primary outcome, 96% at 6-month follow-up and 94% at 12-month follow-up). Results showed that participants in the iExp group made large and superior improvements compared with WLC on FM symptoms and impact (B, -1.93; z, -10.14; P<0.001, between-group Cohen d=0.90), as well as all secondary outcomes (between-group Cohen d ranging from 0.44 to 1.38) with sustained results. CONCLUSIONS: We conclude that iExp seems to be an efficacious treatment for FM compared with no treatment, and the results also highlight the potential increase of accessibility by using the Internet format to deliver psychological treatments for these patients. Future trials with active control conditions are warranted.

Comparing group-based acceptance and commitment therapy (ACT) with enhanced usual care for adolescents with functional somatic syndromes: a study protocol for a randomised trial.

INTRODUCTION: Functional somatic syndromes (FSS) are common in adolescents, characterised by severe disability and reduced quality of life. Behavioural treatments such as acceptance and commitment therapy (ACT) has shown promising results in children and adolescents with FSS, but has focused on specific syndromes such as functional pain. The current study will compare the efficacy of group-based ACT with that of enhanced usual care (EUC) in adolescents with a range of FSS operationalised by the unifying construct of multiorgan bodily distress syndrome (BDS). METHODS AND ANALYSIS: A total of 120 adolescents aged 15-19 and diagnosed with multiorgan BDS, of at least 12 months duration, will be assessed and randomised to either: (1) EUC: a manualised consultation with a child and adolescent psychiatrist and individualised treatment plan or (2) manualised ACT-based group therapy plus EUC. The ACT programme consists of 9 modules (ie, 27 hours) and 1 follow-up meeting (3 hours). The primary outcome is physical health, assessed by an Short Form Health Survey (SF-36) aggregate score 12 months after randomisation. Secondary outcomes include self-reported symptom severity, symptom interference, depression and anxiety, illness worry, perceived stress and global improvement; as well as objective physical activity and bodily stress response measured by heart rate variability, hair cortisol and inflammatory biomarkers. Process measures are illness perception, illness-related behaviour and psychological flexibility. ETHICS AND DISSEMINATION: The study is conducted in accordance with Helsinki Declaration II. Approval has been obtained from the Science Ethics Committee of the Central Denmark Region and the Danish Data Protection. The results will be sought to be published according to the CONSORT statement in peer-reviewed journals. DISCUSSION: This is one of the first larger randomised clinical trials evaluating the effect of a group-based intervention for adolescents with a range of severe FSS. TRIAL REGISTRATION NUMBER: NCT02346071; Pre-results.

Low-grade inflammation may moderate the effect of behavioral treatment for chronic pain in adults.

The purpose of the present pilot study was to explore the moderating role of basal inflammation on the effects of behavioral pain treatment in 41 patients with long-standing pain. Baseline pro-inflammatory status moderated behavioral treatment outcomes: higher pre-treatment levels of Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6 were related to less improvement in pain intensity, psychological inflexibility and in mental health-related quality of life. The treatment outcomes improved in the subgroup that had low levels of pro-inflammatory cytokines at baseline, while the subjects with higher pro-inflammatory status did not. Altogether, results indicate that low-grade inflammation may influence the behavioral treatment outcomes and provide a possible explanation of the heterogeneity in treatment response.

Development and validation of the English Pain Interference Index and Pain Interference Index-Parent report.

OBJECTIVE: Measurement of pain interference in children is challenged by a lack of validated measures with a parent proxy report. This study investigated the psychometric properties of the Pain Interference Index (PII), a six-item questionnaire originally developed in Swedish, in chronically ill youth. METHODS: We adapted the PII for English-speaking participants and created a parallel parent proxy measure. Respondents indicate how much pain has interfered with the child's life in the past 2 weeks (0-6 scale); higher scores indicate more pain interference. Eligible participants included individuals 6-25 years with neurofibromatosis type 1 (NF1) and cancer. Internal consistency was assessed; validity was examined by correlating PII scores with existing measures of pain interference (Modified Brief Pain Inventory [MBPI]) and pain intensity (visual analogue scale [VAS]), and with measures of disease severity. RESULTS: Among 60 participants (mean age 14.7 years, range 6-24) and their parents, PII internal consistency was 0.84 and 0.96, respectively. PII scores correlated with MBPI (r = 0.81, P < 0.0001) and VAS (r = 0.55, P < 0.0001) scores and differentiated between patients with mild vs moderate/severe NF1 disease severity (P < 0.05). The PII-Parent was significantly correlated with the mothers' and fathers' VAS rating of the child's pain intensity (Ps < 0.01). CONCLUSIONS: Internal consistency of the English PII is high; validity is supported by the PII's correlations with other measures of pain interference and pain intensity, and with disease severity in patients with NF1. Preliminary data indicate that the English PII is a reliable, valid, feasible pain interference measure for youth with NF1 and cancer.

Internet-delivered acceptance and values-based exposure treatment for fibromyalgia: a pilot study.

BACKGROUND: Acceptance and commitment therapy (ACT) is a promising treatment option for fibromyalgia (FM). Studies have shown that many cognitive behavioral protocols can be transferred to the Internet with sustained efficacy. However, no study has investigated the effect on an Internet-delivered ACT-based protocol for FM. This study evaluated the efficacy, acceptability, and the health economic effects of an Internet-delivered acceptance and values-based exposure treatment for FM. METHODS: This open pilot trial included 41 self-referred women with a FM diagnosis. The 10-week Internet-delivered treatment included acceptance, mindfulness, work with life-values, and systematic exposure to FM symptoms and FM-related situations. Participants also had regular contact with an assigned online therapist. Assessments were made at pretreatment, post-treatment, and 6-month follow-up. RESULTS: The treatment was completed by 70% of the participants. Attrition rates were low, with 98% completing the post-treatment assessment and 90% completing the 6-month follow-up assessment. Multiple imputations were used to replace missing values. Pre- to post-treatment within-group effect sizes were in the moderate to large range (Cohen's d = 0.62-1.56) on measures of FM symptoms and impact, disability, quality of life, depression, anxiety, fatigue, and psychological flexibility. All improvements were maintained at follow-up. Economical analyses revealed significant societal cost reductions that offset the treatment costs within 2 months of treatment completion. CONCLUSIONS: An Internet-delivered psychological treatment based on acceptance and exposure principles seems to be an efficacious, acceptable, and cost-effective treatment for FM. Randomized controlled trials are needed to confirm these results.