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- Brodda Jansen, Gunilla
(författare)
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Contributions of calcitonin gene-related peptide in ischemia, inflammation and nociception
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The sensory neuropeptide Calcitonin gene-related peptide (CGRP) is a very potent vasodilator with a wide distribution in peripheral sensory nerves, often co-stored with substance P. In the present study, the effects of CGRP in different models of ischemia, inflammation and nociception were examined. Calcitonin gene-related peptide, but not substance P (SP), was found to inhibit edema-promoting actions of inflammatory mediators (histamine, leukotrine B4, 5-hydroxytryptamine, 5-HT) in vivo in the hamster cheek pouch, human skin, and rat paw. Accordingly, the CGRP antagonist CGRP8-37 enhanced 5-HT-induced edema in the rat paw. The effect of CGRP in the cheek pouch was present in the low nanomolar dose range, and it was mimicked by activation of sensory nerves with capsaicin which caused release of endogenous CGRP-like immunoreactivity (-LI). The findings suggest that the release of CGRP following sensory nerve activation during inflammatory processes may play an anti-inflammatory role. Activation of sensory nerves and local injection of CGRP in surgical skin flaps in rats significantly increased blood flow and flap survival. Intraperitoneal pretreatment with very low doses of CGRP dose-dependently increased the survival of flaps. Moreover, CGRP significantly reduced the marked surgery-induced accumulation of myeloperoxidase (a marker for neutrophil recruitment) in the flaps. In addition, it was found that inhibition of mast cell activation with disodium cromoglycate significantly improved the flap survival, and that CGRP had the capacity to inhibit mast cell mediator release. These findings indicate that the beneficial effect of CGRP on flap survival may involve inhibition of surgically induced neutrophil recruitment, possibly via a mechanism involving inhibition of mast cell function. The effect of peripheral and intrathecal administration of CGRP and the CGRP antagonist CGRP8-37 on nociception was studied. Subplantar injection of CGRP or CGRP8-37 into the rat hind paw did not affect the withdrawal response to nociceptive thermal stimuli or mechanical stimulation. Injection of s-HT into one hindpaw reduced withdrawal responses, a reduction which was not affected by pretreatment with CGRP or CGRP8 37. On the other hand, intrathecal administration of CGRP8-37 increased hind paw withdrawal latency to noxious thermal and mechanical stimulation. This effect was more pronounced in intact rats than in rats with unilateral carrageenan-induced hind paw inflammation. The effect of intrathecal CGRP8 37 on withdrawal responses was partly reversed by intrathecal injection of naloxon, indicating that opioids modulate the effect of CGRP in the spinal cord. The unilateral injection of carrageenan was found to cause a bilateral decrease in withdrawal response, and increased CGRP-LI in the perfusate of both hind paws as well as in the cerebrospinal fluid after 24 h. Taken together, the results indicate that CGRP modulates nociception via central but not peripheral mechanisms. Moreover, CGRP has anti-inflammatory actions which may help explain the beneficial effects seen on survival of surgical flaps.
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- Clason van de Leur, Jakob, et al.
(författare)
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Mediators during a multimodal intervention for stress-induced exhaustion disorder
- 2024
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Ingår i: Cognitive Behaviour Therapy. - : Routledge. - 1650-6073 .- 1651-2316. ; 53:3, s. 235-253
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Tidskriftsartikel (refereegranskat)abstract
- Our understanding of the underlying psychological processes of development, maintenance, and treatments for stress-induced exhaustion disorder (ED) remains limited. Therefore, the current study aimed to explore whether sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility mediate change in exhaustion symptoms during a Multimodal intervention for ED based on Cognitive behavioral therapy principles. Participants (N = 913) were assessed at three time points, and mediation was explored using a two-criteria analytical model with linear mixed-effects models (criterion one) and random intercepts cross-lagged panel modeling (criterion 2). Criterion one for mediation was successfully met, as the findings indicated significant associations between time in treatment, with all suggested mediators, and exhaustion symptoms (significant ab-products). However, criterion two was not satisfied as changes in the mediators did not precede changes in exhaustion symptoms. Therefore, mediation could not be established. Instead, changes in the suggested mediators appeared to result from changes in exhaustion symptoms. Consequently, sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility appear to improve in conjunction with exhaustion symptoms during treatment, where improvement in exhaustion is indicated as the main driving factor, based on this exploratory analysis. The implications of these findings are contextualized within a broader framework of process-based therapy.
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- Clason van de Leur, Jakob, et al.
(författare)
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Predictors and sub-groups in the treatment of stress-induced exhaustion disorder
- 2023
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Ingår i: Cognitive Behaviour Therapy. - : Taylor & Francis Group. - 1650-6073 .- 1651-2316. ; 52:4, s. 397-418
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about psychological interventions for stress-induced Exhaustion disorder (ED), and there is a need for more research to improve the outcomes obtained in treatments. The present study examines predictors of improvement, including sub-group responses, in a large sample of ED patients receiving a Multimodal intervention (MMI) based on Cognitive Behavior Therapy (N = 915). In step one, available variables were explored separately as predictors of improvement in ED symptoms. In step two, sub-groups were explored through Latent Class Analysis to reduce the heterogeneity observed in the larger group and to investigate whether combining the variables from step one predicted symptom improvement. Younger age, no previous sick leave due to ED, and scoring high on anxiety, depression, insomnia, perfectionism, and treatment credibility emerged as separate predictors of improvement. In the sub-group analyses, a sub-group including participants who were single and had a lower income showed less improvement. Overall, people with ED participating in MMI report symptom improvement regardless of characteristics before treatment. However, the present findings do have the potential to inform future treatments for ED, as they highlight perfectionism as a predictor of improvement and the importance of assessing treatment credibility during treatment.
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- Clason van de Leur, Jakob
(författare)
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Psychological Treatment of Stress-Induced Exhaustion Disorder : Towards a Contextual Behavioral Approach
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Long-term sick leave due to stress-related disorders has been steadily increasing in Western society. A portion of these sick leave rates is attributed to severe symptoms of exhaustion, assumed to be the result of persistent work stress. In Sweden, this symptomatology is currently classified using the diagnosis of stress-induced exhaustion disorder (ED). There are, however, no evidence-based treatments for ED, nor are there any established theoretical models to guide clinical interventions. Most current treatments revolve around promoting recovery behaviors, as ED is assumed to result from depleted psychophysiological resources. This thesis discusses the merits of this assumption and whether it is compatible with contemporary theories of stress and a contextual behavioral treatment approach. Additionally, a contextual behavioral model of ED is introduced with an accompanying biopsychosocial treatment, aiming to bridge the gap between theories of stress, basic learning principles, and clinically useful methods. The model suggests that ED can be conceptualized as a crisis of engagement rather than a result of depleted psychophysiological resources.Complementing this theoretical work are empirical studies of different aspects of multimodal interventions (MMI) for ED with the overarching aim of fostering a more theoretically coherent ED treatment that can be made accessible to more patients. Study I was an open clinical trial tracking ED patients (N = 390) participating in a 24-week MMI based on cognitive behavior therapy (CBT). Study II explored sub-groups and predictors of improvements in a large cohort (N = 915) of ED patients participating in the same MMI as Study I. Study III explored mediators commonly suggested to be relevant within ED treatment in the same cohort as Study II: sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility. Study IV was an uncontrolled pilot trial (N = 26) of the biopsychosocial treatment for ED presented in this thesis, delivered within a 12-week online MMI. In summary, the results of this thesis indicate that ED patients participating in CBT-based MMI benefit from treatment and report few adverse effects. Moreover, high degrees of perfectionism and high treatment credibility were identified as predictors of improvement, indicating the importance of addressing perfectionistic behaviors and treatment credibility in ED treatment. With positive results similar to those of Study I, Study IV provides preliminary support that ED can be treated more effectively with fewer clinical resources than more extensive MMIs when a more focused and theoretically stringent approach is utilized.
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- Clason van de Leur, Jakob, et al.
(författare)
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Standardized multimodal intervention for stress-induced exhaustion disorder : an open trial in a clinical setting
- 2020
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Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundLong-term sick-leave due to stress-related ill-health is increasing in several economically developed countries. Even though different forms of interventions are administered in regular care for stress-related disorders, such as Stress-induced Exhaustion disorder (SED), the scientific evidence for the effectiveness of such treatments is sparse. The objective of this study was to explore changes in SED-symptoms and return-to-work-rates in a large group of SED-patients participating in a standardized Multimodal intervention (MMI) in a clinical setting.MethodThis open clinical trial tracked 390 patients who fulfilled the criteria for SED undergoing a 24-week MMI, including return-to-work-strategies. Before inclusion, all patients underwent a multi-professional assessment by a team of licensed physicians, licensed psychologists, and licensed physiotherapists. Self-rated questionnaires were administered before treatment, at treatment-start, mid-treatment, post-treatment, and at 12-month follow-up. Within-group change was evaluated over time with mixed-effects models. Beyond different symptoms, working time, sick-leave compensation, and adverse effects were also measured.ResultsThere were significant improvements in symptoms of SED, burnout, anxiety, depression, and insomnia, with large within-group effect sizes (d = 0.91–1.76), improvements that were maintained at 12-month follow-up. Furthermore, there was a significant increase in quality of life and large improvements in average working time and sick-leave compensation. Some adverse effects were reported, mainly concerning an increase in stress, anxiety, and worry.ConclusionSED-patients participating in this standardized MMI reported large symptom alleviation, increased working time and reduced sick-leave compensation, indicating a beneficial treatment. There were some adverse effects, but no more so than other psychological treatments. This study confirms previous findings that high levels of depression and anxiety decrease to sub-clinical levels during treatment, while symptoms of SED also decline, yet still persists above sub-clinical levels at 12-month follow-up. On the whole, this open clinical trial suggests that a standardized MMI, administered in a clinical setting, improves symptoms and return-to-work rates in a clinically representative SED-population.
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- Gerdle, Björn, et al.
(författare)
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The importance of emotional distress, cognitive behavioural factors and pain for life impact at baseline and for outcomes after rehabilitation - a SQRP study of more than 20,000 chronic pain patients
- 2019
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Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter GmbH. - 1877-8860 .- 1877-8879. ; 19:4, s. 693-711
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims Although literature concerning chronic pain patients indicates that cognitive behavioural variables, specifically acceptance and fear of movement/(re)injury, are related to life impact, the relative roles of these factors in relation to pain characteristics (e.g. intensity and spreading) and emotional distress are unclear. Moreover, how these variables affect rehabilitation outcomes in different subgroups is insufficiently understood. This study has two aims: (1) to investigate how pain, cognitive behavioural, and emotional distress variables intercorrelate and whether these variables can regress aspects of life impact and (2) to analyse whether these variables can be used to identify clinically meaningful subgroups at baseline and which subgroups benefit most from multimodal rehabilitation programs (MMRP) immediately after and at 12-month follow-up. Methods Pain aspects, background variables, psychological distress, cognitive behavioural variables, and two life impact variables were obtained from the Swedish Quality Registry for Pain Rehabilitation (SQRP) for chronic pain patients. These data were analysed mainly using advanced multivariate methods. Results The study includes 22,406 chronic pain patients. Many variables, including acceptance variables, showed important contributions to the variation in clinical presentations and in life impacts. Based on the statistically important variables considering the clinical presentation, three clusters/subgroups of patients were identified at baseline; from the worst clinical situation to the relatively good situation. These clusters showed significant differences in outcomes after participating in MMRP; the subgroup with the worst situation at baseline showed the most significant improvements. Conclusions Pain intensity/severity, emotional distress, acceptance, and life impacts were important for the clinical presentation and were used to identify three clusters with marked differences at baseline (i.e. before MMRP). Life impacts showed complex relationships with acceptance, pain intensity/severity, and emotional distress. The most significant improvements after MMRP were seen in the subgroup with the lowest level of functioning before treatment, indicating that patients with complex problems should be offered MMRP. Implications This study emphasizes the need to adopt a biopsychosocial perspective when assessing patients with chronic pain. Patients with chronic pain referred to specialist clinics are not homogenous in their clinical presentation. Instead we identified three distinct subgroups of patients. The outcomes of MMRP appears to be related to the clinical presentation. Thus, patients with the most severe clinical presentation show the most prominent improvements. However, even though this group of patients improve they still after MMRP show a complex situation and there is thus a need for optimizing the content of MMRP for these patients. The subgroup of patients with a relatively good situation with respect to pain, psychological distress, coping and life impact only showed minor improvements after MMRP. Hence, there is a need to develop other complex interventions for them.
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