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2.  Multidimensional associative factors for improvement in pain, function, and working capacity after rehabilitation of whiplash associated disorder: a prognostic, prospective outcome study 
Background
Whiplash associated disorders (WAD) have dramatic consequences for individual and public health. Risk factors for better and worse outcomes are important to optimize management. This study aimed to determine short- and mid-term associative co-factors of neck pain relief, improved physical functioning, and improved working capacity (dependent variables) in patients suffering from whiplash associated disorder who participated in a standardized, inpatient pain management program.
Methods
Naturalistic, observational, prospective cohort study. Outcome was measured by standardized assessment instruments. Co-factors covered sociodemographics, comorbidities, social participation, affective health, and coping abilities. Stepwise, multivariate linear regression analysis was performed at discharge and at the 6-month follow-up.
Results
All regression models explained high proportions of variance (53.3% – 72.1%). The corresponding baseline level was significantly associated with a change in every dependent variable (explained variances: 11.4%-56.7%). Pain relief significantly depended on improved function and vice-versa (3.4%-14.8%). Improved ability to decrease pain was associated with pain relief at discharge (9.6%). Functional improvement was associated with decreased catastrophizing (19.4%) at discharge and decreased depression (20.5%) at the 6 month follow-up.
Conclusions
Pain relief, improved physical function and working capacity were associated with each other. Improved coping (catastrophizing and ability to decrease pain) and reduced depression may act as important predictors for pain relief and improved function. These findings offer toe-holds for optimized therapy of chronic WAD.
doi:10.1186/1471-2474-15-130
PMCID: PMC3996256  PMID: 24739588
Whiplash; Prediction; Pain; Function; Coping; Catastrophizing
3.  Reliability of the Multidimensional Pain Inventory and stability of the MPI classification system in chronic back pain 
Background
This cross validation study examined the reliability of the Multidimensional Pain Inventory (MPI) and the stability of the Multidimensional Pain Inventory Classification System of the empirically derived subgroup classification obtained by cluster analysis in chronic musculoskeletal pain. Reliability of the German Multidimensional Pain Inventory was only examined once in the past in a small sample. Previous international studies mainly involving fibromyalgia patients showed that retest resulted in 33–38% of patients being assigned to a different Multidimensional Pain Inventory subgroup classification.
Methods
Participants were 204 persons with chronic musculoskeletal pain (82% chronic non-specific back pain). Subgroup classification was conducted by cluster analysis at 4 weeks before entry (=test) and at entry into the pain management program (=retest) using Multidimensional Pain Inventory scale scores. No therapeutic interventions in this period were conducted. Reliability was quantified by intraclass correlation coefficients (ICC) and stability by kappa coefficients (κ).
Results
Reliability of the Multidimensional Pain Inventory scales was least with ICC = 0.57 for the scale life control and further ranged from ICC = 0.72 (negative mood) to 0.87 (solicitous responses) in the other scales. At retest, 82% of the patients in the Multidimensional Pain Inventory cluster interpersonally distressed (κ = 0.69), 80% of the adaptive copers (κ = 0.58), and 75% of the dysfunctional patients (κ = 0.70) did not change classification. In total, 22% of the patients changed Multidimensional Pain Inventory cluster group, mainly into the adaptive copers subgroup.
Conclusion
Test-retest reliability of the German Multidimensional Pain Inventory was moderate to good and comparable to other language versions. Multidimensional Pain Inventory subgroup classification is substantially stable in chronic back pain patients when compared to other diagnostic groups and other examiner-based subgroup Classification Systems. The MPI Classification System can be recommended for reliable and stable specification of subgroups in observational and interventional studies in patients with chronic musculoskeletal pain.
doi:10.1186/1471-2474-13-155
PMCID: PMC3495019  PMID: 22916687
Reliability; Back pain; Cluster; Subgroup; MPI; Classification
4.  ATP Induced Brain-Derived Neurotrophic Factor Expression and Release from Osteoarthritis Synovial Fibroblasts Is Mediated by Purinergic Receptor P2X4 
PLoS ONE  2012;7(5):e36693.
Brain-derived neurotrophic factor (BDNF), a neuromodulator involved in nociceptive hypersensitivity in the central nervous system, is also expressed in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We investigated the role of P2 purinoreceptors in the induction of BDNF expression in synovial fibroblasts (SF) of OA and RA patients. Cultured SF from patients with symptomatic knee OA and RA were stimulated with purinoreceptor agonists ATP, ADP, or UTP. The expression of BDNF mRNA was measured by quantitative TaqMan PCR. BDNF release into cell culture supernatants was monitored by ELISA. P2X4 expression in synovial tissue was detected by immunohistochemistry. Endogenous P2X4 expression was decreased by siRNA transfection before ATP stimulation. Kinase pathways were blocked before ATP stimulation. BDNF mRNA expression levels in OASF were increased 2 h and 5 h after ATP stimulation. Mean BDNF levels in cell culture supernatants of unstimulated OASF and RASF were 19 (±9) and 67 (±49) pg/ml, respectively. BDNF levels in SF supernatants were only elevated 5 h after ATP stimulation. BDNF mRNA expression in OASF was induced both by P2X receptor agonists ATP and ADP, but not by UTP, an agonist of P2Y purinergic receptors. The ATP-induced BDNF mRNA expression in OASF was decreased by siRNA-mediated reduction of endogenous P2X4 levels compared to scrambled controls. Inhibition of p38, but not p44/42 signalling reduced the ATP-mediated BDNF mRNA induction. Here we show a functional role of the purinergic receptor P2X4 and p38 kinase in the ATP-induced expression and release of the neurotrophin BDNF in SF.
doi:10.1371/journal.pone.0036693
PMCID: PMC3360754  PMID: 22715356
5.  Differences in pain, function and coping in Multidimensional Pain Inventory subgroups of chronic back pain: a one-group pretest-posttest study 
Background
Patients with non-specific back pain are not a homogeneous group but heterogeneous with regard to their bio-psycho-social impairments. This study examined a sample of 173 highly disabled patients with chronic back pain to find out how the three subgroups based on the Multidimensional Pain Inventory (MPI) differed in their response to an inpatient pain management program.
Methods
Subgroup classification was conducted by cluster analysis using MPI subscale scores at entry into the program. At program entry and at discharge after four weeks, participants completed the MPI, the MOS Short Form-36 (SF-36), the Hospital Anxiety and Depression Scale (HADS), and the Coping Strategies Questionnaire (CSQ). Pairwise analyses of the score changes of the mentioned outcomes of the three MPI subgroups were performed using the Mann-Whitney-U-test for significance.
Results
Cluster analysis identified three MPI subgroups in this highly disabled sample: a dysfunctional, interpersonally distressed and an adaptive copers subgroup. The dysfunctional subgroup (29% of the sample) showed the highest level of depression in SF-36 mental health (33.4 ± 13.9), the interpersonally distressed subgroup (35% of the sample) a modest level of depression (46.8 ± 20.4), and the adaptive copers subgroup (32% of the sample) the lowest level of depression (57.8 ± 19.1). Significant differences in pain reduction and improvement of mental health and coping were observed across the three MPI subgroups, i.e. the effect sizes for MPI pain reduction were: 0.84 (0.44 - 1.24) for the dysfunctional subgroup, 1.22 (0.86 - 1.58) for the adaptive copers subgroup, and 0.53 (0.24 - 0.81) for the interpersonally distressed subgroup (p = 0.006 for pairwise comparison). Significant score changes between subgroups concerning activities and physical functioning could not be identified.
Conclusions
MPI subgroup classification showed significant differences in score changes for pain, mental health and coping. These findings underscore the importance of assessing individual differences to understand how patients adjust to chronic back pain.
doi:10.1186/1471-2474-12-145
PMCID: PMC3141610  PMID: 21718525
6.  Is Supplementation of Vitamin D Beneficial for Fracture Healing? A Short Review of the Literature 
There has been a surge of interest regarding the benefits of vitamin D supplementation to prevent fractures. But can it also make them heal more quickly once they have occurred—that is, is supplementation of vitamin D beneficial for fracture healing? We found 13 studies that met our inclusion criteria, 11 of these were performed in animals. Two animal studies showed negative, 2 neutral, and 7 positive results. One clinical case series in humans was inconclusive in our opinion, and one randomized double-blind placebo-controlled trial showed that supplementation of vitamin D3 and calcium in elderly women with reduced bone mass and a proximal humerus fracture had a positive influence on bone healing. The major weakness of the latter study is low number of participants. A clear statement on the benefits of vitamin D for fracture healing awaits further trials, but all types of fractures in elderly individuals indicate the need for secondary prevention and the implementation of appropriate guidelines concerning falls, vitamin D, and osteoporosis.
doi:10.1177/2151458511408568
PMCID: PMC3597312  PMID: 23569676
fracture healing; vitamin D; osteoporosis
7.  Does classification of persons with fibromyalgia into Multidimensional Pain Inventory subgroups detect differences in outcome after a standard chronic pain management program? 
INTRODUCTION:
The present study aimed to replicate and validate the empirically derived subgroup classification based on the Multidimensional Pain Inventory (MPI) in a sample of highly disabled fibromyalgia (FM) patients. Second, it examined how the identified subgroups differed in their response to an intensive, interdisciplinary inpatient pain management program.
METHODS:
Participants were 118 persons with FM who experienced persistent pain and were disabled. Subgroup classification was conducted by cluster analysis using MPI subscale scores at entry to the program. At program entry and discharge, participants completed the MPI, Medical Outcomes Study Short Form-36, Hospital Anxiety and Depression Scale and Coping Strategies Questionnaire.
RESULTS:
Cluster analysis identified three subgroups in the highly disabled sample that were similar to those described by other studies using less disabled samples of FM. The dysfunctional subgroup (DYS; 36% of the sample) showed the highest level of depression, the interpersonally distressed subgroup (ID; 24%) showed a modest level of depression and the adaptive copers subgroup (AC; 38%) showed the lowest depression scores in the MPI (negative mood), Medical Outcomes Study Short Form-36 (mental health), Hospital Anxiety and Depression Scale (depression) and Coping Strategies Questionnaire (catastrophizing). Significant differences in treatment outcome were observed among the three subgroups in terms of reduction of pain severity (as assessed using the MPI). The effect sizes were 1.42 for DYS, 1.32 for AC and 0.62 for ID (P=0.004 for pairwise comparison of ID-AC and P=0.018 for ID-DYS).
DISCUSSION:
These findings underscore the importance of assessing individuals’ differences in how they adjust to FM.
PMCID: PMC2807772  PMID: 20011715
Cluster analysis; Fibromyalgia (FM); MPI; Pain management program; Subgroups
8.  DREAM is reduced in synovial fibroblasts of patients with chronic arthritic pain: is it a suitable target for peripheral pain management? 
Introduction
The endogenous pain-relieving system depends in part on the regulation of nociceptive signals through binding of opioids to the corresponding opioid receptor. Interfering with the trans-repression effect of downstream regulatory element antagonist modulator (DREAM) on the transcription of the opioid dynorphin-encoding prodynorphin (pdyn) gene might enhance pain relief in the periphery.
Methods
Expression levels were measured in osteoarthritis (OA) synovial fibroblast-like cells (SFLCs) (n = 8) and in peripheral blood mononuclear cells (PBMCs) from OA patients (n = 53) and healthy controls (n = 26) by real-time polymerase chain reaction. Lysed OA SFLCs were analyzed by immunoprecipitation. Translation of DREAM mRNA was inhibited by small interfering RNAs (siRNAs). Expressions of DREAM, pdyn, and c-fos mRNAs were measured at 24, 48, and 72 hours after transfection.
Results
The expression of DREAM mRNA was shown in both healthy and OA SFLCs as well as PBMCs. Inhibiting transcription using siRNAs led to a marked reduction in DREAM expression after 24, 48, and 72 hours. However, no significant changes in c-fos and pdyn expression occurred. In addition, DREAM mRNA expression was significantly reduced in OA patients with chronic pain (pain intensity as measured by a visual analog scale scale of greater than 40), but no pdyn expression was detectable.
Conclusion
To our knowledge, this is the first report showing the expression of DREAM in SFLCs and PBMCs on the mRNA level. However, DREAM protein was not detectable. Since repression of pdyn transcription persists after inhibiting DREAM translation, DREAM appears to play no functional role in the kappa opioid receptor system in OA SFLCs. Therefore, our data suggest that DREAM appears not to qualify as a target in peripheral pain management.
doi:10.1186/ar2431
PMCID: PMC2483451  PMID: 18507845
9.  Responsiveness of five condition-specific and generic outcome assessment instruments for chronic pain 
Background
Changes of health and quality-of-life in chronic conditions are mostly small and require specific and sensitive instruments. The aim of this study was to determine and compare responsiveness, i.e. the sensitivity to change of five outcome instruments for effect measurement in chronic pain.
Methods
In a prospective cohort study, 273 chronic pain patients were assessed on the Numeric Rating Scale (NRS) for pain, the Short Form 36 (SF-36), the Multidimensional Pain Inventory (MPI), the Hospital Anxiety and Depression Scale (HADS), and the Coping Strategies Questionnaire (CSQ). Responsiveness was quantified by effect size (ES) and standardized response mean (SRM) before and after a four week in-patient interdisciplinary pain program and compared by the modified Jacknife test.
Results
The MPI measured pain more responsively than the SF-36 (ES: 0.85 vs 0.72, p = 0.053; SRM: 0.72 vs 0.60, p = 0.027) and the pain NRS (ES: 0.85 vs 0.62, p < 0.001; SRM: 0.72 vs 0.57, p = 0.001). Similar results were found for the dimensions of role and social interference with pain. Comparison in function was limited due to divergent constructs. The responsiveness of the MPI and the SF-36 was equal for affective health but both were better than the HADS (e.g. MPI vs HADS depression: ES: 0.61 vs 0.43, p = 0.001; SF-36 vs HADS depression: ES: 0.54 vs 0.43, p = 0.004). In the "ability to control pain" coping dimension, the MPI was more responsive than the CSQ (ES: 0.46 vs 0.30, p = 0.011).
Conclusion
The MPI was most responsive in all comparable domains followed by the SF-36. The pain-specific MPI and the generic SF-36 can be recommended for comprehensive and specific bio-psycho-social effect measurement of health and quality-of-life in chronic pain.
doi:10.1186/1471-2288-8-26
PMCID: PMC2386498  PMID: 18439285

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