Predictors for severe persisting pain in rheumatoid arthritis are associated with pain origin and appraisal of pain.

OBJECTIVES: To determine the proportion of patients with rheumatoid arthritis (RA) with severe persisting pain and to identify predictive factors despite treatment-controlled disease activity. METHODS: This prospective multicentre study included outpatients with RA scheduled for escalation of anti-inflammatory treatment due to active disease and severe pain (Disease Activity Score 28 (DAS28)>3.2 and Visual Analogue Scale (VAS)>50). At week 24, patients were stratified into reference group (DAS28 improvement>1.2 or DAS28≤3.2 and VAS pain score<50), non-responders (DAS28 improvement≤1.2 and DAS28>3.2, regardless of VAS pain score) and persisting pain group (DAS28 improvement>1.2 or DAS28≤3.2 and VAS pain score≥50). The former two subgroups ended the study at week 24. The latter continued until week 48. Demographic data, DAS28-C reactive protein, VAS for pain, painDETECT Questionnaire (PD-Q) to identify neuropathic pain (NeP) and the Pain Catastrophising Scale were assessed and tested for relation to persisting pain. RESULTS: Of 567 patients, 337 (59.4%) were classified as reference group, 102 (18.0%) as non-responders and 128 (22.6%) as patients with persisting pain. 21 (8.8%) responders, 28 (35.0%) non-responders and 27 (26.5%) persisting pain patients tested positive for NeP at week 24. Pain catastrophising (p=0.002) and number of tender joints (p=0.004) were positively associated with persisting pain at week 24. Baseline PD-Q was not related to subsequent persisting pain. CONCLUSIONS: Persisting and non-nociceptive pain occur frequently in RA. Besides the potential involvement of NeP, pain catastrophising and a higher number of tender joints coincide with persisting pain.

Neurohumoral Profiles and Childhood Adversity of Patients with Multisomatoform Disorder and Pain as the Leading Bodily Symptom.

OBJECTIVE: Patients suffering from chronic pain often present with multifactorial underlying conditions, sometimes without concrete pathological physical findings. Functional somatic syndromes (FSS) and somatoform disorders show a high prevalence of 8-20% and are often associated with adverse childhood experiences (ACE) and chronic stress. As many different FSS have overlapping symptoms, the concept of multisomatoform disorder (MSD) has been introduced as an encompassing concept. We hypothesize that a common neurohumoral profile is present in patients with MSD that is distinct from gender- and age-matched controls and thus provides insight into possible common underlying mechanisms. DESIGN: In 151 patients with MSD (138 females) and 149 matched controls (131 females), we determined ACE by the Childhood Trauma Questionnaire (CTQ) and chronic stress by the Trier Inventory for Chronic Stress (TICS). Furthermore, the serum levels of leptin, FSH, LH, cortisol, DHEA-S, and IGF-1 have been assessed. RESULTS: There were significant differences in the levels of leptin, FSH, IGF-1, and cortisol between patients and controls, mainly driven by female participants. Levels of leptin were significantly correlated with BMI in patients, in controls, and in the female subgroup. This correlation was exaggerated in female patients when compared to female controls. Both CTQ and TICS predicted MSD directly and indirectly through the levels of leptin. CONCLUSION: There is evidence of a distinct neurohumoral profile in female patients with MSD when compared to matched healthy controls, similar to what has been demonstrated in other chronic pain states. The observed profile can be taken as possible evidence for a dysregulated response to chronic stress and metabolic balance as well as a state of hypocortisolism and HPA-axis dysfunction. ACE and chronic stress play a major role in the development of MSD and altered neurohumoral profile.

Quantitative Sensory Testing in Patients with Multisomatoform Disorder with Chronic Pain as the Leading Bodily Symptom-a Matched Case-Control Study.

OBJECTIVE: Chronic pain is a debilitating condition of multifactorial origin, often without physical findings to explain the presenting symptoms. Of the possible etiologies of persisting painful symptoms, somatoform disorders and functional somatic syndromes (FSS) are among the most challenging, with a prevalence of 8-20%. Many different somatoform disorders and FSS have overlapping symptoms, with pain being the most prevalent one. The concept of multisomatoform disorder (MSD) has been developed to acknowledge that fact. We hypothesized that the concept of MSD will be reflected in a distinct sensory profile of patients compared with healthy controls and possibly provide insight into the type and pathophysiology of the pain commonly experienced by patients. DESIGN: We performed comprehensive quantitative sensory testing (QST) in 151 patients and 149 matched controls. RESULTS: There were significant differences in the sensory profiles of patients compared with controls. Patients with MSD showed a combination of tactile and thermal hypesthesia combined with mechanical and cold hyperalgesia. This was true for measurements at test and control sites, with the exception of vibration detection threshold and mechanical pain threshold. Among the observed changes, a marked sensory loss of function, as evidenced by an increase in cold detection threshold, and a marked gain of function, as evidenced by a decrease of pressure pain threshold, were most notable. There was no evidence of concurrent medication influencing QST results. CONCLUSIONS: The observed somatosensory profile of patients with MSD resembles that of patients suffering from neuropathic pain with evidence of central sensitization.

Association of TNF-α polymorphism rs1800629 with multisomatoform disorder in a group of German patients and healthy controls: an explorative study.

INTRODUCTION: The etiology of multisomatoform disorder (MSD) is still largely unknown, but genetic factors seem to have an influence on pathogenesis. Pain is a major symptom of MSD and polymorphisms of different proinflammatory cytokines have been found associated with pain in former studies. Therefore, we presumed that cytokine polymorphisms could also be associated with MSD. PATIENTS AND METHODS: Groups of 148 MSD patients with pain as the leading clinical symptom and 149 age and gender matched healthy controls participated in this study. Nine cytokine polymorphisms were genotyped and statistically analyzed for associations with MSD. RESULTS: Allelic and genotypic associations were found for rs16944 (interleukin 1ß), rs1800629 (tumor necrosis factor) and rs909253 (lymphotoxin α). After correcting for multiple testing, the association of rs1800629 with MSD remained significant. The rare A-allele was correlated with MSD (p=0.007). DISCUSSION: Since the common G-allele of rs1800629 (TNFα) occurs much more often in the control group than in the MSD group it is assumed to be protective. Being carrier of the A-allele seems to be a risk factor for MSD.

Ca++/CaMKII switches nociceptor-sensitizing stimuli into desensitizing stimuli.

Many extracellular factors sensitize nociceptors. Often they act simultaneously and/or sequentially on nociceptive neurons. We investigated if stimulation of the protein kinase C epsilon (PKCε) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKCs is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKCε signaling pathway resulted in PKCε translocation. We identified a novel inhibitory cascade to branch off upstream of PKCε, but downstream of Epac via IP3-induced calcium release. This signaling branch actively inhibited subsequent translocation and even attenuated ongoing translocation. A second 'sensitizing' stimulus was rerouted from the sensitizing to the inhibitory branch of the signaling cascade. Central for the rerouting was cytoplasmic calcium increase and CaMKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a CaMKII-dependent manner. This mechanism was also observed by in vivo C-fiber electrophysiology corroborating the peripheral location of the switch. Thus, we conclude that the net effect of signaling in nociceptors is defined by the context of the individual cell's signaling history.

Interaction of the dopaminergic and serotonergic systems significantly influences the risk for multisomatoform disorder: a controlled pilot study.

The etiology of multisomatoform disorder (MSD) is largely unknown, but an influence of genetic factors is likely. Since pain is a major component of MSD and dopamine as well as serotonin are involved in pain pathways, genes of the dopaminergic and serotonergic system are promising candidate genes and we assumed that polymorphisms could be associated with MSD. One hundred forty-nine patients with MSD and 149 age- and gender-matched healthy controls participated in this study. DNA from all participants was genotyped for 22 single nucleotide polymorphisms (SNPs) within genes of the dopaminergic and serotonergic system by polymerase chain reaction, a restriction enzyme analysis, and pyrosequencing. The distribution of SNP alleles, genotypes, and haplotypes was compared between patients and controls. Neither an allelic nor a genotypic association was found for any individual SNP, but testing for a haplotypic association revealed that a haplotype of the serotonergic genes HT(1B) and HT(1D) indicated a lower risk. However, this statistically insignificant protective effect became highly significant on the background of two DAT1 haplotypes. Interestingly, if these two DAT1 haplotypes are analyzed without considering the serotonergic genes as confounders, they are significantly associated with an enhanced risk. Taking into account observations from recent publications, this apparent contradiction might be explained with the complex interaction of the dopaminergic and serotonergic systems. To conclude, our results reveal an involvement of polymorphisms in dopaminergic and serotonergic genes in the etiology of MSD in patients of German descent, but their exact role in MSD requires further investigation.

Cost of illness in rheumatoid arthritis in Germany in 1997-98 and 2002: cost drivers and cost savings.

OBJECTIVE: Comparison of overall RA-related costs and of relative contribution of single-cost domains before and after the introduction of TNF-blocking agents in Germany. METHODS: Two cohorts of RA outpatients (ACR '87 criteria) with long-standing disease are assessed in terms of disease-related costs and cost composition (n = 106 patients in 1997-98 and n = 180 patients in 2002 with similar patient characteristics). Full-cost analyses are performed including direct disease-related costs (medical and non-medical) and productivity costs as collected by patient questionnaires. Absolute costs (€/patient/year) are compared and the impact of single-cost domains on overall costing in RA is estimated (relative proportions of cost components within samples). RESULTS: Overall costs are comparable (1997-98: €4280; 2002: €3830; not significant). Differences can be observed in medication (1997-98: €550; 2002: €1580; P < 0.001) and hospitalization costs (1997-98: €1240; 2002: €500; P < 0.001). Productivity costs are significantly lower (€1480 vs €850; P < 0.05) in 2002. The impact of medication costs is outstanding in the 2002 sample (42 vs 12%), the proportion of hospitalization costs is substantially lower (29 vs 13%). Costs for DMARDs in 2002 are mostly driven by TNF blockers (37%). The number of DMARDs per patient is higher in 2002 as are costs for osteoporosis medication and gastroprotective treatment. CONCLUSION: Although overall costs before and after the introduction of TNF blockers are comparable, the decrease in hospitalization and productivity costs is promising in terms of future long-term cost savings. The development of these aspects and of the increasing medication costs will have to be evaluated with longer time frames.

Catechol-O-methyltransferase gene polymorphisms are not associated with multisomatoform disorder in a group of German multisomatoform disorder patients and healthy controls.

The etiology of multisomatoform disorder (MSD) is largely unknown, but genetic disposition may be one of several risk factors. As pain is a major component of MSD, and polymorphisms in the catechol-O-methyltransferase (COMT) gene are associated with COMT enzymatic activity and pain sensitivity, we assumed that COMT polymorphisms could be associated with MSD. One hundred and forty-nine patients with MSD and 149 age- and sex-matched healthy controls participated in this study. The inclusion criteria for MSD were in accordance with the structured clinical interview of the diagnostic and statistical manual of mental disorders IV. DNA from MSD patients and controls was genotyped for six single-nucleotide polymorphisms (SNPs) within the COMT locus by polymerase chain reaction and restriction enzyme analysis. The distribution of COMT SNP alleles, genotypes, and haplotypes was compared between patients and controls. None of the investigated SNPs, including the functionally relevant common SNP in codon 158 (Val158Met), showed a statistically significant allelic, genotypic, or haplotypic association with MSD. We conclude that COMT polymorphisms on their own do not seem to play a relevant role as major genetic risk factors for MSD.

First non-contingent respiratory biofeedback placebo versus contingent biofeedback in patients with chronic low back pain: a randomized, controlled, double-blind trial.

Previous studies reported that respiratory feedback (RFB) aids in alleviating chronic pain. However, to date, this adjunct treatment has not been rigorously tested against non-contingent (placebo) feedback. Forty-two patients with chronic low back pain were randomized to either RFB or non-contingent RFB. Both groups performed a daily 30-min home training for 15 consecutive days. A respiratory associated relaxation index (RI) was measured. Pain levels and a somatosensory profile were assessed before and after intervention. Additionally, pain levels were assessed 3 months after the end of intervention. Secondary outcome parameters included daily functioning, psychopathology, and suggestibility. T-tests showed higher and significant pain reductions for RFB, compared to non-contingent RFB. Between-group comparisons reached no significance. However, changes were more pronounced in the RFB condition, which was also true for the course of the RI and the psychopathological scores. This is the first study using a non-contingent respiratory placebo feedback in a randomized, controlled design. Within this design previous positive findings of symptom reductions in patients treated with RFB could partially replicated. Nonetheless, tendencies suggest that contingent feedback patients compared to placebo patients profit more from RFB in the long run regarding reduction of chronic pain and psychological distress.

Acupuncture induces a pro-inflammatory immune response intensified by a conditioning-expectation effect.

BACKGROUND: In a previous study it has been shown that acupuncture activates the respiratory burst (RB) of neutrophils as measured by the differences to baseline of the mean channel number of fluorescence intensity (mfi) in volunteers. Since this result could have been affected by a placebo effect, a study has been designed that controls for the different facets of placebo mechanisms such as expectancy, suggestibility, and conditioning. PARTICIPANTS AND METHODS: 60 healthy volunteers were randomized either to acupuncture of the acupoint Large Intestine 11 (LI 11) (groups 1 and 2) or relaxation (group 3) twice a week for 4 weeks. Only acupuncture group 1 and the relaxation group were provided with the additional suggestion that the treatment may strengthen the immune system. RESULTS: The repeated measurement analysis for differences of follow-ups to baseline showed significantly different treatment effects for neutrophils but not for monocytes (unprimed neutrophils: p = 0.004; neutrophils primed with TNF-alpha/FMLP or with FMLP only: p = 0.026 and p = 0.019, respectively) between groups. For both cell types post-hoc Dunnett's t-tests using the relaxation group as control showed significantly stronger treatment effects for acupuncture group 1. Combining all priming procedures, the average increase in mfi for both cell types was about 30% greater in acupuncture group 1 than in the relaxation group. Plasma concentrations of pro-inflammatory cytokines only increased significantly in the acupuncture groups. CONCLUSION: Repetitive acupuncture increases the cytotoxicity of leukocytes in healthy volunteers, which might be intensified by a conditioning-expectation effect.

The first scintigraphic detection of tumor necrosis factor-alpha in patients with complex regional pain syndrome type 1.

Tumor necrosis factor (TNF)-alpha has been identified as a pathogenic factor in many immunologically based diseases and complex regional pain syndrome (CRPS). In this case series, we used radiolabeled technetium anti-TNF-alpha antibody to scintigraphically image TNF-alpha in 3 patients with type 1 CRPS. The results show that TNF-alpha was localized only in affected hands of patients with early-stage CRPS. No uptake was seen in clinically unaffected hands and late-stage CRPS. Our findings support the growing evidence for neuroimmune disturbance in patients with CRPS and may have important further implications for specific anticytokine treatment in patients with CRPS.

Perceived pain and temporomandibular disorders in neuromuscular diseases.

Little is known about pain associated with temporomandibular disorders (TMD) in neuromuscular diseases. Inpatients (N = 134) with neuromuscular disorder diagnoses were given questionnaires to estimate pain localization and intensity. Research Diagnostic Criteria for Temporomandibular Disorders and the Temporomandibular Index (TMI) were utilized to assess TMD. Pain was reported by 116 patients (86%). Legs (52%) and arms (33%) were the most common locations for pain localization, but the highest Pearson correlations (TMI vs. perceived pain) appeared for pain located in the trunk and arms (0.861, P < 0.01). No correlation between TMI and diagnosis group existed except for "acquired myopathy" and "miscellaneous neuromuscular diseases." These results suggest that the degree of TMD does not correlate with pain according to disease, although common mechanisms might be responsible for pain development in specific body regions connected with TMD. Most important, higher levels of TMD are associated with higher levels of perceived pain.

Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis.

INTRODUCTION: We previously described the presence of nerve growth factor receptors in the inflamed synovial compartment. Here we investigated the presence of the corresponding nerve growth factors, with special focus on nerve growth factor (NGF). METHODS: mRNA expression levels of four ligands (NGF, brain derived growth factor (BDNF), neurotrophin (NT)-3, NT-4) and their four corresponding receptors (tyrosine kinase (trk) A, trkB, trkC, NGFRp75) were determined in the synovial fluid (SF) cells of 9 patients with rheumatoid arthritis (RA) and 16 with spondyloarthritis (SpA) and compared with 7 osteoarthritis (OA) patients. NGF was also determined in synovial tissue (ST) biopsies of 10 RA and 10 SpA patients. The production of NGF by monocytes and lymphocytes was assessed by flow cytometry of SF cells, synovial tissue derived fibroblast-like synoviocytes (FLS) were assessed by ELISA on culture supernatant. RESULTS: SF cell analysis revealed a clear BDNF and NGF mRNA expression, with significantly higher NGF expression in RA and SpA patients than in the OA group. NGF expression was higher in ST samples of RA as compared to SpA. Using intracellular FACS analysis, we could demonstrate the presence of the NGF protein in the two inflammatory arthritis groups on both CD3+ T lymphocytes and CD14+ cells, i.e. monocytes/macrophages, whereas cultured FLS did not produce NGF in vitro. CONCLUSIONS: Neurotrophins and especially NGF are expressed in the synovial fluid and tissue of patients with peripheral synovitis. The presence of neurotrophins as well as their receptors, in particular the NGF/trkA-p75 axis in peripheral synovitis warrants further functional investigation of their active involvement in chronic inflammatory arthritis.

Influence of the temporomandibular joint on range of motion of the hip joint in patients with complex regional pain syndrome.

OBJECTIVE: This study evaluated if patients with complex regional pain syndrome (CRPS) would have an increase in range of motion (ROM) after myofascial release and a similar ROM decrease after jaw clenching, whereas in healthy subjects these effects would be minimal or nonexistent. METHODS: Documentation of patients with CRPS (n = 20) was established using the research diagnostic criteria for CRPS, questionnaires, average pain intensity for the past 4 weeks, and the temporomandibular index (TMI). Healthy subjects (n = 20, controls) also underwent the same testing. Hip ROM (alpha angle) was measured at 3 time points as follows: baseline (t1), after myofascial release of the temporomandibular joint (t2), and after jaw clenching for 90 seconds (t3). Comparison of the CRPS and control groups was made using t tests. RESULTS: Mean TMI total score and mean pain reported for the last 4 weeks were significantly different between the 2 groups (P < .0005). Hip ROM at t1 was always slightly higher compared to t3, but t2 was always lower in value compared to t1 or t3 for both groups. The differences of all hip ROM values between the groups were significant (P < .0005). Moreover, the difference between t1 or t3 and t2 was significantly different within the CRPS group (t1 = 48.7 degrees ; t2 = 35.8 degrees ; P < .0005). CONCLUSIONS: The results suggest that temporomandibular joint dysfunction plays an important role in the restriction of hip motion experienced by patients with CRPS, which indicated a connectedness between these 2 regions of the body.

Does local immersion in thermo-neutral bath influence surface EMG measurements? Results of an experimental trial.

This study investigated the effect of water immersion on surface electromyography (EMG) signals recorded from the brachioradial muscle of 11 healthy subjects, both in a dry environment and a thermo-neutral forearm bath (36 degrees C). EMG measurements were registered in a sitting position, using waterproof electrodes under 3 conditions: relaxed muscle, maximum voluntary isometric contraction (MVC, 1s, grip test) and 70% of the MVC (5 s). In relaxed muscle, mean EMG values were significantly higher under immersion compared to the dry conditions (dry: 5.4+/-3.6 microV; water: 19.5+/-14.9 microV; p=0.014). In maximum voluntary isometric contraction, there was a significant difference, though not in the same direction (dry: 145.9+/-58.9 microV; water: 73.2+/-35.0 microV; p=0.003). Under 70% MVC, there was no difference between wet and dry conditions (dry: 102.4+/-75.0 microV; water: 100.4+/-65.3 microV; p=0.951). Results suggest that dry and underwater conditions influence EMG readings; however, the results are inconsistent. These findings indicate additional influences on resting muscle activity, as well as MVC. Further measurements with other muscle groups and different types of immersion are needed to clarify conflicting observations.

Sustained effects of comprehensive inpatient rehabilitative treatment and sleeping neck support in patients with chronic cervicobrachialgia: a prospective and randomized clinical trial.

The objective of this study was to investigate the long-term efficacy of inpatient rehabilitation using sleeping neck support in patients suffering from chronic cervicobrachialgia. A prospective, randomized clinical trial with a 12-month follow-up was done. A total of 149 patients suffering from chronic cervicobrachialgia received a 4-week inpatient rehabilitation programme. The patients were randomly divided into two groups. The patients in one group were given a special neck pillow to use during and after the rehabilitative treatment (n=76); the patients in the other group were not given the pillow (n=73). Two weeks before, during, and after (3, 6, 9, and 12 months) the 4-week treatment period, the patients completed a questionnaire dealing with the intensity of their cervicobrachial complaints (pain intensity, muscular tension, paraesthesia, and sleep disorders caused by pain or paraesthesia). During the inpatient treatment period, no significant differences were detected between the groups; however, 1-12 months after discharge, the group with sleeping neck support showed a significantly (P<0.05) smaller increase in the intensity of cervical spine pain. Sleep disturbances caused by pain were also reduced significantly (P<0.001 after 3 months, respectively, P<0.05 after 12 months). Inpatient rehabilitative treatment has sustained effects in patients suffering from chronic cervicobrachialgia, particularly when a sleeping neck support is added.