Hyaluronic Acid in Rheumatology.

Hyaluronic acid (HA), also known as hyaluronan, is an anionic glycosaminoglycan widely distributed throughout various tissues of the human body. It stands out from other glycosaminoglycans as it lacks sulfation and can attain considerable size: the average human synovial HA molecule weighs about 7 million Dalton (Da), equivalent to roughly 20,000 disaccharide monomers; although some sources report a lower range of 3-4 million Da. In recent years, HA has garnered significant attention in the field of rheumatology due to its involvement in joint lubrication, cartilage maintenance, and modulation of inflammatory and/or immune responses. This review aims to provide a comprehensive overview of HA's involvement in rheumatology, covering its physiology, pharmacology, therapeutic applications, and potential future directions for enhancing patient outcomes. Nevertheless, the use of HA therapy in rheumatology remains controversial with conflicting evidence regarding its efficacy and safety. In conclusion, HA represents a promising therapeutic option to improve joint function and alleviate inflammation and pain.

Do Chronic Pain Patients Wish Spiritual Aspects to Be Integrated in Their Medical Treatment? A Cross-Sectional Study of Multiple Facilities.

Background: Chronic pain is a complex, multidimensional experience. Spirituality is hypothesized to impact pain experience in various ways. Nevertheless, the role that spirituality plays in multimodal pain therapy remains controversial and, to date, quantitative data on whether and for which patients spiritual aspects should be considered in the treatment of chronic pain is lacking. The aim of this study was thus to investigate the proportion and characteristics of patients with chronic pain who wish spiritual aspects to be integrated in their treatment. Methods: Two hundred nine patients with chronic pain were recruited from five inpatient departments and outpatient clinics in the German-speaking part of Switzerland. Patients filled out validated questionnaires, such as the Hospital Anxiety and Depression Scale (HADS), the Resilience Scale (RS-11), the Spiritual and Religious Attitudes in Dealing with Illness (SpREUK), and the 12-item Spiritual Well-Being Scale (FACIT-Sp-12). Results: More than 60% (CI95%: 55.5-67.9%) of the patients wanted to address spiritual aspects in their treatment. These patients were significantly younger, had higher levels of education, and suffered from more frequent and more severe pain than patients who did not wish to address spiritual aspects. Furthermore, there were high correlations with existing spiritual resources and higher scores of spirituality. Conclusions: These results confirm that the majority of chronic pain patients wish spiritual aspects to be considered in their treatment. Additionally, the finding that these patients had more spiritual resources underlines the importance of integrating spiritual aspects in a resource-oriented, patient-centered care approach for this condition.

Including the Spiritual Dimension in Multimodal Pain Therapy. Development and Validation of the Spiritual Distress and Resources Questionnaire (SDRQ).

CONTEXT: Valid instruments for assessing spiritual resources and distress in pain therapy are scarce. The Spiritual Distress and Resources Questionnaire (SDRQ) was developed to fill this gap. GOALS: The objective of this study was to investigate the SDRQ's psychometric properties. METHODS: We presented the SDRQ to 219 patients with chronic pain conditions and examined its measurement properties, namely reliability and structural, convergent and discriminant validity. To investigate test-retest reliability, the SDRQ was presented a second time to a subsample of 58 randomly selected participants. RESULTS: Factor analysis required a grouping of the 22 SDRQ items into four subscales: spiritual distress, spiritual coping, immanence and transcendence, the latter two representing spiritual resources. Cronbach's alpha was high for spiritual distress (0.93), transcendence (0.85), and immanence (0.81) while it was somewhat lower but still satisfactory for spiritual coping (0.70). The construct validity of the SDRQ was shown by correlations with established measures in the field. Higher levels of spiritual distress were associated with signs of more severe illness, such as emotional distress and pain intensity. CONCLUSION: The results from this study suggest that the SDRQ is an easy-to-use, reliable and valid screening instrument for assessing spiritual distress, spiritual resources and spiritual coping in patients with chronic pain. The SDRQ has the potential to be used with patients suffering from other chronic diseases and to disseminate the palliative approach to pain treatment to other areas of medicine.

5'UTR polymorphism in the serotonergic receptor HTR3A gene is differently associated with striatal Dopamine D2/D3 receptor availability in the right putamen in Fibromyalgia patients and healthy controls-Preliminary evidence.

BACKGROUND: Extensive literature has investigated the role of serotonin (5-HT) in the control of the central dopamine (DA) systems, and their dysfunction in the pathological conditions. 5-HT stimulates the local DA release in striatal regions via activation of various receptors including serotonin receptor-3 (5-HT3). Several studies have related polymorphisms (SNPs) in the serotonin receptor-3 (HTR3) genes to be associated with the pain modulation and endogenous pain suppression. A few studies suggested a functional role of 5'UTR SNP in the serotonergic receptor HTR3A gene (rs1062613) in the development of the chronic pain and Fibromyalgia syndrome (FMS) in particular. Here, we investigated the effect of a 5'UTR SNP in the serotonergic receptor HTR3A gene (rs1062613) on striatal dopamine D2/D3 receptor (DRD2) availability and reward-associated DA release in response to unpredictable monetary rewards in 23 women with FMS and 17 age-matched healthy female controls. Furthermore, we aimed to examine if SNP rs1062613 is associated with thermal pain and pain tolerance thresholds. METHODS: We used PET and [11 C]raclopride to assess the DRD2 availability. In the same participants we used the [11 C]raclopride PET bolus-plus-infusion method to measure the [11 C]raclopride receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition. DRD2 availability and ΔBP were assessed in MRI-based striatal regions of interest. Thermal pain and pain tolerance thresholds were assessed outside the scanner. RESULTS: The frequency of SNP rs1062613 genotype differed significantly between groups, indicating that CC homozygotes were more frequent in FMS patients (82.6%) than in healthy controls (41.3%). Our results showed a significant main effect of SNP rs1062613 on [11 C]raclopride binding potential in the right caudate nucleus indicating a higher DRD2 receptor availability for CC-genotype of this SNP. Furthermore, we found a significant group × SNP interaction on [11 C]raclopride binding potential in the right putamen, indicating a higher DRD2 availability in T-carriers compared to CC genotype of SNP rs1062613 in FMS patients, whereas this effect was not present in healthy controls. However, we did not find an influence of SNP rs1062613 on reward-related DA release. In addition, there was no association between SNP rs1062613 and pain threshold or pain tolerance threshold in our data. CONCLUSION: These preliminary results indicate that SNP rs1062613 in the serotonergic receptor HTR3A gene possibly modulates the DRD2 receptor availability.

Pain-Associated Transcriptome Changes in Synovium of Knee Osteoarthritis Patients.

Joint pain causes significant morbidity in osteoarthritis (OA). The aetiology of joint pain in OA is not well understood. The synovial membrane as an innervated joint structure represents a potential source of peripheral pain in OA. Here we analyse, using a hypothesis-free next generation RNA sequencing, the differences in protein-coding and non-coding transcriptomes in knee synovial tissues from OA patients with high knee pain (n = 5) compared with OA patients with low knee pain (n = 5), as evaluated by visual analogue scale (VAS). We conduct Gene Ontology and pathway analyses on differentially expressed mRNA genes. We identify new protein-coding, long non-coding RNA and microRNA candidates that can be associated with OA joint pain. Top enriched genes in painful OA knees encode neuronal proteins that are known to promote neuronal survival under cellular stress or participate in calcium-dependent synaptic exocytosis and modulation of GABA(γ-aminobutyric acid)ergic activity. Our study uncovers transcriptome changes associated with pain in synovial microenvironment of OA knees. This sets a firm ground for future mechanistic studies and drug discovery to alleviate joint pain in OA.

Nondermatomal somatosensory deficits in chronic pain are associated with cerebral grey matter changes.

OBJECTIVES: Widespread sensory deficits occur in 20-40% of chronic pain patients on the side of pain, independent of pain aetiology, and are known as nondermatomal sensory deficits (NDSDs). NDSDs can occur in absence of central or peripheral nervous system lesions. We hypothesised that NDSDs were associated with cerebral grey matter changes in the sensory system and in pain processing regions, detectable with voxel-based morphometry. METHODS: Twenty-five patients with NDSDs, 23 patients without NDSDs ("pain-only"), and 29 healthy controls were studied with high resolution structural MRI of the brain. A comprehensive clinical and psychiatric evaluation based on Diagnostic and Statistical Manual was performed in all patients. RESULTS: Patients with NDSDs and "pain-only" did not differ concerning demographic data and psychiatric diagnoses, although anxiety scores (HADS-A) were higher in patients with NDSDs. In patients with NDSDs, grey matter increases were found in the right primary sensory cortex, thalamus, and bilaterally in lateral temporal regions and the hippocampus/fusiform gyrus. "Pain-only" patients showed a bilateral grey matter increase in the posterior insula and less pronounced changes in sensorimotor cortex. CONCLUSIONS: Dysfunctional sensory processing in patients with NDSDs is associated with complex changes in grey matter volume, involving the somatosensory system and temporal regions.

Bilateral Sensory Changes and High Burden of Disease in Patients With Chronic Pain and Unilateral Nondermatomal Somatosensory Deficits: A Quantitative Sensory Testing and Clinical Study.

OBJECTIVES: Widespread sensory deficits resembling hemihypoesthesia occur in 20% to 40% of chronic pain patients on the side of pain, independent of pain etiology, and have been termed nondermatomal sensory deficits (NDSDs). Sensory profiles have rarely been investigated in NDSDs. MATERIALS AND METHODS: Quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS) was performed in the face, hand, and foot of the painful body side and in contralateral regions in chronic pain patients. Twenty-five patients with NDSDs and 23 without NDSDs (termed the pain-only group) were included after exclusion of neuropathic pain. Comprehensive clinical and psychiatric evaluations were carried out. RESULTS: NDSD in chronic pain was associated with high burden of disease and more widespread pain. Only in the NDSD group were significantly higher thresholds for mechanical and painful stimuli found in at least 2 of 3 regions ipsilateral to pain. In addition, we found a bilateral loss of function for temperature and vibration detection, and a gain of function for pressure pain in certain regions in patients with NDSD. Sensory loss and gain of function for pressure pain correlated with pain intensity in several regions. DISCUSSION: This may indicate a distinct sensory profile in chronic non-neuropathic pain and NDSD, probably attributable to altered central pain processing and sensitization. The presence of NDSD in chronic non-neuropathic pain may be regarded as a marker for higher burden of pain disease.

[Drug treatment and interventional pain therapy in back pain patients]. / Medikamente und Infiltrationen bei Rückenschmerzen.

The treatment of chronic, non-malignant low-back pain is based on the patients' history and the clinical examination. It can be assumed that half of the cases present with a neuropathic pain component which needs to be treated with antidepressive and antiepileptic drugs instead of "pure" analgesics. Opioids should be considered with extreme caution because of their toxicity. Chronic non-malignant back pain is the prototype for interdisciplinary treatment approaches and multi-modal interdisciplinary settings, including pain programmes. However, a personalised strategy has to be preferred in most cases. A quick relief of pain is important in order to improve function as well as to re-integrate the patient into professional life. Spinal infiltrations can be of both diagnostic as well as therapeutic benefits. Their indication must be considered carefully, especially if the invasive diagnostic intervention has no therapeutic consequences. The interventional procedures should only be used as part of a multimodal approach in patients without any psychological problem. The sole use of interventions supports the purely somatic orientation of many patients and thus leads us in the wrong direction.

Pain and psychological health status in chronic pain patients with migration background--the Zurich study.

The objective of this paper is to investigate whether there were differences in pain and psychological health status in chronic pain patients with and without migration background before and after an 8-week interdisciplinary outpatient pain programme (IOPP). One hundred eighteen consecutively assessed patients were included. Pain and psychological health were recorded prior to and after the intervention, and at the 3-, 6- and 12-month follow-up. The migrant group experienced a statistically significant and clinically relevant higher amount of pain and worse psychological functioning than the non-migrant group at all time points. Statistically significant differences between the groups for the variables depression, anxiety, kinesiophobia and passive coping, in particular catastrophizing, were observed in the short and long term. The non-migrant group improved continuously on all outcome measurements at all time points. The results show differences in outcome for chronic pain patients with and without migration background. High pain intensity, high levels of depression, anxiety and catastrophizing at baseline appear to be major barriers for improvement in a sample of migrant patients when participating in an IOPP. Treatments may have to be tailored to the specific needs of this patient group to better address their poor psychological health status and to improve the course of the pain disorder.

ATP induced brain-derived neurotrophic factor expression and release from osteoarthritis synovial fibroblasts is mediated by purinergic receptor P2X4.

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.

Effect of an interdisciplinary outpatient pain management program (IOPP) for chronic pain patients with and without migration background: a prospective, observational clinical study.

OBJECTIVES: Short- and long-term effects of an interdisciplinary outpatient pain program (IOPP) in terms of quality of life, coping strategies, experiencing of pain and pain intensity as well as the influence of age, gender, or migration background. DESIGN: Single, prospective cohort with assessments at baseline, posttreatment, and at 3, 6, 12 months follow-up. PATIENTS: A total of 175 patients with chronic, nonmalignant pain syndromes (32.1% male and 67.9% female; age 43 ± 9.6 years). INTERVENTION: Multi-professional, biopsychosocial-oriented pain program for the duration of 8 weeks. OUTCOMES: Pain intensity, Pain Disability Index (German Version of Pain Disability Index, PDI-G), cognitive and behavioral coping strategies (Verarbeitung chronischer Schmerzen FESV), Marburger questionnaire about habitual subjective well-being, and processing of chronic pain (Veränderungsfragebogen des Erlebens und Verhaltens, VEV). The migration background was considered to determine whether this variable influences the clinical outcomes. RESULTS: All the mentioned variables except pain intensity improved significantly after the program (P < 0.05); whereas, after the 1-year follow-up, most of the parameters returned to the baseline values. Solely the subscale "pain-related psychological strain" remained significantly better compared with baseline (P < 0.05). The variable "migration background" influenced the outcomes PDI-G, habitual well-being, and FESV (P < 0.001; variance of 16.7% [95% confidence interval 7.8-25.5]). After 12 months, 49.4% showed an improvement with regard to the VEV outcome measurement, 22.6% showed no changes, and 28% showed worsening of the symptoms. Gender and age did not influence the results at 12 months (P = 0.408; P = 0.964). CONCLUSION: This study provides evidence for the short-term effect of the IOPP in chronic pain patients as well as the long-term effect for the variable "pain-related psychological strain".

Sleep quality, the neglected outcome variable in clinical studies focusing on locomotor system; a construct validation study.

BACKGROUND: In addition to general health and pain, sleep is highly relevant to judging the well-being of an individual. Of these three important outcome variables, however, sleep is neglected in most outcome studies.Sleep is a very important resource for recovery from daily stresses and strains, and any alteration of sleep will likely affect mental and physical health, especially during disease. Sleep assessment therefore should be standard in all population-based or clinical studies focusing on the locomotor system. Yet current sleep assessment tools are either too long or too specific for general use. METHODS: Based on a literature review and subsequent patient-based rating of items, an expert panel designed a four-item questionnaire about sleep. Construct validation of the questionnaire in a random sample of the German-speaking Swiss population was performed in 2003. Reliability, correlation, and tests for internal consistency and validity were analyzed. RESULTS: Overall, 16,634 (70%) out of 23,763 eligible individuals participated in the study. Test-retest reliability coefficients ranged from 0.72 to 0.87, and a Cronbach's alpha of 0.83 indicates good internal consistency. Results show a moderate to good correlation between sleep disturbances and health perception, and between sleep disturbances and overall pain. CONCLUSIONS: The Sleep Standard Evaluation Questionnaire (SEQ-Sleep) is a reliable and short tool with confirmed construct validity for sleep assessment in population-based observational studies. It is easy to administer and therefore suitable for postal surveys of the general population. Criterion validity remains to be determined.

Goal attainment scaling as a measure of treatment success after physiotherapy for chronic low back pain.

OBJECTIVES: In some chronic conditions, patient-specific tools with individualized items have proved to be more sensitive outcome instruments than fixed-item tools; their use has not yet been investigated in chronic low back pain (cLBP). METHODS: Eleven males and 21 females [mean age 44.0 (12.3) years] with cLBP, undergoing a spine-stabilization physiotherapy programme, completed the Roland Morris (RM) Disability Scale and a 0-10 pain scale pre- and post-therapy. Post-therapy, goal attainment scaling (GAS) scores were calculated regarding achievement of 2-6 priority GAS goals established pre-therapy; global outcome of therapy was assessed on a 5-point Likert scale. RESULTS: Approximately one-fifth of the individualized goals were not covered by items of the RM. Of the 121 individualized goals, 41 (34%) were achieved at the expected level, 42 (35%) were exceeded and 38 (31%) were not reached. GAS scores correlated with change scores for pain (r = 0.61, P < 0.0001) and RM (r = 0.49, P = 0.006). Sixty-five per cent of the patients had a successful outcome according to GAS (i.e. a score >or=50); 55%, according to global outcome (therapy helped/helped a lot); 39%, according to the RM score change (score decrease >or=30%); and 44%, according to the pain score change (score decrease >or=30%). CONCLUSIONS: GAS demonstrates the achievement of important goals undetected by fixed-item measures and is a valid and sensitive outcome measure for assessing the success of rehabilitation in patients with cLBP.

Ultrasound tissue Doppler imaging reveals no delay in abdominal muscle feed-forward activity during rapid arm movements in patients with chronic low back pain.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: Comparison of the timing of onset of lateral abdominal muscle activity during rapid arm movements in patients with nonspecific chronic low back pain (cLBP) and back-pain-free controls. SUMMARY OF BACKGROUND DATA: Rapid movements of the arm are normally associated with prior activation of trunk-stabilizing muscles in readiness for the impending postural perturbation. Using invasive intramuscular electromyography techniques, studies have shown that this feed-forward function is delayed in some patients with low back pain (LBP). Ultrasound tissue Doppler imaging (TDI) provides an ultrasound method for quantifying muscle activation in a noninvasive manner, allowing investigation of larger groups of patients and controls. METHODS: Ninety-six individuals participated (48 patients with cLBP and 48 matched LBP-free controls). During rapid shoulder flexion, abduction, and extension, surface electromyographic signals from the deltoid and motion-mode TDI images from the contralateral lateral abdominal muscles were recorded simultaneously. The onset of muscle activity was given by changes in the tissue velocity of the abdominal muscles, as measured with TDI. Pain and disability in the patients were assessed using standardized questionnaires. Data were analyzed using repeated measures analysis of variance. RESULTS: In both groups, feed-forward activity of the lateral abdominal muscles was recorded during arm movements in all directions. The main effect of "group membership" revealed no significant difference between the groups for the earliest onset of abdominal muscle activity (P = 0.398). However, a significant "group x body side" interaction (P = 0.015) was observed, and this was the result of earlier onsets in the cLBP group than controls for the abdominal muscles on the right (but not left) body side. No relationship was found between the time of onset of the earliest abdominal muscle activity and pain intensity, pain frequency, pain medication usage, or Roland Morris disability scores. CONCLUSION: Patients with cLBP did not show a delayed onset of feed-forward activation of the lateral abdominal muscles during rapid arm movements. Earlier activation was observed for one body side compared with the controls. However, the clinical relevance of this finding remains obscure, especially because there was no relationship between the onset of activation and any clinical parameters.