Masseter muscle pain and its relation to pain mediators in fibromyalgia and local myalgia

The aim of this investigation was to study chronic jaw muscle pain in fibromyalgia, local myalgia and healthy individuals in relation to the pain mediators PGE2, LTB4 and NPY and to study the effects of glucocorticoid administration and repetitive isometric contraction. A questionnaire showed presence of symptoms from the temporomandibular region in almost all fibromyalgia patients and the local pain was correlated to the general pain but on a lower level. The clinical part comprised patients with fibromyalgia and local myalgia in the orofacial region as well as healthy individuals. The subjects were examined for local spontaneous pain, palpatory tenderness, pressure pain threshold and tolerance levels of the superficial masseter muscle, bite force, intramuscular temperature and mobility of the mandible. Both patient groups showed low values of pain threshold as well as intramuscular temperature and maximum voluntary mouth opening compared to the healthy individuals. The number of tender mandibular muscles was higher than the pressure pain threshold lower in fibromyalgia than in local mylgia. This result and the high frequency of temporomandibular disorders in the fibromyalgia patients indicates that involvment of the temporomandibular system is common in fibromyalgia. Microdialysis was used to sample PGE2 and LTB4 from the superficial masseter muscle in patients with fibromyalgia and local myalgia as well as in healthy individuals and venous blood was collected for analysis of plasma levels of these substances. Intramuscular PGE2 and LTB4 were found in all groups. LTB4 levels increased upon the trauma created by microdialysis in patients with fibromyalgia and local myalgia, but not in the healthy individuals. PGE2 levels were related to muscular pain in the fibromyalgia patients and was negatively correlated to pressure pain threshold in the healthy individuals. Masseter muscle pain therefore seems to be partly of peripheral inflammatory origin. To evaluate the effects of glucocorticoid administration into the painful masseter muscle microdialysis and clinical examination was performed two weeks before and after its local administration in fibromyalgia and local myalgia. Both groups showed a similar response regarding clinical parameters but only the patients with local myalgia reported a positive subjective treatment result. In the patients with fibromyalgia a reduction of masseter muscle level of PGE2 was associated with a decrease of spontaneous pain, while the masseter muscle level of LTB4 increased in both patient groups after the intramuscular glucocorticoid administration. In an experimental microdialysis study the intramuscular levels of NPY and its relation to development of pain was determined during rest and during repetitive isometric contraction of the superficial masseter and trapezius muscles in healthy females. The NPY level in the masseter muscle at rest was higher than the corresponding levels of the trapezius muscle and plasma. In the trapezius muscle NPY increased during isometric contraction, while development of pain was associated with a high precontraction plasma level of NPY. High precontraction level of NPY in the masseter muscle was associated with development of pain after isometric contraction of this muscle

Salivary biomarkers in children with juvenile idiopathic arthritis and healthy age-matched controls : a prospective observational study.

Monitoring the immune system's regulation and signaling using saliva could be of interest for clinicians and researchers. Saliva, a biofluid with close exchange with serum, is influenced by circadian variance and oral factors such as masticatory function. This study investigated the detectability and concentration of cytokines and chemokines in saliva in children with juvenile idiopathic arthritis (JIA) as well as saliva flow and the influence of orofacial pain on saliva flow. Of the 60 participants (7-14 years old) enrolled, 30 had a diagnosis of JIA and active disease, and 30 were sex- and age-matched healthy controls. Demographic data and three validated questions regarding presence of orofacial pain and dysfunction were recorded. Stimulated whole saliva was collected and analyzed using a customized R&D bead-based immunoassay with 21 targeted biomarkers. Fourteen of these were detectable and showed similar levels in both children with JIA and controls: TNF-alpha, TNFRSF1B, MMP-2, MMP-3, IL-1alpha, IL-1beta, IL-6R alpha, IL-8, S100A8, CCL2, CCL3, IL-10, CCL11, and CXCL9. In addition, there was no difference in salivary flow rate between groups, but there was an association between orofacial pain and reduced saliva flow rate for both groups.Trial registration: ClinicalTrials.gov Protocol id: 2010/2089-31/2

Efficacy of botulinum toxin type A for treatment of persistent myofascial TMD pain : a randomized, controlled, double-blind multicenter study

Evidence of an effect by botulinum toxins is still lacking for most pain conditions. In the present randomized, placebo-controlled, crossover multicenter study, the efficacy of botulinum toxin type A (BTX-A) was investigated in patients with persistent myofascial temporomandibular disorders (TMD). Twenty-one patients with myofascial TMD without adequate pain relief after conventional treatment participated. A total of 50 U of BTX-A or isotonic saline (control) was randomly injected into 3 standardized sites of the painful masseter muscles. Follow-up was performed after 1 and 3 months, followed by a 1-month washout period, after which crossover occurred. Pain intensity at rest was the primary outcome measure, while physical and emotional function, global improvement, side effects, and clinical measures were additional outcome measures. There was no main difference between drugs (ANOVA; P=.163), but there was a significant time effect (P<.001), so BTX-A reduced mean (SD) percent change of pain intensity by 30 (33%) after 1 month and by 23 (30%) after 3 months compared to 11 (40%) and 4 (33%) for saline. The number of patients who received a 30% pain reduction was not significantly larger for BTX-A than after saline at any follow-up visit. The number needed to treat was 11 after 1 month and 7 after 3 months. There were no significant changes after treatment in any other outcome measures, with the exception of pain on palpation, which decreased 3 months after saline injection (P<.05). These results do not indicate a clinical relevant effect of BTX-A in patients with persistent myofascial TMD pain

The proteomic profile of whole and glandular saliva in healthy pain-free subjects

Determination of the variability in the salivary proteome is a prerequisite for the development of saliva as a diagnostic and prognostic tool in particular physiological states. In this context, it is important that technical variability induced by sample collection and processing is kept at minimum to be able to reproducibly assess variability in states of health and disease. In the current study, the proteome profile in unstimulated and stimulated whole, parotid and sublingual saliva was investigated using two-dimensional gel electrophoresis. Saliva samples were structurally collected from ten examined and characterized healthy individuals during the exactly same conditions. The results demonstrated that different collection methods provide clear differences in the snapshot of the salivary proteome and also in the relative amount of specific proteins. The variable nature of the salivary proteome suggests that different approaches may have to be adopted when studying its composition or its possible role as an indicator for particular physiological states. The results emphasize the importance of consistency when collecting saliva samples for proteomic analysis.Funding Agencies|Swedish Research Council; Stockholm County Council; Swedish Dental Society; Folktandvarden Stockholm AB</p

Daytime changes of salivary biomarkers involved in pain

The study aimed to investigate salivary levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), substance P (SP) and glutamate at five time points from morning to afternoon in a well-characterised healthy and pain-free individuals. Ten young adults were included. Unstimulated and stimulated whole saliva were collected from each participant repeatedly across the day. Blood samples were drawn in connection with the first and last saliva sample as reference standard. Levels of NGF and BDNF were determined using gel-free Western blot technology, glutamate levels were analysed using a colorimetric assay, and SP was determined using a commercially available ELISA. Salivary NGF and BDNF showed significant differences between the different collection times in both unstimulated (NGF; P = .006; BDNF; P = .026) and stimulated whole saliva (NGF; P = .006; BDNF; P = .019). The highest concentrations of the neuropeptides were expressed in the early morning, and they thereafter decreased across the day. In contrast, the expression of salivary glutamate and SP did not show any significant changes across the day. Plasma levels of NGF were higher in the evening sample (P = .028); otherwise, there were no significant differences for any of the other markers between morning and evening samples. NGF and BDNF in whole saliva showed a significant variation across the day. On the contrary, no variation in the levels of SP and glutamate was detected. These findings highlight the importance of consistency in the collection time and approach in biomarker studies using saliva.Funding Agencies|County Council of StockholmStockholm County Council; Karolinska InstitutetKarolinska Institutet; Reumatikerforbundet; Public Dental Health in Stockholm; Ake Wiberg Stiftelse; Lansstyrelsen Ostergotland; Sveriges Tandlakarforbund</p

Saliva as a medium to detect and measure biomarkers related to pain

Saliva is often neglected as a body fluid of diagnostic or prognostic value, even though generally well accepted by the patients. This is due to lack of a standardized collection procedure. The aim of this study was to identify the ideal saliva collection technique and develop new sensitive methods to detect and analyse markers related to pain in healthy pain-free subjects. Plasma and five different saliva collection approached was evaluated during strictly controlled conditions. Levels of nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and brain derived neurotropic factor (BDNF) were determined using novel western blotting based technology. Glutamate and substance P (SP) was determined using commercial available methods. Several new isoforms were found for NGF, CGRP and BDNF in saliva. The isoform pattern showed significant variation in both expression and chemiluminescence levels between different collection methods. New sensitive methods to study pain related markers in saliva were developed in this study. Furthermore, we are first to demonstrate a correlation between the Glutamate concentration in stimulated whole saliva and blood. However, the fundamental conclusion drawn is the importance of consistency in the collection method.Funding Agencies|Swedish Research Council [K2009-52P-20943-03-2]; Stockholm County Council (SOF project); Swedish Dental Society; Public Dental Health (Folktandvarden AB) in Stockholm</p

Altered levels of salivary and plasma pain related markers in temporomandibular disorders

Background Different pain syndromes may be characterized by different profiles of mediators reflecting pathophysiological differences, and these alterations may be measured in a simple saliva sample. The aims of the current study were to compare concentration of glutamate, serotonin (5-HT), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and substance P (SP) in saliva and plasma from a well-defined group of patients with chronic temporomandibular disorders myalgia (TMD-myalgia) with a group of pain-free controls, and further investigate the relationship between these markers and clinical characteristics. Methods Patients diagnosed according to the diagnostic criteria for TMD (n = 39), and matched healthy pain-free controls (n = 39) were included. Stimulated whole saliva and plasma samples were collected in the morning. Glutamate was analysed using a colorimetric assay, and 5-HT and SP were analysed by commercially available ELISA. Levels of NGF and BDNF were determined using multiplex electrochemiluminescence assay panel. Results Patients expressed higher salivary and plasma levels of glutamate (saliva: 40.22 +/- 13.23 mu mol/L; plasma: 30.31 +/- 18.73 mu mol/L) than controls (saliva: 33.24 +/- 11.27 mu mol/L; plasma: 20.41 +/- 15.96 mu mol/L) (p &amp;lt; 0.05). Salivary NGF (0.319 +/- 0.261 pg/ml) and BDNF (3.57 +/- 1.47 pg/ml) were lower in patients compared to controls (NGF: 0.528 +/- 0.477 pg/ml; BDNF 4.62 +/- 2.51 pg/ml)(ps &amp;lt; 0.05). Contrary, plasma BDNF, was higher in patients (263.33 +/- 245.13 pg/ml) than controls (151.81 +/- 125.90 pg/ml) (p &amp;lt; 0.05). 5-HT was undetectable in saliva. Neither plasma 5-HT, nor SP levels differed between groups. BDNF and NGF concentrations correlated to levels of psychological distress (p &amp;lt; 0.0005). Conclusion The higher levels of salivary and plasma glutamate in patients with TMD-myalgia compared to controls strengthens its importance in the pathophysiology of TMD-myalgia. However, the lack of correlation to pain levels question its role as a putative biomarker. Patients with TMD-myalgia further had lower levels of salivary NGF and BDNF, but higher plasma BDNF. These results and their correlations to psychological distress warrant further investigations.Funding Agencies|Swedish Research CouncilSwedish Research Council; Swedish Rheumatism Association; Stockholm County Council (SOF-project)Stockholm County Council; Swedish Dental Association; Karolinska InstitutetKarolinska Institutet; Karolinska InstituteKarolinska Institutet</p

Comorbid Conditions in Temporomandibular Disorders Myalgia and Myofascial Pain Compared to Fibromyalgia

The impact of comorbidities in fibromyalgia (FM) and temporomandibular disorders (TMD) have been well documented, but whether TMD sub-diagnoses myalgia (MYA) and myofascial pain with referral (MFP) differ regarding comorbidity is unclear. We aimed to elucidate this by studying the presence and associations of comorbidities in FM, MFP and MYA. An extended version of the Diagnostic Criteria for TMD axis II questionnaire was used to examine demographics, pain and comorbidities in 81 patients with FM, 80 with MYA, and 81 with MFP. Patients with MFP and FM reported a higher percentage of irritable bowel syndrome (IBS), depression, anxiety, somatic symptoms, perceived stress, and insomnia compared to MYA. Patients with FM had more IBS, depression, and somatic symptom disorder versus MFP. After adjusting for confounding variables, participants with anxiety, somatic symptoms disorder, pain catastrophizing, and perceived stress, as well as a greater number of comorbidities, were more likely to have MFP than MYA, whereas FM participants were more associated with IBS, somatic symptoms and insomnia compared to MFP. The number of comorbidities was significantly associated with widespread pain but not pain duration, body mass index or being on sick leave. In conclusion, patients with MFP were more similar to those with FM regarding comorbidity and should be differentiated from MYA in clinical settings and pain management

Temporomandibular condylar alterations in juvenile idiopathic arthritis most common in longitudinally severe disease despite medical treatment

Background: Juvenile idiopathic arthritis (JIA) is an autoimmune, heterogeneous disease and the temporomandibular joint (TMJ) can be affected, with consequences for mandibular growth and function. The aim of this study was to evaluate the importance of longitudinal medical treatment and the burden of disease activity on the development of temporomandibular condylar alterations as judged on panoramic radiographs. Methods: The study was a retrospective evaluation of dental and medical records in consecutive JIA patients referred to three specialist dental clinics in Sweden during an eight-year period. Data on the total pharmacological treatment and disease activity were evaluated longitudinally from disease onset to the time of the panoramic examination, during a median observation period of 2.5 years. The radiographs were analysed in terms of structural and shape alterations in the condyles and judged dichotomously. Results: Panoramic examinations were analysed in 158 patients from 266 referrals diagnosed with JIA. Condylar alterations (shape or structural) were seen in 68 patients (43%). Patients with condylar alterations were more extensively treated over time compared with those without condylar alterations. Powerful disease activity and/or potent medication at any time during the course of the disease implied an increased risk of alterations. Conclusions: Patients with JIA who require more intensive medication over time run the greatest risk of condylar alterations. As yet, current medical programmes have not been specified for the TMJ and more knowledge in this area is needed