Plasma Cytokine Levels in Fibromyalgia and Their Response to 15 Weeks of Progressive Resistance Exercise or Relaxation Therapy.

The aims of this study were to compare circulating cytokines between FM and healthy controls and to investigate the effect on cytokine levels by 15 weeks of progressive resistance exercise or relaxation therapy in FM. Baseline plasma cytokine levels and clinical data were analyzed in 125 women with FM and 130 age-matched healthy women. The FM women were then randomized to progressive resistance exercise (n = 49) or relaxation (n = 43). Baseline IL-2, IL-6, TNF-α, IP-10, and eotaxin were higher in FM than in healthy controls (P < 0.041), whereas IL-1ß was lower (P < 0.001). There were weak correlations between cytokine levels and clinical variables. After both interventions, IL-1ra had increased (P = 0.004), while IL-1ß had increased in the relaxation group (P = 0.002). Changes of IFN-γ, IL-2, IL-4, IL-6, IL-8, and IL-17A were weakly correlated with changes of PPT, but there were no significant correlations between changes of cytokine and changes in other clinical variables. The elevated plasma levels of several cytokines supports the hypothesis that chronic systemic inflammation may underlie the pathophysiology of FM even if the relation to clinical variables was weak. However, 15 weeks of resistance exercise, as performed in this study, did not show any anti-inflammatory effect on neither FM symptoms nor clinical and functional variables. This trial is registered with ClinicalTrials.gov NCT01226784, registered October 21, 2010. The first patient was recruited October 28, 2010.

Reduction in maximum pain after surgery in temporomandibular joint patients is associated with decreased beta-endorphin levels - a pilot study.

The mechanisms of relief from persistent pain after temporomandibular joint (TMJ) surgery are not well studied. It was hypothesized that if persistent pain is relieved by TMJ surgery, up-regulated parts of the central nervous system will be desensitized and the neuroendocrine opioid release will decrease back to normal levels. Eleven female patients with a mean age of 47.4±19.4 years and with TMJ pain due to chronic closed lock were examined before and 6-24 months after TMJ discectomy. The effects on plasma ß-endorphin levels, pain intensity, and pain thresholds were analyzed. Plasma ß-endorphin levels (P=0.032), pain at rest (P=0.003), and movement-evoked pain (P=0.008) were all significantly reduced at follow-up. The reduction in plasma ß-endorphin levels correlated with a reduction in maximum pain intensity (P=0.024) and with a longer time after surgery (P=0.041). Seven out of eight patients who reported a substantial reduction in maximum pain intensity presented a decrease in ß-endorphin levels in the plasma. In conclusion, this pilot study showed a significant reduction in plasma ß-endorphin levels and pain intensity at 6-24 months after TMJ surgery; plasma ß-endorphin levels were correlated with time after surgery. However, the results must be interpreted with caution since this was a single-centre observational study with a small sample size. If replicated in larger sample sets, the measurement of ß-endorphin levels may be of prognostic value for the treatment outcome.

Increased pain and muscle glutamate concentration after single ingestion of monosodium glutamate by myofascial temporomandibular disorders patients.

BACKGROUND: A randomized, double-blinded, placebo-controlled study was conducted to investigate if single monosodium glutamate (MSG) administration would elevate muscle/serum glutamate concentrations and affect muscle pain sensitivity in myofascial temporomandibular disorders (TMD) patients more than in healthy individuals. METHODS: Twelve myofascial TMD patients and 12 sex- and age-matched healthy controls participated in two sessions. Participants drank MSG (150 mg/kg) or NaCl (24 mg/kg; control) diluted in 400 mL of soda. The concentration of glutamate in the masseter muscle, blood plasma and saliva was determined before and after the ingestion of MSG or control. At baseline and every 15 min after the ingestion, pain intensity was scored on a 0-10 numeric rating scale. Pressure pain threshold, pressure pain tolerance (PPTol) and autonomic parameters were measured. All participants were asked to report adverse effects after the ingestion. RESULTS: In TMD, interstitial glutamate concentration was significantly greater after the MSG ingestion when compared with healthy controls. TMD reported a mean pain intensity of 2.8/10 at baseline, which significantly increased by 40% 30 min post MSG ingestion. At baseline, TMD showed lower PPTols in the masseter and trapezius, and higher diastolic blood pressure and heart rate than healthy controls. The MSG ingestion resulted in reports of headache by half of the TMD and healthy controls, respectively. CONCLUSION: These findings suggest that myofascial TMD patients may be particularly sensitive to the effects of ingested MSG. WHAT DOES THIS STUDY ADD?': Elevation of interstitial glutamate concentration in the masseter muscle caused by monosodium glutamate (MSG) ingestion was significantly greater in myofascial myofascial temporomandibular disorders (TMD) patients than healthy individuals. This elevation of interstitial glutamate concentration in the masseter muscle significantly increased the intensity of spontaneous pain in myofascial TMD patients.

Changes in jaw muscle EMG activity and pain after third molar surgery.

Limited jaw-opening capacity is frequently encountered following third molar surgery and may impair function. The aim of this study was to investigate the electromyographic (EMG) activity in jaw muscles after third molar surgery to obtain more insight into the mechanisms of restrictions in jaw opening. Twenty subjects were examined before, 24 h and 1 week after surgery. Ten healthy controls were subjected to the same examination at two different occasions for intersession variability. The EMG activity of the masseter and anterior digastricus muscles was recorded at different jaw positions and during maximum voluntary clenching. Pain intensity was assessed at rest and during movements. The EMG activity in the jaw muscles increased with opening level (P < 0.01), but did not change after surgery. In contrast, the EMG activity during clenching was decreased in all muscles after surgery (P < 0.05). The pain intensity after surgery increased with jaw opening level (P < 0.001), but was in general not correlated to EMG level. Pain intensity during clenching was increased after surgery (P < 0.001), but not correlated to EMG level. The EMG activity did not change between visits in the control group. In conclusion, the results indicate that third molar surgery does not influence the EMG activity in the masseter and anterior digastricus muscles during various levels of static jaw opening, but decreases the EMG activity during clenching. However, these changes are not influenced by pain intensity. The results have implications for the understanding of the phenomenon of trismus.

Pain mediation by prostaglandin E2 and leukotriene B4 in the human masseter muscle.

The pathophysiology behind chronic pain from masticatory muscles is unclear. Our hypothesis was that this pain is of inflammatory origin and associated with release of inflammatory mediators. The aim of this study was therefore to investigate the presence of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the masseter muscle and plasma and their relation to myalgia. Nineteen patients with fibromyalgia, 19 with local myalgia of the masseter muscle, and 11 healthy individuals were examined with regard to local muscular pain intensity at rest and pressure pain threshold. Inclusion criteria were masseter muscle pain for at least 3 months and masseter muscle tenderness on digital palpation. Samples were obtained from the masseter muscle by microdialysis, and the dialysates and venous blood samples were analyzed with regard to PGE2 and LTB4 concentration. Intramuscular levels were found in all groups, with significantly higher levels of LTB4 in the patients with fibromyalgia, in whom PGE2 was positively correlated to muscular pain. In the healthy individuals PGE2 was negatively correlated to pressure pain threshold. In both patient groups but not in the healthy individuals LTB4 increased during the consecutive samplings. PGE2 and LTB4 were detectable in the plasma of all groups. In conclusion, both PGE2 and LTB4 were found in the human masseter muscle. LTB4 levels are increased on needle trauma in patients with myalgia. PGE2 levels are related to muscular pain in patients with fibromyalgia. Masseter muscle pain therefore seems to be partly of peripheral inflammatory origin in fibromyalgia.

Effect of propranolol and granisetron on experimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonin into the human masseter muscle.

We have previously reported that intramuscular injection of serotonin (5-HT) into the masseter muscle elicits pain and allodynia/hyperalgesia in healthy subjects. The aim of this study was to investigate whether the 5-HT(3) receptor antagonist granisetron or 5-HT(1A) receptor antagonist propranolol can reduce 5-HT induced pain and allodynia/hyperalgesia in the masseter muscle. Twenty-four healthy individuals (12 males and 12 females) without pain from the masseter muscle region participated. They were examined clinically including tenderness to digital palpation (TDP) and pressure pain threshold (PPT) of the masseter muscle. 5-HT in combination with granisetron or propranolol was randomly injected on one side in a double-blind manner. 5-HT in combination with saline was used on the contralateral side. After the injections the pain intensity and PPT were recorded 10 times during 30min. After the last recording the TDP was assessed again. The injections were repeated with the other antagonist within 1 week. All three combinations of substances elicited pain after injection, which lasted for 5-8min. 5-HT induced significantly more pain than granisetron+5-HT and propranolol+5-HT. The TDP increased significantly after injection of all combinations of substances, but there was no significant difference between them. The PPT decreased significantly after injection of 5-HT and increased significantly after injection of granisetron+5-HT, while it did not change significantly after injection of propranolol+5-HT. The difference between 5-HT and granisetron+5-HT was significant. In conclusion, the results of this study indicate that injection of granisetron and propranolol into the human masseter muscle reduces pain induced by local administration of 5-HT, but that the effect of granisetron is stronger than that of propranolol. In addition, granisetron totally abolishes allodynia/hyperalgesia.

Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals.

The aim of this study was to investigate the effect of injection of serotonin (5-HT) into the masseter muscle on pain and allodynia/hyperalgesia. Twelve female patients with fibromyalgia (FM) and 12 age-matched female healthy individuals (HI) participated in the study. The current pain intensity (CPI) and the pressure pain threshold (PPT) of the superficial masseter muscles were assessed bilaterally. 5-HT in one of three randomized concentrations (10(-3), 10(-5), 10(-7) M) or isotonic saline was then injected into either of the two masseter muscles in a double-blind manner. After the injections the CPI and PPT were recorded ten times during 30 min. The injections were repeated twice with the other concentrations of 5-HT after 1 and 2 weeks, respectively. In the FM-group there was a non-significant increase of CPI after injection that lasted during the entire 30-min period irrespective of whether 5-HT or saline was injected. Neither did the PPT change significantly. In the HI-group pain developed significantly after injection irrespective of whether 5-HT or saline was injected, but significantly more so after 5-HT at 10(-3) M than saline injection. CPI decreased quickly and then remained on a very low level for most of the experiment. 5-HT at both 10(-5) M and 10(-3) M caused a significantly greater decrease of PPT than saline. In conclusion, our results show that 5-HT injected into the masseter muscle of healthy female subjects elicits pain and allodynia/hyperalgesia, while no such responses occur in patients with fibromyalgia.

Plasma and serum serotonin levels and their relationship to orofacial pain and anxiety in fibromyalgia.

AIMS: Serum serotonin levels (S-5-HT) have been reported to be reduced in patients with fibromyalgia and to show a negative correlation with pain. We hypothesized that one mechanism behind this could be that platelets are activated to release 5-HT into the plasma compartment (P-5-HT), which then binds to nociceptors. The aims of this study were therefore to investigate the relation between P-5-HT and S-5-HT and their relationship versus orofacial pain and anxiety in fibromyalgia. METHODS: Twelve patients with fibromyalgia, 12 patients with rheumatoid arthritis, and 12 healthy individuals participated in the study. Pain measures used were pain intensity assessed with a visual analog scale, pain drawings, and influence of pain on daily living activities (ADL). The Spielberger State and Trait Anxiety Inventory (STAI) scale was used for self-rating of anxiety levels. The participants were examined clinically, and the pressure pain threshold (PPT) over the masseter muscle was assessed. Finally, venous blood was collected for analysis of P-5-HT and S-5-HT. RESULTS: The ratio between P-5-HT and S-5-HT was calculated to determine the relative plasma fraction of serotonin (RPS). Patients with fibromyalgia showed significantly lower S-5-HT than did patients with rheumatoid arthritis. They also showed significantly higher STAI scores and tender point index of orofacial muscles and significantly lower PPT than the healthy individuals. High RPS was associated with high ADL and STAI scores. CONCLUSION: This study indicates that a high level of plasma serotonin in relation to serum level is associated with pain discomfort and increased anxiety in fibromyalgia.

The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia.

The aim of this study was to investigate if serotonin is present in the human masseter muscle and if so, whether it is involved in the modulation of local muscle pain or allodynia. Thirty-five patients with pain and tenderness of the masseter muscle as well as ten healthy individuals were included in the study. Of the patients, 18 suffered from fibromyalgia and 17 had localized myalgia, e.g. myofascial pain in the temporomandibular system. The participants were examined clinically with special consideration to the masseter muscle and the pressure pain threshold as well as tolerance levels of this muscle were assessed. Intramuscular microdialysis was performed in order to sample serotonin and a venous blood sample was collected for analysis of the serum level of serotonin. Serotonin was present in the masseter muscle and the level was significantly higher in the initial sample than in the sample collected during steady state. The level of serotonin in the masseter muscle in relation to the level of serotonin in the blood serum was calculated. This fraction of serotonin was higher in the patients with fibromyalgia than in healthy individuals and high level of serotonin was associated with pain as well as allodynia of the masseter muscle. In conclusion, the results of this study show that serotonin is present in the human masseter muscle both immediately following puncture and in a subsequent steady state and that it is associated with pain and allodynia. The origin of the serotonin seems partly to be the blood, but our results indicate that peripheral release also occurs.

Pain, allodynia, and serum serotonin level in orofacial pain of muscular origin.

AIMS: This study was conducted to investigate the serum level of serotonin (S-5-HT) in patients with temporomandibular disorders (TMD) of muscular origin, i.e., localized myalgia, and to compare it to that found in healthy individuals and patients with fibromyalgia. A second aim was to investigate the association between S-5-HT and pain parameters. METHODS: Twenty patients with localized myalgia participated in the study. Twenty age- and gender-matched healthy individuals and twenty patients with fibromyalgia served as controls. The participants were examined clinically as to the condition of the temporomandibular region and S-5-HT. RESULTS: The levels of S-5-HT did not differ significantly between the groups. However, in patients with localized myalgia there was a negative correlation between S-5-HT and tenderness of the temporomandibular muscles. CONCLUSION: The results of this study indicate that allodynia of orofacial muscles in patients with TMD is significantly related to S-5-HT concentration.

Presence of orofacial pain and temporomandibular disorder in fibromyalgia. A study by questionnaire.

The objective of this study was to evaluate subjective symptoms from the temporomandibular system in patients with fibromyalgia. Two hundred and thirty-seven individuals with fibromyalgia affiliated to the Stockholm Rheumatologic Association were included in the study. A questionnaire about symptoms of temporomandibular disorders (TMD) was mailed and returned by 191 (81%). The participants reported frequent and severe symptoms of TMD, 94% reported local pain from the temporomandibular system with a mean duration of 12 years. The most frequent sites were the temple, temporomandibular joint and neck regions. General body pain had a significantly longer duration than TMD, which indicates that fibromyalgia starts in other parts of the body and later extends to the temporomandibular region. The severity of general pain scored significantly higher than local pain, but there was a significant positive correlation between the two conditions. High frequency, 73-78 %, of headache, facial pain and tiredness of the jaws was found and about fifty percent of the patients also complained about difficulties to open the mouth and to chew. Fibromyalgia is thus a probable cause of TMD. In conclusion this study shows that patients with fibromyalgia often suffer from symptoms of TMD, and that the intensity of the pain is correlated to general body pain. These findings indicate that fibromyalgia is one of the causes of TMD.

Interleukin-1beta in synovial fluid from the arthritic temporomandibular joint and its relation to pain, mobility, and anterior open bite.

PURPOSE: The purpose of this study was to investigate whether interleukin-1beta in synovial fluid or blood plasma is involved in the development of pain or hyperalgesia of the temporomandibular joint (TMJ), as well as reduced mandibular mobility and anterior open bite. PATIENTS AND METHODS: Twenty-nine patients with TMJ arthritis and seven healthy subjects were studied. VAS measurement of TMJ tenderness on palpation of the TMJ (TDP), TMJ pressure pain threshold and tolerance level (PPTL), mandibular mobility, pain during joint movements, and degree of anterior open bite (AOB) were assessed. IL-1beta levels were analyzed in TMJ synovial fluid (SF-IL-1beta) and blood samples and correlated with the preceding factors. RESULTS: SF-IL-1beta showed significant positive correlations with VAS measurement of pain, TDP, and AOB and a negative correlation with PPTL. CONCLUSIONS: This study indicates that IL-1beta in the synovial fluid is associated with pain and hyperalgesia in the TMJ region as well as an anterior open bite. Concerning the latter condition, IL-1beta seems to be a warning signal of tissue destruction.

Effect of local glucocorticoid injection on masseter muscle level of serotonin in patients with chronic myalgia.

The aim of this study was to compare the effects on the level of serotonin (5-HT) in the masseter muscle by intramuscular glucocorticoid (GC) administration in patients with fibromyalgia (FM) and localized myalgia (LM), as well as to determine associated changes in pain, tenderness, and microcirculation. The study comprised 22 patients with pain and tenderness in the masseter muscle region. Ten patients (all women) had FNI, and 12 (1 man and 11 women) had LM involving the temporomandibular system. The patients were examined clinically and by microdialysis at 2 visits 2-3 weeks apart and received local glucocorticoid treatment at the first visit. The ratio (S1/S2) between the initial level of 5-HT (S1) and steady state level (S2) was used as a relative measure of the intramuscular release of 5-HT. This ratio decreased significantly after treatment in the FM group. In the FM group there was also a negative correlation regarding changes between visits of 5-HT and changes of intramuscular temperature. In the LM group there was a negative correlation regarding changes between visits of 5-HT and changes of pressure pain threshold and pressure pain tolerance level. This study indicates that there is a reduction of the ratio between initial 5-HT and steady state level in the painful masseter muscle after intramuscular GC administration to FM patients, a reduction not present in the LM patients. In addition, 5-HT seems to be involved in the modulation of local muscle microcirculation in FM patients and in hyperalgesia in LM patients.

Short-term effect of glucocorticoid injection into the superficial masseter muscle of patients with chronic myalgia: a comparison between fibromyalgia and localized myalgia.

The aim of this study was to investigate whether the treatment effect of intramuscular glucocorticoid injection differs between patients with fibromyalgia and those with localized myalgia of the masseter muscle concerning pain, tenderness to digital palpation, pressure pain threshold, pressure pain tolerance level, maximum voluntary occlusal force, or intramuscular temperature. Twenty-five patients with fibromyalgia and 25 patients with localized myalgia of the masseter muscle were first asked to assess their pain on a visual analogue scale; afterward, a routine clinical examination, including tenderness to digital palpation, was performed. For each patient, the pressure pain threshold, pressure pain tolerance level, and maximum voluntary occlusal force, as well as the intramuscular temperature, were recorded. Finally each patient received an injection of glucocorticoid. The examination and glucocorticoid treatment were repeated after approximately 2 weeks, and a follow-up was performed after another 5 weeks. In the fibromyalgia group, there was a reduced tenderness to digital palpation in response to the treatment. The localized myalgia group responded with a general improvement of symptoms as well as a significant reduction of pain intensity and tenderness to digital palpation. The results of this study indicate that patients with fibromyalgia and localized myalgia in many respects show a similar response to local glucocorticoid treatment.

Symptoms and signs of temporomandibular disorders in patients with fibromyalgia and local myalgia of the temporomandibular system. A comparative study.

Symptoms and signs of temporomandibular disorders (TMD) in 46 patients were investigated and compared with those in 20 healthy individuals. Twenty-three patients had fibromyalgia (FM) and 23 had local myalgia (LM). Facial pain was assessed with a visual analogue scale, and a clinical examination was performed, including maximum voluntary mouth opening, temporomandibular joint sounds, tenderness to digital palpation in the masticatory muscles, pressure pain threshold and tolerance level of the superficial masseter muscle, intramuscular temperature, and maximum voluntary bite force. There was a difference in the number of tender muscles between the groups. Pressure pain threshold and tolerance levels were lower in the FM than in the LM group, whereas both showed lower values than a control group (C). The intramuscular temperature and maximum voluntary mouth opening were lower in the patient groups than in the C group. TMJ sounds showed a difference between all three groups. In conclusion, this study shows that FM patients frequently have TMD and indicates several differences between patients with FM and LM with regard to clinical variables.