Understanding and restoring dopaminergic function in fibromyalgia patients using a mindfulness-based psychological intervention: a [18F]-DOPA PET study. Study protocol for the FIBRODOPA study-a randomized controlled trial.

BACKGROUND: Fibromyalgia (FM) is a very prevalent and debilitating chronic pain disorder that is difficult to treat. Mindfulness-based techniques are regarded as a very promising approach for the treatment of chronic pain and in particular FM. The Mindfulness-Oriented Recovery Enhancement (MORE) intervention, a mindfulness-based group intervention, has shown beneficial effects in opioid-treated chronic pain patients, including reduced pain severity, functional interference, and opioid dosing, by restoring neurophysiological and behavioral responses to reward. The first evidence for a hypodopaminergic state and impaired reward processing in FM has been reported. However, little is known about its impact on dopamine (DA) function and in particular with regard to DA responses to monetary reward in FM. The aim of the present study protocol is to evaluate if MORE is able to restore the DA function in FM patients, in particular with regard to the DA responses to reward, and to reduce pain and mood complaints in FM. METHODS: The present study is a multi-center interventional RCT with 3 time points: before the intervention, after completion of the intervention, and 3 months after completion of the intervention. Sixty-four FM patients will be randomly assigned to either the MORE intervention (N = 32) or a non-intervention control group (N = 32). Additionally, a comparison group of healthy women (N = 20) for PET measures will be enrolled and another group of healthy women (N = 15) will do the ambulatory assessments only. The MORE intervention consists of eight 2-h-long group sessions administered weekly over a period of 8 weeks. Before and after the intervention, FM participants will undergo [18F] DOPA positron emission tomography (PET) and functional MR imaging while performing a reward task. The primary outcome will be endogeneous DA changes measured with [18F] DOPA PET at baseline, after the intervention (after 8 weeks for the non-intervention control group), and at 3 months' follow-up. Secondary outcomes will be (1) clinical pain measures and FM symptoms using standardized clinical scales; (2) functional brain changes; (3) measures of negative and positive affect, stress, and reward experience in daily life using the ambulatory assessment method (AA); and (4) biological measures of stress including cortisol and alpha-amylase. DISCUSSION: If the findings of this study confirm the effectiveness of MORE in restoring DA function, reducing pain, and improving mood symptoms, MORE can be judged to be a promising means to improve the quality of life in FM patients. The findings of this trial may inform health care providers about the potential use of the MORE intervention as a possible non-pharmacological intervention for FM. TRIAL REGISTRATION: ClinicalTrials.gov NCT04451564 . Registered on 3 July 2020. The trial was prospectively registered.

Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression--A [¹¹C] raclopride PET-study.

Dopamine D2/D3 receptor availability at rest and its association with individual pain perception was investigated using the [(11)C] raclopride PET-method in 24 female Fibromyalgia (FMS) participants with (FMS+, N=11) and without (FMS-, N=13) comorbid depression and in 17 healthy women. Thermal pain thresholds (TPT) and pain responses were assessed outside the scanner. We compared the discriminative capacity, i.e. the individual׳s capacity to discriminate between lower and higher pain intensities and the response criterion, i.e. the subject׳s tendency to report pain during noxious stimulation due to psychological factors. [(11)C] raclopride binding potential (BP), defined as the ratio of specifically bound non-displaceable radioligand at equilibrium (BP(ND)) was used as measure of D2/D3 receptor availability. We found significant group effects of BP(ND) in striatal regions (left ventral striatum, left caudate nucleus and left nucleus accumbens) between FMS+ and FMS- compared to healthy subjects. Correlational analysis showed negative associations between TPT and D2/D3 receptor availability in the left caudate nucleus in FMS-, between TPT and D2/D3 receptor availability in the right caudate nucleus in FMS + and positive associations between TPT and D2/D3 receptor availability in the left putamen and right caudate nucleus in healthy controls. The response criterion was positively associated with D2/D3 receptor availability in the right nucleus accumbens in FMS - and negatively with D2/D3 receptor availability in the left caudate nucleus in healthy controls. Finally, no significant associations between D2/D3 receptor availability and discriminative capacity in any of the groups or regions were determined. These findings provide further support for a disruption of dopaminergic neurotransmission in FMS and implicate DA as important neurochemical moderator of differences in pain perception in FMS patients with and without co-morbid depression.

Fear-learning deficits in subjects with fibromyalgia syndrome?

BACKGROUND: Fibromyalgia syndrome (FMS) is frequently associated with psychiatric conditions, particularly anxiety. Deficits in contingency learning during fear conditioning have been hypothesized to increase anxiety and, consequently, pain sensation in susceptible individuals. The goal of this study was to examine the relationship between contingency learning and pain experience in subjects with FMS and rheumatoid arthritis (RA). METHODS: Fourteen female FMS subjects, 14 age-matched female RA subjects and 14 age-matched female healthy controls (HCs) were included in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs, the unconditioned stimulus (US) of thermal stimuli. CS- predicted low-temperature exposure (US), while CS+ was followed by low or high temperature. RESULTS: In the FMS group, only 50% of the subjects were aware of the US-CS contingency, whereas 86% of the RA subjects and all of the HCs were aware of the contingency. CS+ induced more anxiety than CS- in RA subjects and HCs. As expected, low-temperature exposure was experienced as less painful after CS- than after CS+ in these subjects. FMS subjects did not show such adaptive conditioning. The effects of the type of CS on heart rate changes were significant in the HCs and the aware FMS subjects, but not in the unaware FMS subjects. CONCLUSIONS: Contingency learning deficits represent a potentially promising and specific, but largely unstudied, psychopathological factor in FMS. Deficits in contingency learning may increase anxiety and, consequently, pain sensation. These findings have the potential to contribute to the development of novel therapeutic approaches for FMS.

How well do observed functional limitations explain the variance in Roland Morris scores in patients with chronic non-specific low back pain undergoing physiotherapy?

PURPOSE: Self-rated activity limitations in patients with non-specific chronic low back pain (cLBP) do not correlate well with performance in traditional tests of impairment (e.g. back strength, ROM, etc.). Tests using more "functional activities" have therefore been recommended as alternative "objective" outcome measures. We examined the relationship between a battery of such tests and self-reported activity limitations, before and in response to physiotherapy, and the influence of psychological factors on the relationship. METHODS: 37 patients with cLBP took part (45 ± 12 years; 23 female, 14 male); 32 completed 9 weeks' physiotherapy. Before and after therapy, the patients completed the Roland Morris (RM) disability questionnaire and questionnaires to assess fear avoidance beliefs, catastrophising and psychological disturbance. They also performed eight simple functional tests (stair climb, prolonged flexion, stand to floor, lift test, sock test, roll-up test, pick-up test, fingertip-to-floor test). RESULTS: Baseline RM scores were significantly (p < 0.05) correlated with all but one of the functional test scores (ranging from r = -0.34 (half-flexion) to 0.56 (pick-up test), and with a functional test index score for all tests together (r = 0.60, p < 0.0001). The correlation between the change-scores (after treatment) for RM and for the functional test index was 0.55 (p = 0.001). Psychological factors explained 7-23 % variance in RM scores (baseline, post-therapy, and change scores), beyond that which was explained by the functional tests. Effect sizes for patients with a self-rated "good global outcome" were 1.23 for RM and 0.75 for the functional test index; for those with a "poor outcome", they were -0.08 and 0.23, respectively. CONCLUSION: Moderately high correlations (for both absolute and change scores) were observed between the subjective and observed measures of activity limitation. This indicates that to some extent they are assessing the same underlying construct, but it also suggests that each is delivering a certain amount of unique information. Psychological factors explained some of the discrepancy between the two types of measure. Both were responsive to therapy, and their change scores reflected well the patients' global outcome ratings. The two methods of assessing activity limitations should serve to complement one another in the assessment of treatment outcome.

Spine stabilisation exercises in the treatment of chronic low back pain: a good clinical outcome is not associated with improved abdominal muscle function.

INTRODUCTION: Various studies have shown that spine stabilisation exercise therapy elicits improvements in symptoms/disability in patients with chronic non-specific low back pain (cLBP). However, few have corroborated the intended mechanism of action by examining whether clinical improvements (1) are greater in patients with functional deficits of the targeted muscles and (2) correlate with post-treatment improvements in abdominal muscle function. METHODS: Pre and directly after 9 weeks' therapy, 32 cLBP patients (44.0 ± 12.3 years) rated their LBP intensity (0-10) and disability (0-24, Roland-Morris; RM) and completed psychological questionnaires. At the same timepoints, the voluntary activation of transversus abdominis (TrA), obliquus internus and obliquus externus during "abdominal-hollowing" and the anticipatory ("feedforward") activation of these muscles during rapid arm movements were measured using M-mode ultrasound with tissue Doppler imaging. RESULTS: Pre-therapy to post-therapy, RM decreased from 8.9 ± 4.7 to 6.7 ± 4.3, and average pain, from 4.7 ± 1.7 to 3.5 ± 2.3 (each P < 0.01). The ability to voluntarily activate TrA increased by 4.5% (P = 0.045) whilst the anticipatory activation of the lateral abdominal muscles showed no significant change (P > 0.05). There was no significant correlation between the change in RM scores after therapy and either baseline values for voluntary (r = 0.24, P = 0.20) or anticipatory activation (r = 0.04, P = 0.84), or their changes after therapy (voluntary, r = 0.08, P = 0.66; anticipatory, r = 0.16, P = 0.40). In multiple regression, only a reduction in catastrophising (P = 0.0003) and in fingertip-floor distance (P = 0.0006) made unique contributions to explaining the variance in the reduction in RM scores. CONCLUSION: Neither baseline lateral abdominal muscle function nor its improvement after a programme of stabilisation exercises was a statistical predictor of a good clinical outcome. It is hence difficult to attribute the therapeutic result to any specific effects of the exercises on these trunk muscles. The association between changes in catastrophising and outcome serves to encourage further investigation on larger groups of patients to clarify whether stabilisation exercises have some sort of "central" effect, unrelated to abdominal muscle function per se.

[Quality control of the rheumatological interdisciplinary pain-consultation]. / Qualitätskontrolle der Rheumatologischen Interdisziplinären Schmerz-Sprechstunde.

The Rheumatologic Interdisciplinary pain assessment (RIPA) was evaluated for the time period between February 2002 and December 2005 by Scascighini and Sprott in 2007. The objective behind this quality control (performed for the time period from January 2006 through June 2010) was to analyse differences between employed and unemployed patients. Patients were interviewed in a longitudinal profile with a follow-up of three months after the interdisciplinarian evaluation (including medical, physio/occupational therapy as well as psychological evaluations). Client management for the group of currently unemployed persons was simplified for 63.8% of referring doctors following these consultations hours. With the group of currently employed persons it even facilitated client management for 79.2% of referring doctors, subsequent to consultation hours. 92.5% of these referring doctors would recommend the RIPA to colleagues and interested parties.

Ultrasound assessment of transversus abdominis muscle contraction ratio during abdominal hollowing: a useful tool to distinguish between patients with chronic low back pain and healthy controls?

Spine stabilisation exercises, in which patients are taught to preferentially activate the transversus abdominus (TrA) during "abdominal hollowing" (AH), are a popular treatment for chronic low back pain (cLBP). The present study investigated whether performance during AH differed between cLBP patients and controls to an extent that would render it useful diagnostic tool. 50 patients with cLBP (46.3 ± 12.5 years) and 50 healthy controls (43.6 ± 12.7 years) participated in this case-control study. They performed AH in hook-lying. Using M-mode ultrasound, thicknesses of TrA, and obliquus internus and externus were determined at rest and during 5 s AH (5 measures each body side). The TrA contraction-ratio (TrA-CR) (TrA contracted/rest) and the ability to sustain the contraction [standard deviation (SD) of TrA thickness during the stable phase of the hold] were investigated. There were no significant group differences for the absolute muscle thicknesses at rest or during AH, or for the SD of TrA thickness. There was a small but significant difference between the groups for TrA-CR: cLBP 1.35 ± 0.14, controls 1.44 ± 0.24 (p < 0.05). However, Receiver Operator Characteristics (ROC) analysis revealed a poor and non-significant ability of TrA-CR to discriminate between cLBP patients and controls on an individual basis (ROC area under the curve, 0.60 [95% CI 0.495; 0.695], p = 0.08). In the patient group, TrA-CR showed a low but significant correlation with Roland Morris score (Spearman Rho = 0.328; p = 0.02). In conclusion, the difference in group mean values for TrA-CR was small and of uncertain clinical relevance. Moreover, TrA-CR showed a poor ability to discriminate between control and cLBP subjects on an individual basis. We conclude that the TrA-CR during abdominal hollowing does not distinguish well between patients with chronic low back pain and healthy controls.

[Is fibromyalgia a viral disease?]. / Ist die Fibromyalgie eine Viruserkrankung?

Are viruses responsible for the pain in patients with fibromyalgia? Are viruses the trigger for rheumatoid arthritis? Is chronic fatigue syndrome a viral disease? There are many open questions with few or controversial answers. According to the current state of knowledge on the origin of the pain in fibromyalgia the varied symptomatic of fibromyalgia is triggered by peripheral as well as central mechanisms. Despite the broad spectrum of symptoms the disease is a specific entity which is mainly treated with dual reuptake inhibitors, anticonvulsives, tramadol, selective serotonin reuptake inhibitors, gamma-hydroxybutyrate and dopamine agonists in individually selected combinations.

Age- and gender-specific normative data of grip and pinch strength in a healthy adult Swiss population.

Assessment of hand strength is used in a wide range of clinical settings especially during treatment of diseases affecting the function of the hand. This investigation aimed to determine age- and gender-specific reference values for grip and pinch strength in a normal Swiss population with special regard to old and very old subjects as well as to different levels of occupational demand. Hand strength data were collected using a Jamar dynamometer and a pinch gauge with standard testing position, protocol and instructions. Analysis of the data from 1023 tested subjects between 18 and 96 years revealed a curvilinear relationship of grip and pinch strength to age, a correlation to height, weight and significant differences between occupational groups. Hand strength values differed significantly from those of other populations, confirming the thesis that applying normative data internationally is questionable. Age- and gender-specific reference values for grip and pinch strength are presented.

[Peripheral mechanisms of joint pain with special focus on the synovial fibroblast]. / Periphere Mechanismen von Gelenkschmerzen mit speziellem Fokus auf den synovialen Fibroblasten.

Joint pain is one of the most common forms of pain and is experienced by almost a third of the population at some time. To date, it has not been possible to treat joint pain effectively and side effects of commonly prescribed drugs are often hazardous. Therefore, improvements in our understanding of causes and mechanisms associated with joint pain are required. Joints and their neighbouring structures are well endowed with nerve fibres which respond to mechanical stimuli. Following local inflammation, the activation threshold of these afferent nerve fibres is significantly decreased, such that even low level stimuli encode nociception.Currently, there is a lack about local mechanisms in synovial tissue. Various receptors, well known from the nervous system, are increasingly being detected in synovial fibroblasts. However, little is known about their function. Innovative new therapies are expected to emerge by targeting various receptors, e.g. the TRPV1- or the P(2)X(4) receptor system.

Multidisciplinary treatment for chronic pain: a systematic review of interventions and outcomes.

OBJECTIVES: To provide an overview of the effectiveness of multidisciplinary treatments of chronic pain and investigate about their differential effects on outcome in various pain conditions and of different multidisciplinary treatments, settings or durations. METHODS: In this article, the authors performed a systematic review of all currently available randomized controlled trials (RCTs) fulfilling the inclusion criteria, by using a recently developed rating system aimed to assess the strength of evidence with regard to the methodological quality of the trials. RESULTS: Compared with other non-disciplinary treatments, moderate evidence of higher effectiveness for multidisciplinary interventions was shown. In contrast to no treatment or standard medical treatment, strong evidence was detected in favour of multidisciplinary treatments. The evidence that comprehensive inpatient programmes were more beneficial that outpatient programmes was moderate. Fibromyalgia and chronic back pain patients tended to profit more substantially than patients with diverse origins or chronic pain diagnoses. No evidence was found that treatment variables, such as duration or programme components, were influential for the success of the intervention. CONCLUSION: A standard of multidisciplinary programmes should be internationally established to guarantee generally good outcomes in the treatment of chronic pain. Our results highlight the lack of quality of design, execution or reporting of many of the RCTs included in this article. Future studies should more specifically focus on differential effects of treatment components and patient variables, allowing the identification of subgroups, which most probably would profit from multidisciplinary pain programmes.

A new method for the noninvasive determination of abdominal muscle feedforward activity based on tissue velocity information from tissue Doppler imaging.

Rapid arm movements elicit anticipatory activation of the deep-lying abdominal muscles; this appears modified in back pain, but the invasive technique used for its assessment [fine-wire electromyography (EMG)] has precluded its widespread investigation. We examined whether tissue-velocity changes recorded with ultrasound (M-mode) tissue Doppler imaging (TDI) provided a viable noninvasive alternative. Fourteen healthy subjects rapidly flexed, extended, and abducted the shoulder; recordings were made of medial deltoid (MD) surface EMG and of fine-wire EMG and TDI tissue-velocity changes of the contralateral transversus abdominis, obliquus internus, and obliquus externus. Muscle onsets were determined by blinded visual analysis of EMG and TDI data. TDI could not distinguish between the relative activation of the three muscles, so in subsequent analyses only the onset of the earliest abdominal muscle activity was used. The latter occurred <50 ms after the onset of medial deltoid EMG (i.e., was feedforward) and correlated with the corresponding EMG onsets (r = 0.47, P < 0.0001). The mean difference between methods was 20 ms and was likely explained by electromechanical delay; limits of agreement were wide (-40 to +80 ms) but no greater than those typical of repeated measurements using either technique. The between-day standard error of measurement of the TDI onsets (examined in 16 further subjects) was 16 ms. TDI yielded reliable and valid measures of the earliest onset of feedforward activity within the anterolateral abdominal muscle group. The method can be used to assess muscle dysfunction in large groups of back-pain patients and may also be suitable for the noninvasive analysis of other deep-lying or small/thin muscles.

Abdominal muscle size and symmetry at rest and during abdominal hollowing exercises in healthy control subjects.

The symmetry of, and physical characteristics influencing, the thickness of the lateral abdominal muscles at rest and during abdominal exercises were examined in 57 healthy subjects (20 men, 37 women; aged 22-62 years). M-mode ultrasound images were recorded from the abdominal muscles at rest and during abdominal hollowing exercises in hook-lying. The fascial lines bordering the transvs. abdominis, obliquus internus and obliquus externus were digitized and the absolute thickness, relative thickness (% of total lateral thickness) and contraction ratio (thickness during hollowing/thickness at rest), as well as the asymmetry (difference between sides expressed as a percent of the smallest value for the two sides) for each of these parameters were determined for each muscle. Both at rest and during hollowing, obliquus internus was the thickest and transvs. abdominis the thinnest muscle. There were no significant differences between left and right sides for group mean thicknesses of any muscle; however, individual asymmetries were evident, with mean values for the different muscles ranging from 11% to 26%; asymmetry was much less for the contraction ratios (mean % side differences, 5-14% depending on muscle). Body mass was the most significant positive predictor of absolute muscle thickness, for all muscles at rest and during hollowing, accounting for 30-44% variance. Body mass index explained 20-30% variance in transvs. abdominis contraction ratio (negative relationship). The influence of these confounders must be considered in comparative studies of healthy controls and back pain patients, unless groups are very carefully matched. Asymmetries observed in patients should be interpreted with caution, as they are also common in healthy subjects.

[Referral and patient satisfaction after an rheumatological interdisciplinary pain assessment]. / Sind Zuweiser und Patienten nach einer Rheumatologischen Interdisziplinären Schmerz--Sprechstunde zufrieden?

The aim of this quality assessment was to evaluate the specific satisfaction issues of the referring physician and of the patient after the rheumatological interdisciplinary pain assessment (RIPA). The prevalence of chronic pain disorders appear to grow worldwide. In the daily routine we are confronted with the problem, that the waiting list for such assessments is increasing. Our opinion is that the RIPA could be helpful for a second opinion, to improve the therapeutic alliance and the management of the patient. The study population was analysed in a longitudinal cross-sectional design with a follow up at three months after an interdisciplinary assessment (rheumatologist, physiotherapist, occupational therapist and psychologist). On the average reported the patients acceptable satisfaction values. The feedback of the referrers after RIPA was positive. It was remarkable that most of the referrers would recommend this kind of interdisciplinary assessment to other colleagues. From the clinicians perspective seems that such triages might be advantageous in order to achieve an effective patient-management.

Analgesic action of acetaminophen in symptomatic osteoarthritis of the knee.

OBJECTIVES: The study was designed to investigate the analgesic effects and mechanisms of acetaminophen (paracetamol) in symptomatic osteoarthritis (OA) of the knee. METHODS: Twenty patients with symptomatic OA were randomly allocated to two groups treated with either acetaminophen or rofecoxib for 3 months. Visits and measurements were scheduled upon entry (T0), at month 1 (T1) and at month 3 (T3). The intensity of joint pain was evaluated with a 100-mm visual analogue scale (VAS). The physical function of the affected knee was evaluated with a questionnaire comparable to the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Levels of serotonin, substance P (SP) and beta-endorphin (BEND) were determined with commercial enzyme-linked immunoassay kits. The expression of kappa opioid receptor (KOR) in peripheral mononuclear blood cells (PBMCs) was quantified by real-time PCR. RESULTS: Both acetaminophen and rofecoxib relieved pain considerably but with different kinetics, and affected different biomarkers. Rofecoxib appeared to be more efficient, reducing pain intensity by 56% at T1 (P<0.01), whereas acetaminophen reduced it by only 29%. Physical function improved in both groups by T3. Correlated with the pain relief, acetaminophen significantly reduced plasma BEND levels, whereas rofecoxib did not do so. In both groups plasma SP levels were elevated compared with T0. A reduction in serum serotonin was detected in the rofecoxib group at T1 (P=0.004) but had recovered at T3. No changes in KOR mRNA in PBMCs were observed in either group. CONCLUSIONS: There is a correlation between reduction in circulating BEND and OA pain relief in patients treated with acetaminophen.

The expression of cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase in inflammatory muscle tissue of patients with polymyositis and dermatomyositis.

OBJECTIVE: To describe cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) expression in muscle tissue in patients with idiopathic inflammatory myopathies (IIM) - dermatomyositis (DM) and polymyositis (PM) and to find out if any differences between affected and non-affected muscles detected by MRI exist. METHODS: Samples of muscle tissue from 7 patients with dermatomyositis (DM) and from 4 with polymyositis (PM) were obtained by needle biopsy from affected and non-affected sites distinguished by magnetic resonance imaging. In situ hybridization with antisense mRNA probes was employed to detect COX-1, COX-2 and 5-LOX mRNA. RESULTS: Expression of COX-1, COX-2, and 5-LOX mRNA was found in all samples - in the muscle cells, inflammatory cells and in vessels. COX-1 mRNA expression predominated in the inflammatory cells and vessels and was higher in affected than in non-affected sites detected by MRI (mean intensity 3.22+/-0.67 vs. 2.0+/-0.87; p = 0.0006). The expression of COX-2 mRNA was high mainly in inflammatory cells and/or vessels and was increased in MRI-detected affected tissues (3.5+/-0.88; 1.9+/-1.1; p = 0.003), as was the expression of COX-2 mRNA in muscle cells (2.1+/-1.0 vs. 1.3+/-1.0; p = 0.021). 5-LOX mRNA was largely expressed in muscle cells from MRI-detected affected sites and the signal intensity was higher in comparison with samples taken from non-affected tissues detected by MRI (3.22+/-0.7 vs. 1.67+/-0.7; p = 0.0007). CONCLUSION: Expression of COX-1, COX-2 and 5-LOX mRNA was observed for the first time in muscle tissues from IIM patients. This expression was increased in affected tissues detected by MRI, which may suggest a role of COX-1, COX-2, and 5-LOX in the pathogenesis of IIM.

Increased DNA fragmentation and ultrastructural changes in fibromyalgic muscle fibres.

OBJECTIVE: To determine whether there is evidence of increased DNA fragmentation and ultrastructural changes in muscle tissue of patients with fibromyalgia (FM) compared with healthy controls. METHODS: Muscle tissues from 10 community residents with FM and 10 age and sex matched healthy controls were examined "blindly" for the presence of DNA fragmentation by two different methods: terminal deoxynucleotidyl transferase (TdT) staining (TUNEL) and the FragEL-Klenow DNA fragmentation detection kit. Ultrastructural analysis of tissue was performed by electron microscopy. RESULTS: DNA fragmentation was detected by both methods in 55.4 (SEM 2.5)% of the nuclei in muscle tissue of patients with FM compared with 16.1 (4.1)% (p<0.001) of the nuclei in healthy controls. Contrary to expectation, no typical features of apoptosis could be detected by electron microscopy. The myofibres and actin filaments were disorganised and lipofuscin bodies were seen; glycogen and lipid accumulation were also found. The number of mitochondria was significantly lower in patients with FM than in controls and seemed to be morphologically altered. CONCLUSION: The ultrastructural changes described suggest that patients with FM are characterised by abnormalities in muscle tissue that include increased DNA fragmentation and changes in the number and size of mitochondria. These cellular changes are not signs of apoptosis. Persistent focal contractions in muscle may contribute to ultrastructural tissue abnormalities as well as to the induction and/or chronicity of nociceptive transmission from muscle to the central nervous system.