Variations in brain gray matter associated with chronic pain.

Variations in brain gray matter volume and density have been reported in association with a variety of disorders characterized by chronic pain, including chronic low back pain, fibromyalgia, and irritable bowel syndrome. Correlation analyses have demonstrated relationships between morphometric and clinical variables. However, conclusions regarding the nature of these relationships are problematic given that currently available data are derived exclusively from cross-sectional studies. Further efforts to determine the relationship between chronic pain and variations in brain morphometry will depend in part on longitudinal studies of patients at various stages of illness, as well as those at risk of the development of chronic pain. Interpretation of findings from morphometric studies also must take into account genetic and experiential factors that recently have been demonstrated to influence brain morphometry and the risk of developing chronic pain.

Enhanced pain perception in rheumatoid arthritis: novel considerations.

Enhanced pain perception is common among patients with rheumatoid arthritis (RA). Given the putative role of proinflammatory cytokines in the development of hyperalgesia, a greater understanding of factors that facilitate increased cytokine expression in RA stands to increase understanding of the sources of enhanced pain perception. Patients with RA have significantly greater stress-induced proinflammatory cytokine release. Although absolute deficiencies in cortisol have not been demonstrated, functional abnormalities have been described, including "abnormally normal" cortisol levels in the face of increased inflammation and deficient responses to stressful challenges. Parasympathetic insufficiency has also been demonstrated, which may enhance pain perception indirectly through disinhibited cytokine expression. Several psychological variables have also been demonstrated to affect pain perception in patients with RA. Identification of factors that contribute to enhanced pain perception in RA may aid in the development of novel analgesic strategies that, in turn, may decrease disease activity and improve general clinical outcomes.

Changes in hippocampal metabolites after effective treatment for fibromyalgia: a case study.

BACKGROUND: Fibromyalgia has been associated with disrupted hippocampal brain metabolite ratios by studies using single voxel magnetic resonance spectroscopy (1H-MRS). Exposure to stress is considered a risk factor for the development and exacerbation of fibromyalgia symptoms. Basic science has demonstrated the hippocampus to be exquisitely sensitive to the effects of stressful experience, which results in changes including alterations in metabolite content and frank atrophy. METHODS: This report details the case of a 47-year-old woman with fibromyalgia who was originally found to have a profound depression of the ratio of N-acetylaspartate to creatine in her right hippocampus during participation in a study to assess brain metabolite disturbances in fibromyalgia utilizing single voxel proton magnetic resonance spectroscopy. An individualized treatment strategy was developed based both on physiological abnormalities associated with the disorder and symptoms that characterized the patient's unique clinical profile. RESULTS: Clinical and spectroscopic evaluation following nine months of treatment demonstrated both an improvement in her clinical profile and normalization of the NAA/Cr ratio within her right hippocampus. DISCUSSION: Therapeutic strategies aimed at demonstrable lesions associated with fibromyalgia appear to represent rational targets for pharmacological intervention. The rationale for development of novel pharmacotherapies for this unusual disorder is discussed.

Symptom clusters in fibromyalgia: potential utility in patient assessment and treatment evaluation.

BACKGROUND: Recent evidence points to the likelihood of heterogeneity in the presentation and, perhaps, etiology of fibromyalgia (FM). A clearer understanding of the symptomatology and consideration of potential FM subtypes could add insights regarding this condition. OBJECTIVE: The aim of this study was to determine whether clusters could be identified among 20 symptoms that participants in a prior online study identified and to elucidate the underlying structure of resultant clusters. METHODS: Factor analysis was used on data from a study sponsored by the National Fibromyalgia Association in which 2,569 persons with FM responded to an online survey during a 3-day period in 2005. RESULTS: In this well-educated, primarily Caucasian sample, morning stiffness, fatigue, and not feeling rested in the morning were the symptoms with the highest severity scores. A series of exploratory factor analyses and subsequent confirmatory factor analysis with Cronbach's alpha testing led to a five-factor model with the following domains containing 17 symptoms: Somatic, Distress, Fibromyalgia Core, Dyscognition, and Sleep Problems. DISCUSSION: The findings support the heterogeneity of the FM experience and the presence of symptom clusters within the greater spectrum of symptoms comprising the FM syndrome. These observations suggest the possibility of tailoring interventions based upon individual patient symptomatology. Further work is needed to develop symptom inventories that can be used in clinical trials as outcome metrics and by healthcare providers to describe clinical burden and effect of treatments.

Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism.

UNLABELLED: Fibromyalgia (FM) has been associated with alterations in brain morphometry and abnormal dopaminergic neurotransmission. Evidence from preclinical models has demonstrated that dopamine plays a role in promoting neuronal integrity. We therefore sought to confirm previous findings of reduced gray matter density in subjects with FM and to determine whether variations in dopamine metabolism might affect gray matter density. Voxel-based morphometry was used to evaluate anatomical magnetic resonance imaging data from 30 female FM subjects in comparison with 20 age- and gender-matched healthy control subjects. In addition, data from a subset of subjects from both groups who had previously participated in our positron emission tomography study using radiolabeled DOPA (n = 14; 6 FM subjects and 8 control subjects) was used to determine whether correlation might exist between gray matter density and dopamine metabolism. We found a significant reduction in gray matter density within the bilateral parahippocampal gyri, right posterior cingulate cortex, and left anterior cingulate cortex. In addition, a positive correlation was demonstrated between an index of dopamine metabolism from the ventral tegmental area wherein cell bodies of corticolimbic projection neurons originate and gray matter density, specifically in the bilateral parahippocampal gyri and left pregenual cortex. The current results confirm our previous findings that FM is associated with altered brain morphometry. Alterations in dopamine metabolism might contribute to the associated changes in gray matter density. PERSPECTIVE: Fibromyalgia is associated with reductions in gray matter density within brain regions ostensibly involved in phenomena related to the disorder, including enhanced pain perception, cognitive dysfunction, and abnormal stress reactivity. Given mounting evidence of abnormal dopaminergic neurotransmission associated with the disorder, the strong correlation between dopamine metabolism and gray matter density provides insight as to the pathophysiology that might contribute to these changes.

Hippocampal metabolite abnormalities in fibromyalgia: correlation with clinical features.

UNLABELLED: Although the pathology of fibromyalgia is poorly understood, a growing body of evidence suggests involvement of the central nervous system. The hippocampus is a brain center that is sensitive to the effects of stress exposure and has been demonstrated to be affected in a variety of disorders whose onset, like fibromyalgia, are associated with stressful experience. We therefore interrogated the bilateral hippocampus of 16 female fibromyalgia patients in comparison to 8 age- and gender-matched healthy control subjects using single voxel proton magnetic resonance spectroscopy. Our results demonstrate a significant reduction in the ratio of N-acetylaspartate to creatine (NAA/Cr) in fibromyalgia patients versus matched control subjects specifically in the right temporal lobe from a voxel centered on the right hippocampus (patient vs control, mean +/- standard deviation: 1.20 +/- 0.13 vs 1.34 +/- 0.10, P = .03). Moreover, correlation analysis demonstrated a significant negative correlation between patient scores on the Fibromyalgia Impact Questionnaire and NAA/Cr ratio within the right hippocampus (Spearman rank correlation, rho = -0.681, P = .018). Our results indicate that fibromyalgia is associated with brain metabolite abnormalities within the right hippocampus that correlate with patient symptoms. PERSPECTIVE: We have demonstrated an abnormality in hippocampal brain metabolites in premenopausal female fibromyalgia patients with no psychiatric comorbidity. A significant negative correlation between patient subjective experience of symptoms and a reduced NAA/Cr ratio suggests a role for hippocampal pathology in fibromyalgia.

Role of central dopamine in pain and analgesia.

Recent insights have demonstrated a central role for dopaminergic neurotransmission in modulating pain perception and natural analgesia within supraspinal regions, including the basal ganglia, insula, anterior cingulate cortex, thalamus and periaqueductal gray. In addition, while the participation of serotonin and norepinephrine in spinal descending inhibition of pain is well known, a critical role for dopamine in descending inhibition has also been demonstrated. Decreased levels of dopamine likely contribute to the painful symptoms that frequently occur in Parkinson's disease. Moreover, abnormalities in dopaminergic neurotransmission have been objectively demonstrated in painful clinical conditions, including burning mouth syndrome, fibromyalgia and restless legs syndrome. Evidence from animal models and indirect evidence from pharmaceutical trials also suggest a role for dopamine in chronic regional pain syndrome and painful diabetic neuropathy. Several novel classes of medication with analgesic properties have bearing on dopaminergic activity as evident in the capacity of dopamine antagonists to attenuate their analgesic capacity. An expanded appreciation for the role of dopamine in natural analgesia provides the impetus for further study involving preclinical models and advanced neuroimaging techniques in humans, which may lead to the development of novel therapeutic strategies.

Insular hypometabolism in a patient with fibromyalgia: a case study.

BACKGROUND: Neuroimaging studies have demonstrated differential involvement of a variety of brain centers in fibromyalgia both at baseline and in response to stimulation. The insular cortex is one such structure. FINDINGS: A 46-year-old woman with chronic widespread pain underwent positron emission tomography utilizing 18F-fluorodeoxyglucose while participating as a healthy control subject in a brain imaging study. Analysis of the scan revealed metabolic hypoactivity within the left insular cortex as an incidental finding. Soon after her scan, she underwent further clinical evaluation and was subsequently diagnosed with fibromyalgia. DISCUSSION: The potential contribution of insular dysfunction to the development of hyperalgesia has been demonstrated in rat models via local manipulations of dopaminergic, gamma-aminobutyric acid (GABA) ergic, and opioidergic neurotransmission within this region. Thus, our demonstration of insular hypometabolism in this patient's case may have bearing on her experience of chronic widespread pain.

Fibromyalgia patients show an abnormal dopamine response to pain.

Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.

Novel pharmacotherapy for fibromyalgia.

Fibromyalgia is a common disorder that is characterized by chronic widespread pain, tenderness to light palpation, fatigue and sleep disturbances. The present lack of a well-accepted model of the disorder has hampered progress towards adequate treatment. A review of potential models to explain the pathophysiology underlying its primary symptom (i.e., chronic widespread pain) lends insight on the therapeutic potential of novel therapies. Following this, a mechanistic evaluation of those medications that are under consideration for the treatment of the disorder is offered. Adequate treatment will be likely to involve the identification of biologic subgroups within the greater fibromyalgia construct. Key insights from basic research are the basis for increased optimism for effective relief among patients and clinicians.

Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain?

Fibromyalgia is an intractable widespread pain disorder that is most frequently diagnosed in women. It has traditionally been classified as either a musculoskeletal disease or a psychological disorder. Accumulating evidence now suggests that fibromyalgia may be associated with CNS dysfunction. In this study, we investigate anatomical changes in the brain associated with fibromyalgia. Using voxel-based morphometric analysis of magnetic resonance brain images, we examined the brains of 10 female fibromyalgia patients and 10 healthy controls. We found that fibromyalgia patients had significantly less total gray matter volume and showed a 3.3 times greater age-associated decrease in gray matter than healthy controls. The longer the individuals had had fibromyalgia, the greater the gray matter loss, with each year of fibromyalgia being equivalent to 9.5 times the loss in normal aging. In addition, fibromyalgia patients demonstrated significantly less gray matter density than healthy controls in several brain regions, including the cingulate, insular and medial frontal cortices, and parahippocampal gyri. The neuroanatomical changes that we see in fibromyalgia patients contribute additional evidence of CNS involvement in fibromyalgia. In particular, fibromyalgia appears to be associated with an acceleration of age-related changes in the very substance of the brain. Moreover, the regions in which we demonstrate objective changes may be functionally linked to core features of the disorder including affective disturbances and chronic widespread pain.

Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study.

UNLABELLED: Although the pathophysiology underlying the pain of fibromyalgia syndrome (FMS) remains unknown, a variety of clinical and investigational findings suggests a dysregulation of dopaminergic neurotransmission. We therefore investigated presynaptic dopaminergic function in 6 female FMS patients in comparison to 8 age- and gender-matched controls as assessed by positron emission tomography with 6-[(18)F]fluoro-L-DOPA as a tracer. Semiquantitative analysis revealed reductions in 6-[(18)F]fluoro-L-DOPA uptake in several brain regions, indicating a disruption of presynaptic dopamine activity wherein dopamine plays a putative role in natural analgesia. Although the small sample size makes these findings preliminary, it appears that FMS might be characterized by a disruption of dopaminergic neurotransmission. PERSPECTIVE: An association between FMS and reduced dopamine metabolism within the pain neuromatrix provides important insights into the pathophysiology of this mysterious disorder.

A reconsideration of the relevance of systemic low-dose ketamine to the pathophysiology of fibromyalgia.

UNLABELLED: Fibromyalgia is a common disorder characterized by chronic widespread pain that affects an estimated 2% of the general population. Recent advances have shed insight on this mysterious disorder, leading to the growing conclusion that disturbances of pain-related processes within the central nervous system, termed central sensitization, represent its most likely source. The phenomenon of central sensitization depends on plasticity in function of N-methyl-D-aspartate (NMDA) subtype glutamate receptors. Earlier studies implicated increased sensitivity of central NMDA receptors as playing a primary role in fibromyalgia, as evidenced by a significant reduction in symptoms among a large subset of patients in response to low doses of ketamine, a noncompetitive NMDA receptor antagonist. However, recent insights into the pharmacology of this drug cast doubt on a direct contribution of NMDA receptors and add credence to a model of the disorder that suggests that the primary pathology of fibromyalgia is a suppression of the normal activity of dopamine-releasing neurons within the limbic system. The implications for future therapies for fibromyalgia, and indeed many other chronic pain conditions, are discussed in light of these insights. PERSPECTIVE: The current lack of a demonstrable pathology underlying the pain of fibromyalgia has hampered progress toward adequate treatment of this mysterious disorder. Accumulating evidence suggests that fibromyalgia may represent a dysregulation of dopaminergic neurotransmission, which may provide insights to guide both rational clinical interventions as well as system-specific research models.

Open trial of pindolol in the treatment of fibromyalgia.

BACKGROUND: Evidence suggests that fibromyalgia is related to both chronic sympathetic hyperactivity and decreased levels of serotonin. OBJECTIVE: To examine the efficacy of pindolol, a mixed serotonin (5-HT)(1A) presynaptic autoreceptor/beta-adrenergic receptor antagonist, in the treatment of fibromyalgia. METHODS: An open trial was conducted using 20 female patients who met the American College of Rheumatology criteria for fibromyalgia. Treatment was initiated with pindolol 7.5 mg/day and titrated to a maximum dose of 15 mg/day for a total of 90 days. Primary outcome measures were tender point analysis and the Fibromyalgia Impact Questionnaire (FIQ). Anxiety and depression were measured with the Hamilton Depression and Anxiety Scales and Beck Depression Inventory. RESULTS: There was significant improvement in primary outcome measures, including Tender Point Count (mean +/- SD, 16.3 +/- 2.2 vs 12.3 +/- 5.0; F = 8.9; p < 0.001), Tender Point Score (24.4 +/- 5.7 vs 17.5 +/- 9.4; F = 7.8; p < 0.001), and FIQ (45.3 +/- 10.8 vs 35.0 +/- 15.0; F = 5.6; p < 0.005). The depression and anxiety scores did not change significantly among women who completed the study, while the impact on cardiovascular parameters was clinically insignificant. CONCLUSIONS: While the current results are encouraging, further studies are needed to determine whether pindolol might be effective in the treatment of fibromyalgia. Limitations of this study include small group size and lack of placebo control.

Stress and dopamine: implications for the pathophysiology of chronic widespread pain.

Fibromyalgia has been called a "stress-related disorder" due to the onset and exacerbation of symptoms in the context of stressful events. Evidence suggests that inhibition of tonic pain is mediated by activation of mesolimbic dopamine neurons, arising from the cell bodies of the ventral tegmental area and projecting to the nucleus accumbens. This pain-suppression system is activated by acute stress, via the release of endogenous opioids and substance P within the ventral tegmental area. However, prolonged exposure to unavoidable stress produces both reduction of dopamine output in the nucleus accumbens and development of persistent hyperalgesia. It is proposed that a stress-related reduction of dopaminergic tone within the nucleus accumbens contributes to the development of hyperalgesia in the context of chronic stress and thus plays a role in the pathogenesis of fibromyalgia. A stress-related dysfunction of mesolimbic dopaminergic activity might serve as the basis for other fibromyalgia-associated phenomena as well.