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The underlying neurophysiology of acute pain is fairly well characterized, whereas the central mechanisms operative in chronic pain states are less well understood. Fibromyalgia (FM), a common chronic pain condition characterized by widespread pain, is thought to originate largely from altered central neurotransmission. We compare a sample of 17 FM patients and 17 age- and sex-matched healthy controls, using μ-opioid receptor (MOR) positron emission tomography. We demonstrate that FM patients display reduced MOR binding potential (BP) within several regions known to play a role in pain modulation, including the nucleus accumbens, the amygdala, and the dorsal cingulate. MOR BP in the accumbens of FM patients was negatively correlated with affective pain ratings. Moreover, MOR BP throughout the cingulate and the striatum was also negatively correlated with the relative amount of affective pain (McGill, affective score/sensory score) within these patients. These findings indicate altered endogenous opioid analgesic activity in FM and suggest a possible reason for why exogenous opiates appear to have reduced efficacy in this population.

Objective: Central pain augmentation resulting from enhanced excitatory and/or decreased inhibitory neurotransmission is a proposed mechanism underlying the pathophysiology of functional pain syndromes such as fibromyalgia (FM). Multiple functional magnetic resonance imaging studies implicate the insula as a region of heightened neuronal activity in this condition. Since glutamate (Glu) is a major cortical excitatory neurotransmitter that functions in pain neurotransmission, we undertook this study to test our hypothesis that increased levels of insular Glu would be present in FM patients and that the concentration of this molecule would be correlated with pain report.Methods: Nineteen FM patients and 14 age‐ and sex‐matched pain‐free controls underwent pressure pain testing and a proton magnetic resonance spectroscopy session in which the right anterior insula and right posterior insula were examined at rest.Results: Compared with healthy controls, FM patients had significantly higher levels of Glu (mean ± SD 8.09 ± 0.72 arbitrary institutional units versus 6.86 ± 1.29 arbitrary institutional units; P = 0.009) and combined glutamine and Glu (i.e., Glx) (mean ± SD 12.38 ± 0.94 arbitrary institutional units versus 10.59 ± 1.48 arbitrary institutional units; P = 0.001) within the right posterior insula. No significant differences between groups were detected in any of the other major metabolites within this region (P > 0.05 for all comparisons), and no group differences were detected for any metabolite within the right anterior insula (P > 0.11 for all comparisons). Within the right posterior insula, higher levels of Glu and Glx were associated with lower pressure pain thresholds across both groups for medium pain (for Glu, r = −0.43, P = 0.012; for Glx, r = −0.50, P = 0.003).Conclusion: Enhanced glutamatergic neurotransmission resulting from higher concentrations of Glu within the posterior insula may play a role in the pathophysiology of FM and other central pain augmentation syndromes.

Background: Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment. Methods: To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia. Results: The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = −0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo. Conclusions: The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.

Objective: Fibromyalgia (FM) is a chronic widespread pain condition that is thought to arise from augmentation of central neural activity. Glutamate (Glu) is an excitatory neurotransmitter that functions in pain‐processing pathways. This study was carried out to investigate the relationship between changing levels of Glu within the insula and changes in multiple pain domains in patients with FM.Methods: Ten patients with FM underwent 2 sessions of proton magnetic resonance spectroscopy (H‐MRS) and 2 sessions of functional magnetic resonance imaging (FMRI), each conducted before and after a nonpharmacologic intervention to reduce pain. During H‐MRS, the anterior and posterior insular regions were examined separately using single‐voxel spectroscopy. The levels of Glu and other metabolites were estimated relative to levels of creatine (Cr) (e.g., the Glu/Cr ratio). During FMRI, painful pressures were applied to the thumbnail to elicit neuronal activation. Experimental pressure‐evoked pain thresholds and clinical pain ratings (on the Short Form of the McGill Pain Questionnaire [SF‐MPQ]) were also assessed prior to each imaging sessionResults: Both experimental pain (P = 0.047 versus pretreatment) and SF‐MPQ–rated clinical pain (P = 0.043 versus pretreatment) were reduced following treatment. Changes from pre‐ to posttreatment in Glu/Cr were negatively correlated with changes in experimental pain thresholds (r = −0.95, P < 0.001) and positively correlated with changes in clinical pain (r = 0.85, P = 0.002). Changes in the FMRI‐determined blood oxygenation level–dependent effect (a measure of neural activation) were positively correlated with changes in Glu/Cr within the contralateral insula (r = 0.81, P = 0.002).Conclusion: Changes in Glu levels within the insula are associated with changes in multiple pain domains in patients with FM. Thus, H‐MRS data may serve as a useful biomarker and surrogate end point for clinical trials of FM.