Cornea confocal microscopy (CCM) is a novel non-invasive method to detect small nerve fiber pathology. CCM generally correlates with outcomes of skin biopsies in patients with small fiber pathology. The aim of this study was to quantify the morphology of small nerve fibers of the cornea of patients with fibromyalgia in terms of density, length and branching and further phenotype these patients using standardized quantitative sensory testing (QST). Small fiber pathology was detected in the cornea of 51% of patients: nerve fiber length was significantly decreased in 44% of patients compared to age- and sex-matched reference values; nerve fiber density and branching were significantly decreased in 10% and 28% of patients. The combination of the CCM parameters and sensory tests for central sensitization, (cold pain threshold, mechanical pain threshold, mechanical pain sensitivity, allodynia and/or windup), yielded four phenotypes of fibromyalgia patients in a subgroup analysis: one group with normal cornea morphology without and with signs of central sensitization, and a group with abnormal cornea morphology parameters without and with signs of central sensitization. In conclusion, half of the tested fibromyalgia population demonstrates signs of small fiber pathology as measured by CCM. The four distinct phenotypes suggest possible differences in disease mechanisms and may require different treatment approaches.

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Offset analgesia (OA) is a form of endogenous pain inhibition characterized by a disproportionately large reduction in pain perception after a small decrease in temperature during noxious thermal stimulation. In this study, the presence of OA was evaluated in patients with fibromyalgia and compared with healthy age-matched and sex-matched controls. Offset analgesia was induced by noxious thermal stimulation on the arm, causing a visual analog score (VAS) of about 50 mm, followed by a 1°C temperature decrease. The OA response is defined by the reduction in VAS induced by the 1°C stimulus decrease. To assess whether the OA response could be enhanced, 2 tests were applied: repetition of the OA paradigm and 1°C temperature downward steps after an initial OA test (downward step test). To assess whether OA affects onset of pain, OA steps at increasing temperatures (upward OA step test) were applied. Patients with fibromyalgia had reduced OA responses with a reduction in VAS of 65.3 ± 4.5% (mean ± SD) vs controls 97.8 ± 4.6% (P < 0.001). Decreased OA responses were not enhanced or restored by repeating the OA paradigm or by the downward step test. Defective engagement of OA had a significant effect on pain onset, as observed from the upward OA step test, with less tolerability to noxious pain stimulation in patients with fibromyalgia. In conclusion, patients with fibromyalgia showed less pain inhibition as measured by the OA paradigm, which influenced both the onset and offset of pain.

Patients may perceive paradoxical heat sensation during spinal anesthesia. This could be due to deafferentation-related functional changes at cortical, subcortical, or spinal levels. In the current study, the effect of spinal deafferentation on sensory (pain) sensitivity was studied and linked to whole-brain functional connectivity as assessed by resting-state functional magnetic resonance imaging (RS-fMRI) imaging. Deafferentation was induced by sham or spinal anesthesia (15 mg bupivacaine injected at L3-4) in 12 male volunteers. RS-fMRI brain connectivity was determined in relation to eight predefined and seven thalamic resting-state networks (RSNs) and measured before, and 1 and 2 h after spinal/sham injection. To measure the effect of deafferentation on pain sensitivity, responses to heat pain were measured at 15-min intervals on nondeafferented skin and correlated to RS-fMRI connectivity data. Spinal anesthesia altered functional brain connectivity within brain regions involved in the sensory discriminative (i.e., pain intensity related) and affective dimensions of pain perception in relation to somatosensory and thalamic RSNs. A significant enhancement of pain sensitivity on nondeafferented skin was observed after spinal anesthesia compared to sham (area-under-the-curve [mean (SEM)]: 190.4 [33.8] versus 13.7 [7.2]; p<0.001), which significantly correlated to functional connectivity changes observed within the thalamus in relation to the thalamo-prefrontal network, and in the anterior cingulate cortex and insula in relation to the thalamo-parietal network. Enhanced pain sensitivity from spinal deafferentation correlated with functional connectivity changes within brain regions involved in affective and sensory pain processing and areas involved in descending control of pain.