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New evidence for central sensitization of fibromyalgia patients: Windup maintenance is abnormal
S6
Abstracts
C. Disease Entities (Human) C07 - Myofascial Pain and Fibromyalgia
D. Treatment Approaches (Medical/Interventional) D13 - NSAIDs and Acetaminophen
(324) New evidence for central sensitization of Fibromyalgia patients: Windup maintenance is abnormal
(324) Acetaminophen inhibition of COX-2 function in a clinical model of tissue injury
R. Staud, M. Robinson, D. Price, C. Vierck; University of Florida, Gainesville, FL Windup of 2nd pain(WU)can be used to evaluate central sensitization of fibromyalgia (FM) patients. We have previously shown that FM-patients have abnormal WU and WU-aftersensations. Animal experiments have demonstrated that once WU has been established, only low frequency nociceptive input is required to maintain the sensitized state (WU-maintenance or WU-M). Like WU, WU-M also represents a central pain state which is dependent on stimulus frequency and level of central hypersensitivity. Because FM-patients display features of central sensitization, we hypothesized that WU-M would be abnormal in FM-subjects compared to normal controls (NC). A numerical scale with verbal anchors (NPS), was used for all pain ratings. Thermal WU-stimuli were adjusted to each subject’s heat sensitivity to achieve similar WU-pain ratings after 15 heat-taps at 0.3Hz in FM-subjects and NC (WU-induction). We measured WU-M of 94 FM and 72 NC using thermal stimulus frequencies of 0.16Hz and 0.08Hz. Mean maximal WU-ratings of all study subjects was 50.2 NPS. ANOVAs showed that WU-induction was similar for both NC and FM-subjects (p.05). WU-M pain ratings of FM-subjects, however, decreased much slower than NC over 10 stimuli at 0.16 Hz and 0.08 Hz, (p⬍.001). In addition, WU-M sensations of FM-subjects were greater at each tap compared to NC (p⬍.001). WU-decay was significantly delayed for FM-subjects than NC at 15s and 30s (p⬍.001). Our method of equating thermal test stimuli to each individual’s WU-sensitivity removed rating bias related to FM-subjects’ known heat hyperalgesia. WU-M stimuli resulted in greater and more prolonged pain sensations of FM than NC-subjects at stimulus frequencies that by themselves are unable to induce WU. Furthermore, WU-aftersensations were much prolonged in FM-subjects. Our results show that FM-subjects display abnormal WU-M and WU-aftersensations thus providing additional evidence for central sensitization in this chronic pain population.
Y. Lee, J. Brahim, G. Carmona, J. Rowan, G. Lee, R. Dionne; National Institutes of Health, Bethesda, MD Acetaminophen is widely used drug for pain management and antipyresis in children, pregnant women and the elderly as an alternative to aspirin and NSAIDs. However, the mechanism of action is still poorly defined. Although it does not inhibit cyclooxygenase (COX) enzymes at therapeutic concentrations in vitro, acetaminophen may reduce PG synthesis in vivo by inhibiting an unknown variant of COX enzymes. Simmons et al. demonstrated a COX-2 variant which is especially sensitive to acetaminophen,1 but later reported a splice variant of COX-1, named as COX-3 which is also sensitive to acetaminophen.2 The current study evaluated acetaminophen’s effect on peripheral PGE2 release in human subjects undergoing surgical removal of two impacted mandibular third molars. Microdialysis was used to collect submucosal perfusate from the surgical site at 20 minutes intervals for three hours postoperatively. The effect of acetaminophen on PGE2 levels was compared to the effect of a dual COX-1/-2 inhibitor (ketorolac), a selective COX-2 inhibitor (rofecoxib), and placebo. PGE2 levels were significantly suppressed by ketorolac, rofecoxib, and acetaminophen compared to placebo over the last two hours of the postoperative period (p ⬍ 0.05). PGE2 suppression by acetaminophen was less than ketorolac but comparable to rofecoxib. However, TXB2 levels were significantly suppressed only by ketorolac (p ⬍ 0.01). These findings demonstrate that the analgesic effect of acetaminophen is, at least in part, attributed to decrease in peripheral PGE2 release. As acetaminophen inhibited PGE2 release at time points associated with COX-2 expression without affecting TXB2 release similar to selective COX-2 inhibitors,3 our data support the view that there may be a functional variant of COX-2 which is sensitive to acetaminophen. (1. Proc Natl Acad Sci, 1999; 2. Proc Natl Acad Sci, 2002; 3.Khan et al., Clin Pharmacol Ther, 2002)
C15 - Visceral Pain Clinical
F. Treatment Approaches (Psychosocial & Cognitive) F01 - Cognitive/Behavioral Approaches
(324) Visceral and thermal hypersensitivity in the Irritable Bowel Syndrome and Fibromyalgia B. Moshiree, R. Gaible, M. Robinson, D. Price, G. Verne; Department of Veterans Affairs, Gainesville, FL Irritable Bowel Syndrome (IBS) is one of the most common gastrointestinal disorders and is characterized by visceral hypersensitivity. We have previously shown that IBS patients also have evidence of thermal hypersensitivity that is suggestive of a central sensitization mechanism, similar to that present in Fibromyalgia. The purpose of the study was to compare the magnitude of visceral and thermal hypersensitivity in IBS patients and Fibromyalgia (FMS) patients with IBS compared to controls. Fifteen patients (12 F, 3M) with IBS, ten patients (10 F) with FMS⫹IBS, and seventeen controls (13 F, 4 M), rated pain intensity/unpleasantness to phasic distension of the rectum (35, 55 mmHg) and hot water immersion (45, 47°C) of the hand/foot on a 0-10 M-VAS scale. The data was analyzed with 3 separate one-way ANOVA’s with Post-hoc Tukey tests. For both visceral and thermal stimuli, the control group had lower pain ratings than either the IBS or FMS⫹IBS groups (p⬍0.001). IBS patients rated rectal distension as more painful than the FMS⫹IBS group (p⫽0.004). During hot water immersion of the foot, the FMS⫹IBS group had higher pain ratings than the IBS group (p⫽.027). During hand immersion, FMS⫹IBS and IBS patients did not significantly differ in their pain intensity ratings (p⫽0.15). Both patient groups had higher scores than controls to somatic focus, state anxiety and depression. No significant differences were found between the IBS and FMS⫹IBS groups on any psychological measures. FMS⫹IBS patients demonstrate greater thermal hypersensitivity compared to IBS patients. However, IBS patients exhibit higher pain ratings to rectal distension compared to FMS⫹IBS patients. These data suggest that regions of primary and secondary hyperalgesia are to some extent dependent on the primary pain complaint. Supported by a Veterans Administration Merit Review Award (PI: GN Verne) and NIH/NCCAM (R01AT001424; PI: ME Robinson).
(324) Top-down and bottom-up fMRI BOLD signal changes in response to selective attention during mechanical pressure pain T. Papageorgiou, E. Jackson, K. Anderson, S. Mahankali, C. Cleeland; University of Texas - M.D. Anderson Cancer Center, Houston, TX Neuroimaging studies have amply shown that pain perception can be modulated by selectively redirecting attention from a thermal, chemical, or electrical painful stimulus. However, no such studies have been published assessing attentional modulation during the application of a mechanical pressure pain stimulus. This study assessed modulation to pain perception by selectively attending to cued mental imagery using functional magnetic resonance imaging (fMRI) Blood-Oxygen-Level-Dependent (BOLD) signal. Eight healthy volunteers participated in three experimental conditions: (i) attention toward mechanical pressure pain, which activates bottom-up neuronal pathways; (ii) attention away from mechanical pressure pain, which activates top-down and bottom-up mechanisms and (iii) a mechanical pressure pain-free control condition. The volume of pain-related cortical metabolic activity was significantly decreased during the attention away from mechanical pain condition compared to the volume activated during the attention towards the mechanical pain condition. The attention toward mechanical pressure pain condition evoked increased activity in the occipital cortex and the sensory-discriminative pain-cortical areas, consistent with a bottom-up process of activation. The attention away from mechanical pressure pain resulted in cortical circuitry similar to the one involved in selective attention and mental imagery; i.e., increased orbitofrontal and prefrontal cortex activity, indicative of top-down (antinociceptive) mechanisms, while the activity of bottom-up (nociceptive) neuronal processes was attenuated. Furthermore, a significant positive linear correlation was noted between pain-intensity ratings on a numeric rating scale and cortical activity in each of the three conditions. Our findings indicate that modulation of pain perception via selective attention to mental imagery is achieved by the activation of top-down cognitive functions, which inhibit bottom-up neuronal pathways. Therefore, a reduction in the sensory-discriminative (bottom-up) cortical pain processing produced by mechanical pressure pain seems to be associated with BOLD signal changes in the cognitive-evaluative (top-down) pain-related cortical regions.
Abstracts
C. Disease Entities (Human) C07 - Myofascial Pain and Fibromyalgia
D. Treatment Approaches (Medical/Interventional) D13 - NSAIDs and Acetaminophen
(324) New evidence for central sensitization of Fibromyalgia patients: Windup maintenance is abnormal
(324) Acetaminophen inhibition of COX-2 function in a clinical model of tissue injury
R. Staud, M. Robinson, D. Price, C. Vierck; University of Florida, Gainesville, FL Windup of 2nd pain(WU)can be used to evaluate central sensitization of fibromyalgia (FM) patients. We have previously shown that FM-patients have abnormal WU and WU-aftersensations. Animal experiments have demonstrated that once WU has been established, only low frequency nociceptive input is required to maintain the sensitized state (WU-maintenance or WU-M). Like WU, WU-M also represents a central pain state which is dependent on stimulus frequency and level of central hypersensitivity. Because FM-patients display features of central sensitization, we hypothesized that WU-M would be abnormal in FM-subjects compared to normal controls (NC). A numerical scale with verbal anchors (NPS), was used for all pain ratings. Thermal WU-stimuli were adjusted to each subject’s heat sensitivity to achieve similar WU-pain ratings after 15 heat-taps at 0.3Hz in FM-subjects and NC (WU-induction). We measured WU-M of 94 FM and 72 NC using thermal stimulus frequencies of 0.16Hz and 0.08Hz. Mean maximal WU-ratings of all study subjects was 50.2 NPS. ANOVAs showed that WU-induction was similar for both NC and FM-subjects (p.05). WU-M pain ratings of FM-subjects, however, decreased much slower than NC over 10 stimuli at 0.16 Hz and 0.08 Hz, (p⬍.001). In addition, WU-M sensations of FM-subjects were greater at each tap compared to NC (p⬍.001). WU-decay was significantly delayed for FM-subjects than NC at 15s and 30s (p⬍.001). Our method of equating thermal test stimuli to each individual’s WU-sensitivity removed rating bias related to FM-subjects’ known heat hyperalgesia. WU-M stimuli resulted in greater and more prolonged pain sensations of FM than NC-subjects at stimulus frequencies that by themselves are unable to induce WU. Furthermore, WU-aftersensations were much prolonged in FM-subjects. Our results show that FM-subjects display abnormal WU-M and WU-aftersensations thus providing additional evidence for central sensitization in this chronic pain population.
Y. Lee, J. Brahim, G. Carmona, J. Rowan, G. Lee, R. Dionne; National Institutes of Health, Bethesda, MD Acetaminophen is widely used drug for pain management and antipyresis in children, pregnant women and the elderly as an alternative to aspirin and NSAIDs. However, the mechanism of action is still poorly defined. Although it does not inhibit cyclooxygenase (COX) enzymes at therapeutic concentrations in vitro, acetaminophen may reduce PG synthesis in vivo by inhibiting an unknown variant of COX enzymes. Simmons et al. demonstrated a COX-2 variant which is especially sensitive to acetaminophen,1 but later reported a splice variant of COX-1, named as COX-3 which is also sensitive to acetaminophen.2 The current study evaluated acetaminophen’s effect on peripheral PGE2 release in human subjects undergoing surgical removal of two impacted mandibular third molars. Microdialysis was used to collect submucosal perfusate from the surgical site at 20 minutes intervals for three hours postoperatively. The effect of acetaminophen on PGE2 levels was compared to the effect of a dual COX-1/-2 inhibitor (ketorolac), a selective COX-2 inhibitor (rofecoxib), and placebo. PGE2 levels were significantly suppressed by ketorolac, rofecoxib, and acetaminophen compared to placebo over the last two hours of the postoperative period (p ⬍ 0.05). PGE2 suppression by acetaminophen was less than ketorolac but comparable to rofecoxib. However, TXB2 levels were significantly suppressed only by ketorolac (p ⬍ 0.01). These findings demonstrate that the analgesic effect of acetaminophen is, at least in part, attributed to decrease in peripheral PGE2 release. As acetaminophen inhibited PGE2 release at time points associated with COX-2 expression without affecting TXB2 release similar to selective COX-2 inhibitors,3 our data support the view that there may be a functional variant of COX-2 which is sensitive to acetaminophen. (1. Proc Natl Acad Sci, 1999; 2. Proc Natl Acad Sci, 2002; 3.Khan et al., Clin Pharmacol Ther, 2002)
C15 - Visceral Pain Clinical
F. Treatment Approaches (Psychosocial & Cognitive) F01 - Cognitive/Behavioral Approaches
(324) Visceral and thermal hypersensitivity in the Irritable Bowel Syndrome and Fibromyalgia B. Moshiree, R. Gaible, M. Robinson, D. Price, G. Verne; Department of Veterans Affairs, Gainesville, FL Irritable Bowel Syndrome (IBS) is one of the most common gastrointestinal disorders and is characterized by visceral hypersensitivity. We have previously shown that IBS patients also have evidence of thermal hypersensitivity that is suggestive of a central sensitization mechanism, similar to that present in Fibromyalgia. The purpose of the study was to compare the magnitude of visceral and thermal hypersensitivity in IBS patients and Fibromyalgia (FMS) patients with IBS compared to controls. Fifteen patients (12 F, 3M) with IBS, ten patients (10 F) with FMS⫹IBS, and seventeen controls (13 F, 4 M), rated pain intensity/unpleasantness to phasic distension of the rectum (35, 55 mmHg) and hot water immersion (45, 47°C) of the hand/foot on a 0-10 M-VAS scale. The data was analyzed with 3 separate one-way ANOVA’s with Post-hoc Tukey tests. For both visceral and thermal stimuli, the control group had lower pain ratings than either the IBS or FMS⫹IBS groups (p⬍0.001). IBS patients rated rectal distension as more painful than the FMS⫹IBS group (p⫽0.004). During hot water immersion of the foot, the FMS⫹IBS group had higher pain ratings than the IBS group (p⫽.027). During hand immersion, FMS⫹IBS and IBS patients did not significantly differ in their pain intensity ratings (p⫽0.15). Both patient groups had higher scores than controls to somatic focus, state anxiety and depression. No significant differences were found between the IBS and FMS⫹IBS groups on any psychological measures. FMS⫹IBS patients demonstrate greater thermal hypersensitivity compared to IBS patients. However, IBS patients exhibit higher pain ratings to rectal distension compared to FMS⫹IBS patients. These data suggest that regions of primary and secondary hyperalgesia are to some extent dependent on the primary pain complaint. Supported by a Veterans Administration Merit Review Award (PI: GN Verne) and NIH/NCCAM (R01AT001424; PI: ME Robinson).
(324) Top-down and bottom-up fMRI BOLD signal changes in response to selective attention during mechanical pressure pain T. Papageorgiou, E. Jackson, K. Anderson, S. Mahankali, C. Cleeland; University of Texas - M.D. Anderson Cancer Center, Houston, TX Neuroimaging studies have amply shown that pain perception can be modulated by selectively redirecting attention from a thermal, chemical, or electrical painful stimulus. However, no such studies have been published assessing attentional modulation during the application of a mechanical pressure pain stimulus. This study assessed modulation to pain perception by selectively attending to cued mental imagery using functional magnetic resonance imaging (fMRI) Blood-Oxygen-Level-Dependent (BOLD) signal. Eight healthy volunteers participated in three experimental conditions: (i) attention toward mechanical pressure pain, which activates bottom-up neuronal pathways; (ii) attention away from mechanical pressure pain, which activates top-down and bottom-up mechanisms and (iii) a mechanical pressure pain-free control condition. The volume of pain-related cortical metabolic activity was significantly decreased during the attention away from mechanical pain condition compared to the volume activated during the attention towards the mechanical pain condition. The attention toward mechanical pressure pain condition evoked increased activity in the occipital cortex and the sensory-discriminative pain-cortical areas, consistent with a bottom-up process of activation. The attention away from mechanical pressure pain resulted in cortical circuitry similar to the one involved in selective attention and mental imagery; i.e., increased orbitofrontal and prefrontal cortex activity, indicative of top-down (antinociceptive) mechanisms, while the activity of bottom-up (nociceptive) neuronal processes was attenuated. Furthermore, a significant positive linear correlation was noted between pain-intensity ratings on a numeric rating scale and cortical activity in each of the three conditions. Our findings indicate that modulation of pain perception via selective attention to mental imagery is achieved by the activation of top-down cognitive functions, which inhibit bottom-up neuronal pathways. Therefore, a reduction in the sensory-discriminative (bottom-up) cortical pain processing produced by mechanical pressure pain seems to be associated with BOLD signal changes in the cognitive-evaluative (top-down) pain-related cortical regions.