The journal of pain : official journal of the American Pain Society
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Habituation and sensitization are important features of individual sensitivity to repetitive noxious stimulation and have been investigated in numerous studies. However, it is unclear whether these phenomena vary depending on the site of stimulation. Here we compared short-term and long-term effects of painful heat stimulation on the forehead and limb using an established longitudinal heat pain paradigm performed over 8 consecutive days in 36 healthy volunteers. Participants were randomized into 2 groups; participants received repetitive heat pain stimulation either on the left volar forearm or on the left side of the forehead. Our data show a comparable degree of habituation over the course of 8 days in both groups. However, participants in the trigeminal stimulation group exhibited stronger within-session sensitization (indexed by a higher within-session increase in pain intensity ratings) than those who received the forearm stimulation. Furthermore, over the course of the experiment we found a correlation between habituation and anxiety, showing less habituation in participants with higher trait anxiety scores. Our findings are in line with somatotopic differences in response to painful stimulation and a higher proneness of trigeminal pain to sensitization processes, which might be explained by the biological relevance of the head and facial area for vital functions. The contribution of this sensitivity to the development and maintenance of clinical facial pain and headache disorders warrants further investigation. ⋯ This study uses psychophysical methods to evaluate the differences in long-term habituation and short-term sensitization to heat pain between the trigeminal and spinal systems. We found stronger sensitization for trigeminal compared with nociceptive stimuli on the forearm. The contribution of this sensitivity to clinical pain states warrants further investigation.
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The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia remains incomplete. This study used functional magnetic resonance imaging data from 30 healthy individuals and dynamic causal modeling to investigate changes in effective connectivity associated with the placebo analgesic response. Before scanning, participants were conditioned to expect less thermal pain at 2 of 4 sites on their feet. Visual analog scale pain ratings revealed a significant but small difference between the baseline and placebo sites (mean difference = 6.63, t(29) = 3.91, P ≤ .001, d = .97), confirming an analgesic effect. However, no significant differences in the magnitude of brain activation between conditions were observed via traditional random effects general linear modeling. Dynamic causal modeling was then used to investigate changes in effective connectivity during placebo analgesia. The results indicate that during placebo analgesia but not baseline condition, couplings between brain regions, including those involved in cognitive processes (eg, attention, expectation, evaluation), were significantly enhanced. Specifically, a significantly consistent decrease in the dorsolateral prefrontal cortex → periaqueductal gray coupling was found. These findings highlight the differences between pain processing and modulation at the network level. Moreover, our results suggest that small placebo effects may be better characterized via changes in the temporal dynamics among pain modulatory regions than only via changes in the magnitude of blood oxygenation level dependent activation. Further application of nuanced analytical approaches that are sensitive to temporal dynamics of pain-related processes such as dynamic causal modeling are necessary to better understand the neural mechanisms underlying pain processing in patient populations. ⋯ Changes in effective connectivity among pain-related brain regions may be more sensitive detectors of the neural representation of small placebo effects than are changes in the magnitude of brain activation. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation.
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Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-L6 intervention)-reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties.
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Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. ⋯ This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain.
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Fibromyalgia syndrome (FMS) is characterized by widespread chronic pain, fatigue, sleep disorders, and cognitive-emotional disturbance. Patients with FMS exhibit increased sensitivity to experimental pain and pain-related cues, as well as deficits in emotional regulation. The present study investigated the spatiotemporal patterns of brain activations for observed pain in 19 patients with FMS and 18 age-matched, healthy control individuals using event-related potential analysis. Patients with FMS attributed greater pain and unpleasantness to pain pictures, relative to healthy control participants. An augmented late positive potential (LPP) component (>500 milliseconds) was found in patients viewing both pain and nonpain pictures, and this amplitude difference in the LPP covaried with perceived unpleasantness of pictures. Mid-latency potentials (250-450 milliseconds) demonstrated similar amplitude increases of positive potentials in the FMS patient group. By contrast, the short-latency positive potential (140 milliseconds) was reduced in patients with FMS relative to healthy control participants. Results suggest amplitude increases to mid- to long-latency cortical activations in patients with FMS, which are known to reflect emotional control and motivational salience of stimuli. ⋯ Patients with FMS demonstrate increased activations associated with pain and nonpain pictures. The findings suggest that even innocuous, everyday visual stimuli with somatic connotations may challenge the emotional state of patients with FMS. Our study points toward the importance of cognitive-emotional therapeutic approaches for the treatment of FMS.